Call for collaborative clinical research on developmental disorders

One of the missions of the ERN ITHACA is to promote clinical research and the production of cross-border collaborative work. Our field is confronted with an extremely large number of new genes, for which the clinical spectrum and/or natural history is often barely known; usually, the number of patients published is limited to a handful, their recruitment may be strongly biased towards a clinical sign, and the clinical description is often limited.

Through this section, we share collaborative calls for European series of patients carrying variants in ultra-rare but already known genes.

The main challenge is to recruit cohorts of patients carrying variants in rare genes, where gathering at a single site does not yield significant series.

ITHACA can facilitate this type of study by connecting nearly 70 leading genetics departments.

The principle behind this initiative is simple:

  • Any ITHACA member can submit a call for collaboration on a gene, a group of functionally related genes, a CNV…
  • The call is forwarded to the entire network and remains visible for 6 months.
  • We will limit calls to 2 genes per applicant per year (can be more than 2 per HCP, of course ! )
  • These calls are not necessarily based on fundamental or translational research, but assume that the project leader already has at least 2 or 3 families to start the work.
  • The project leader is committed to bring this work to completion (one publication), and to keep the ITHACA ExCom informed of the progress of the work.
  • ITHACA’s role as facilitator will be highlighted in the acknowledgements in the article.
  • This type of article could be furthermore entrusted to young geneticists (as part of our collaboration with the European group).

You will find the submission template on the ECP Platform, or here : please complete it according to the established criteria and send it back to : alain.verloes@aphp.fr and coordination@ern-ithaca.eu

How to cite ITHACA in your publications?

Aknowledgement
Situation
One of the/The author(s) of this publication are (a) member(s) of the  European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA  [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516].” A general option that members can use regardless of there being 2 or more HCPS involved. This gives attention to the existence of ERN-ITHACA without it acknowledging any direct input from it.
This work has been generated within the  European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]  An option that an HCP can choose to add if the work has come into being by the work carried out by at least 2 ERN-ITHACA members working within the structure of the network
This study/project/publication/Guidelines/survey* has been supported by European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA). ERN-ITHACA is partly co-funded by the European Union [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]

*choose appropriate wording

If funding is allocated to a publication/ project. This will eventually apply but it is not yet the case for the moment.

25/05/2021- Molecular and phenotypic delineation of the MEF2C-related syndrom

Targeted gene(s)/phenotype under study:

  • MEF2C (MIM #613443: Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations)

Abstract:

The MEF2C gene encodes a transcription factor known to play a crucial role in molecular pathways affecting neuronal development. MEF2C haploinsufficiency has been described in the literature over the past decade, with the majority of patients harbouring 5q14.3 microdeletions. Consecutively, point mutations of MEF2C were identified in patients with neurodevelopmental disorders and epilepsy, describing the new MEF2C-related syndrome.

The objective of our work is to collect a cohort of patients with MEF2C mutations to better characterise the associated phenotypic spectrum, specify genotype-phenotype correlations, and propose clinically relevant follow-up recommendations.

Coordinating clinician/researchers:

  • Dr Guillaume Jouret

Institution:

National Center of Genetics (NCG)

Laboratoire National de Santé (LNS)

Dudelange, Luxembourg

Contact email:

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: N0 (or in a second phase, depending on the success of the cohort study)

Resampling of patients: No (or in a second phase, depending on the success of the cohort study)

Linked to a translational/basic research project? No (or in a second phase, depending on the success of the cohort study)

19/05/2021- Genotype-phenotype correlation of the CHD8-related developmental disorder

Targeted gene(s)/phenotype under study:

  • CHD8  (MIM *610528)

Abstract:

Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth. We previously investigated 25 individuals with CHD8 protein-truncating variants (PTVs) and showed that CHD8 haploinsufficiency is associated with a distinctive OGID syndrome with pronounced autistic traits [see PMID: 31001818]. We are collecting patients with

(1) missense CHD8 VOUS and

(2) <1Mb gain CNV including the entire CHD8 gene 

To explore further a possible genotype-phenotype correlation

Coordinating clinician/researchers:

  • Sofia Douzgou Houge

Institution:

Department of Medical Genetics,

Haukeland University Hospital,

Bergen, Norway

Contact email:

 

Collaborating clinician:

  • Siddharth Banka

Institution:

  • Manchester Centre for Genomic Medicine      

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: Yes, methylation profiling of pathogenic missense variants

Resampling of patients: No

Linked to a translational/basic research project? No

14/05/2021- Search for patients patients with recessive variants in the SNX13 gene

Abstract:

We have identified two siblings with a homozygous truncating variant in SNX13, which is not yet known in human pathology. However, SNX13 is known to interact with SNX14, which is involved in a neurodevelopmental phenotype.  Our patients have striking similarities with patients having SNX14 recessive variants with ataxia, cerebellar atrophy, intellectual disability, coarse facial features and hearing impairment. Functional studies are underway for the variant identified in our patient. We aim to find other families with SNX13 recessive variants to confirm the pathogenicity of the variant in our family and further delineate this genetic disease.

Coordinating clinician/researchers:

  • Dr Sandra Whalen

Institution:

Clinical Genetics Departement,

Armand Trousseau hospital,

APHP, Paris

France

Contact email:

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: Skin biobsy if possible

Resampling of patients: If necessary

Linked to a translational/basic research project? No

14/05/2021- Search for patients with severe neonatal presentation due to mutations of the ATL1 gene

Abstract:

ATL1 gene variants are usually responsible for autosomal dominant spastic paraplegia type 3A (MIM #182600), or autosomal dominant hereditary sensory neuropathy (MIM #613708) with onset during childhood or adulthood. Very few cases of neonatal presentations with severe evolution that did not permit to acquire the sitting position or to walk have been described. These clinical presentations are not well-known, since its knowledge is only based on case reports.

We aim at gathering more cases to better describe this extreme end of the clinical spectrum, and possibly describe some genotype-phenotype correlations.

Coordinating clinician/researchers:

  • Pr Laurence Faivre

Institution:

Genetic Centre

CHU Dijon

Dijon, France

Contact email:

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: No

Resampling of patients: No

Linked to a translational/basic research project? No

12/04/2021- Correlation between intellectual disability and cutaneous skin mosaicism

Abstract:

Cutaneous mosaic constitution has been associated with various intellectual disability (ID) phenotypes suggesting a common underlying pathomechanism. The case of ectodermal origin of skin and brain corroborates that a systematic genomic characterization of the skin of these syndromic ID patients could serve as a key to improved understanding of ID pathogenesis. In our DFG-funded project we want to help to clarify these underlying mechanisms by studying patients with ID and cutaneous hyper- and/or hypopigmented skin alterations. In the course of the study, skin biopsies (normally pigmented and hypo-/hyperpigmented skin) of the patients are analysed in comparison with blood of the patients and their parents. In addition to trio based exome sequencing (evaluation low grade mosaicism), methylome and transcriptome analyses, an accurate evaluation of the melanocytes and fibroblasts isolated and cultured from the skin is carried out by means of OMICS analyses. After the genomic characterization of skin and blood of several syndromic ID patients and their parents, we would like to increase the number of patients in order to better delineate the pathogenesis and underlying pathomechanism.

Coordinating clinician/researchers:

  • Dagmar Wieczorek
  • Silke Redler
  • Melanie Föhrenbach

Institution:

Institution of Human Genetics

University Clinic

Heinrich-Heine-University

Universitätsstr. 1 , 40225 Düsseldorf

Germany

Contact email:

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : N/A

Resampling of patients : N/A

Linked to a translational/basic research project? N/A

08/04/2021- ZBTB47/ZNF651 variants

Targeted gene(s)/phenotype under study:

  • ZBTB47/ZNF651 variants

Abstract:

Zinc finger domain proteins play an important role as transcription factors and have been reported with increasing frequency to be associated with a neurodevelopmental disorder, neuropsychiatric disorder, and/or neurological disease phenotype. ZBTB47 (previously known at ZNF651) encodes for a classic Cys2His2 zinc finger protein transcription factor and appears to be expressed strongly in the central nervous system. This gene has not previously been associated with human disease. We have now collected three cases in the United States of patients with de novo ZBTB47 variants affecting highly conserved amino acids that we believe are pathogenic. These three patients have a phenotype including profound global developmental delay, seizures, and abnormal movements. We would like to expand our cohort to include additional cases to better understand the pathogenicity of this gene and to further characterize this neurodevelopmental disorder phenotype.

Coordinating clinician/researchers:

  • Scott Ward
  • Lindsay Burrage
  • Jill Mokry

Collaboration:

  • Cyril Mignot (Reference Centre for Rares Diseases, APHP – Paris Sorbonne University)

Institution:

Department of Molecular and Human Genetics

Baylor College of Medicine

Houston, TX, USA

Contact email:

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : No

Linked to a translational/basic research project? No

01/04/2021- TRIP12-associated neurodevelopmental disorder

Targeted gene(s)/phenotype under study:

  • TRIP12 (OMIM #604506)

Abstract:

Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD) and variable degree of intellectual disability (ID). Different types of mutations have been described, but it remains a rare cause of ID. After identifying several patients with a mutation in this gene, we wish to increase the number of newly diagnosed patients in order to better delineate the neuropsychological phenotype.

Coordinating clinician/researchers

  • Hilde Van Esch

Institution:

Center for Human Genetics

University Hospitals Leuven,

3000 Leuven, Belgium

Contact email:

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : No

Linked to a translational/basic research project? No

11/02/2021- SF1 variants in neurodevelopmental disorders

Targeted gene(s)/phenotype under study:

  • SF1 variants (OMIM #601516)

Abstract:

SF1 codes for Splicing Factor 1, a nuclear pre-mRNA splicing factor. It is involved in the ATP-dependent formation of the spliceosome complex. Its role in human physiology is poorly understood and has not been reported yet in pathology.

Through international collaborations, we have already collected 7 cases carrying de novo SF1 truncating variants or variants affecting highly conserved domains of the protein. All these patients share developmental disorder / intellectual disability associated with some specific clinical features such as enophtalmos and limbs anomalies (nails hypoplasia, broad thumbs).

We now would like to enrich our cohort with some additional cases to better delineate the SF1-related neurodevelopmental disorder and proceed to functional validation.

Coordinating clinician/researchers

  • Thomas Courtin
  • Cyril Mignot

Institution:

Medical Genetics

APHP Hôpital Pitié-Salpêtrière

Paris, France

Contact email:

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : Yes

Linked to a translational/basic research project? Yes

05/02/2021- KDM4B gene: clinical phenotype and methylation signature

Targeted gene(s)/phenotype under study:

  • KDM4B (OMIM 609765)

Abstract:

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/demethylation-modified histones, which displays an important epigenetic mechanism on gene expression in animal development and cancer. Its role on human development is poorly defined.

In a recent publication (Duncan et al., 2020), we described nine individuals with pathogenic or likely pathogenic variants in KDM4B, who presented with dysmorphic features and global developmental delay. Four had neuroanatomical defects compatible with those identified in a mouse model.

We aim to better delineate the phenotypic spectrum of KDM4B-related disorder. We are looking for patients carrying predicted damaging heterozygous variants, either de novo or inherited from an affected parent. A collaborative work with the team of Prof. Bekim Sadikovic (University of Western Ontario) is in place to identify a blood-derived DNA methylation signature.

Coordinating clinician/researchers

  • Mrs Caroline Racine (resident)
  • Dr Antonio Vitobello

Institution:

Genetics of Developmental Disorders

Dijon Bourgogne University Hospital

Inserm UMR 1231 GAD team, Bâtiment B3

15 boulevard Maréchal De Lattre de Tassigny

21070 DIJON Cedex, France

Contact email:

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : Yes

Resampling of patients : Yes

Linked to a translational/basic research project? No

03/02/2021- Geleophysic and acromicric dysplasias: study of the natural history

Targeted gene(s)/phenotype under study:

Geleophysic dysplasia (ORPHA:2623 or MIM 231050 / 614185 / 617809)

  • ADAMTSL2 (OMIM 612277)
  • FBN1 (OMIM 134797)
  • LTBP3 (OMIM 602090)

Acromicric dysplasia (ORPHA: 969 or MIM102370)

    • FBN1 (OMIM 134797)
    • LTBP3 (OMIM 602090)

Abstract:

Geleophysic dysplasia (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group characterized by severe short stature, short extremities, progressive joint limitation, and pseudo-muscular build. While AD is associated with a good prognosis, GD patients can develop progressive cardiac valvular thickening, tracheal stenosis, and respiratory insufficiency, responsible for life-threatening complications.

Dominant mutations in the FBN1 and LTBP3 genes are responsible for GD and AD, whereas recessive mutations in the ADAMTSL2 gene are associated only with GD. These genes encode proteins involved in the microfibrillar network, a key component of the extracellular matrix with an important role in its mechanical function and the bioavailability and activity of the TGF-β superfamily.

Natural history of AD and GD, especially cardiorespiratory issues into adulthood, is still misunderstood and has to be better delineated. The aim of this study is to further define the natural history of GD and AD into childhood and adulthood, to examine the causes of death among these patients, and finally, to propose guidelines for patient management.

Coordinating clinician/researchers

  • Pr Valérie Cormier-Daire
  • Dr Pauline Marzin

Institution:

Fédération de Génétique médicale

Centre de référence pour les maladies osseuses constitutionnelles AP-HP

Hôpital Necker-Enfants malades

F-75015 Paris, France

Contact email:

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : No

Linked to a translational/basic research project? Yes

01/02/2021- Consortium for treating Kosaki syndrome

Targeted gene(s)/phenotype under study:

  • PDGFRB

Abstract:

Kosaki overgrowth syndrome is an ultrarare disorder characterized by characteristic facial features, tall stature, scoliosis, hyperelastic thin skin with lipodystrophy. Vascular and neurological deterioration may arise. This disorder is due to heterozygous activating variants in PDGFRB, also responsible for Penttinen syndrome and infantile myofibromatosis.

Imatinib has been used successfully for years in the treatment of lymphoid and myeloid neoplasms with PDGFRB rearrangements, by downregulating PDGFRB. To date, 5 patients have been reported in the literature with Penttinen syndrome and infantile myofibromatosis, with interesting results.

We would like to set up a consortium for treating Kosaki syndrome, with the establishment of a common protocol and follow-up meetings. This consortium will optimise the sharing of knowledge and experience around the efficacy and tolerance of Imatinib.

To date, this consortium brings together 5 international teams following a patient with Kosaki syndrome and interested in a therapeutic project (France, UK, Sweden, Spain and Australia). We are looking for teams who would be interested in joining this consortium.

Coordinating clinician/researchers

  • Prof. Laurence Faivre

Institution:

Medical Genetics

Dijon University Hospital

France

Contact email:

25/01/2021- TRA2B-associated neurodevelopmental delay

Targeted gene(s)/phenotype under study:

  • TRA2B (OMIM *602719)

Abstract:

TRA2B codes for Transformer-2 protein homolog beta, a factor putatively involved in the control of pre-mRNA splicing. Via international collaborative efforts we are aware of at least 7 index cases carrying different de novo TRA2B variants. All individuals have a developmental delay with variable additional clinical features including seizures, microcephaly, and growth retardation.

We would like to expand the cohort of patients with TRA2B variants in order to delineate the phenotype of this rare disease and are currently planning functional validation of pathogenicity of the variants

Coordinating clinician/researchers

  • Tobias Haack

Institution:

  • University hospital Tübingen, Tübingen, Germany

Contact email:

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : Yes

Resampling of patients : Yes

Linked to a translational/basic research project? Yes

22/01/2021-A novel neurodevelopmental disorders associated with heterozygous DLX1 variants

Targeted gene(s)/phenotype under study:

  • DLX1: (OMIM# or ORPHA code) NOT AVAILABLE

Abstract:

By trio-based exome sequencing, we identified a missense variant (c.542C>A:p.S181Y) in DLX1, in a female patient with severe intellectual disability, microcephaly, structural brain anomalies, epilepsy and behavioural anomalies such Rett-like features. Through collaborations, we have collected additional cases with similar phenotype, harbouring either missense or nonsense variants in DLX1

DLX1 encodes a member of a homeobox transcription factor gene family similiar to the Drosophila distal-less gene. It plays a regulatory role in the development of the ventral forebrain, specifically promoting the synthesis, synaptogenesis and dendritogenesis of GABAergic interneurons. Moreover, DLX1 has been  suggested as a candidate gene for Autism spectrum disorder.

We are planning to generate patients’ iPSC-derived neurons and investigate the underlying neurodevelopmental processes by an integrated approach, involving high resolution imaging techniques, electrophysiology and transcriptomics.

In summary there is a growing body of evidence to consider DLX1 as a novel neurodevelopmental disorder gene. We look for further patients with DLX1 variants displaying similar clinical features.

Coordinating clinician/researchers:

  • Andrea Accogli
  • Valeria Capra

Institution:

  • Medical Genetics, Istituto G.Gaslini, Genoa, Italy

Contact email:

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : No

Linked to a translational/basic research project? Yes

18/01/2021-Defining Myhre syndrome in Adulthood

Targeted gene(s)/phenotype under study :

  • Myhre syndrome: (OMIM #139210 or ORPHA 2588)

Abstract :

Myhre syndrome is a connective tissue disorder with multisystem involvement including short stature, progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery. Most individuals also have variable intellectual disability, and in some instances, autistic-like behavior. Cardiovascular, respiratory, gastrointestinal, and cutaneous involvement are, usually, of clinical concern. Myhre syndrome is caused by gain-of-function variants in SMAD4 (affecting residues p.Arg496 and p.Ile500).

We aim to define the clinical presentation in adulthood. We ask ERN-ITHACA based clinicians to contact us if they would like to share clinical data and facial photographs of individuals with Myhre syndrome aged 18 years old and above. Following consent, individuals/their legal representatives will also be asked to complete the Myhre syndrome association registry (https://research.sanfordhealth.org/rare-disease-registry).

Coordinating clinician/researchers:

  • Bert Callewaert
  • Sofia Douzgou Houge
  • Nicola Brunetti-Pierri

Institution :

  1. Center for Medical Genetics, Ghent University Hospital, Belgium.
  2. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
  3. Department of Translational Medicine, University of Naples “Federico II”, Italy.

Contact email:

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : No

Linked to a translational/basic research project? No

14/01/2021-Mild phenotype of EEF1A2 variants

Targeted gene(s)/phenotype under study :

  • Gene: EEF1A2 (OMIM # 602959)
  • Phenotype: intellectual disability, epileptic encephalopathy

Abstract :

EEF1A2 gene, encodes eukaryotic translation elongation factor 1 (eEF1A)-alpha 2, a protein mainly expressed in neurons and muscle and playing a key role in protein synthesis, apoptosis suppression and cytoskeletal regulation. Up to know, around 30 patients have been reported in literature with EEF1A2 variants. Patients are reported with early epilepsy, global developmental delay evolving to severe to profound intellectual disability, autistic behaviour and dysmorphic features. Affected individuals are often nonverbal and nonambulatory. We have identified two patients with EEF1A2 variants and a mild mental retardation without epilepsy. We would like to collect other patients with a mild delay to extend phenotype of EEF1A2 variants.

Coordinating clinician/researchers:

  • Dr Lyse RUAUD

Institution :

Clinical Genetics Department

Robert Debré University Hospital

75019 Paris

Contact email:

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : No

Linked to a translational/basic research project? No

12/01/2021 – XPO7-associated neurodevelopmental disorder

Targeted gene(s)/phenotype under study :

  • Gene: ZNF142 (OMIM 604083)
  • Disorder: NEDISHM (Neuordevelopmental disorder with impaired speech and hyperkinetic movements) (OMIM 618425)

Abstract :

XPO7 encodes for exportin 7 or RAN-Binding Protein 16, a member of the importin-beta superfamily of nuclear transport receptors and implicated in the nuclear transport of proteins. Exportin 7 is highly expressed in brain but not yet reported in human pathology. We have collected 8 patients from different countries with (de novo) XPO7 variants and neurodevelopmental disorders. The phenotype is broad (developmental delay, intellectual disability, dysmorphic features, seizures, microcephaly) but patients share similarities and interestingly, four patients have the same missense variant.

We would like to constitute a cohort of patients with XPO7 variants in order to delineate the phenotype of this rare disease and are currently planning functional validation of pathogenicity of the variants.

Institution :

Clinical Genetics Department

Robert Debré University Hospital

75019 Paris

Coordinating Clinician :

  • Dr Lyse RUAND

Contact email:

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : Yes 

Resampling of patients : Yes

Linked to a translational/basic research project? Yes

05/01/2021 – ZNF142-associated neurodevelopmental disorder

Targeted gene(s)/phenotype under study :

  • Gene: ZNF142 (OMIM 604083)
  • Disorder: NEDISHM (Neuordevelopmental disorder with impaired speech and hyperkinetic movements) (OMIM 618425)

Abstract :

Zinc finger protein 142 (ZNF142) is involved in the development of the nervous system, but the pathogenic ZNF142 variants are extremely rare, and to date, only four families have been reported. The current knowledge suggests that a defective ZNF142 leads to an autosomal recessive disorder characterized by intellectual disability, speech impairment, seizures and movement disorder. We have identified two families with compound heterozygous ZNF142 variants leading to neurodevelopmental disturbances without movement disorder. We will be very interested in including further patients, as this will be very important to understand the clinical features related to ZNF142 variants.

We plan to submit the manuscript to Clinical Genetics by the end of January 2021.

Coordinating clinician/researchers:

  • Zeynep Tümer

Institution :

Kennedy Center, Department of Clinical Genetics,

Copenhagen University Hospital, Rigshospitalet

Danemark

Contact :

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No 

Resampling of patients : No

Linked to a translational/basic research project? No

04/01/2021 – CTNNA3 microdeletion: a description of clinical features

Targeted gene(s)/phenotype under study :

  • CTNNA3 gene (OMIM 607667)

Abstract :

CTNNA3 gene is located on long arm of chromosome 10 and it encodes a protein that belong to the vinculin/alpha-catenin family. This protein plays a role in cell-cell adhesion. Microdeletions in this gene may are associated with arrhythmogenic right ventricular dysplasia 13, autism spectrum disorder and multiple fetal anomalies.

The echography controls in a pregnant were suggestive for duodenal stenosis, a genetic analysis was performed and it identified a microdeletion in CTNNA3.

Microdeletions in CTNNA3 gene are poorly reported in the literature. Therefore, the aim of this study is to collect clinical data on additional patients with a CTNNA3 microdeletion and to better describe the clinical features of this specific mutation.

Coordinating clinician/researchers:

  • Alessandra Ferrarini

Institution :

Service of Medical Genetics,

Italian Hospital of Lugano and University of Lugano,

6900 Lugano, Switzerland (CH)

Contact :

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No 

Resampling of patients : No

Linked to a translational/basic research project? Yes

14/12/2020 – POGZ variants in neurodevelopmental disorders

Targeted gene(s)/phenotype under study :

  • POGO TRANSPOSABLE ELEMENT WITH ZNF DOMAIN; POGZ (OMIM: 614787)/WHITE-SUTTON SYNDROME; WHSUS (OMIM: 616364; ORPHA:468678)

Abstract :

Recently discovered, POGZ gene codes for a heterochromatin protein, playing as a transcriptional regulator involved in chromatin remodeling, neuronal proliferation and synaptic function.

Heterozygous pathogenic variants in POGZ, mostly occurring de novo, have been recently associated to neurodevelopmental disorders, intellectual disability, developmental delay with or without autism spectrum disorder (ASD) and White-Sutton Syndrome. To date, over 50 individuals with mutation in POGZ have been reported worldwide, mostly presenting truncating or splice-site pathogenetic variants.

POGZ knock-in mice exhibit abnormally elevated activation of excitatory neurons resulting in impaired neuronal development and altered behavioral performances, improved by the inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated synaptic transmission.

The aim of the study is to collect molecular and clinical data of POGZ-affected subjects in order to expande the knowledge of pathological mechanism and further investigate the already detected genotype-phenotype correlations in the light of proposing new therapeutic strategies

Coordinating clinician/researchers:

  • Agnese Feresin, Maria Teresa Bonati

Institution :

Department of Genetics

Institute for Maternal and Child Health IRCCS Burlo Garofolo

Trieste, Italy

Contact :

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : Yes 

Resampling of patients : Yes

Linked to a translational/basic research project? Potential study could be developed

10/12/2020 – BCL11B related disorder : clinical phenotype, neuropsychological profile, brain MRI characteristics and epigenetic signature

Targeted gene(s)/phenotype under study :

  • Gene BCL11B, no Orphanet number, OMIM :663309 intellectual developmental disorder with speech delay, dysmorphic facies, and T cell abnormalities IDDSFTA disorder; 618092
  • Aims: Better delineation of clinical phenotype
  • Neuropsychological study based on WISC/WAIS standard tests
  • Brain MRI characteristic
  • Epigenetic signature on blood DNA samples in collaboration with Bekim SADICOVIK (London CANADA)

Abstract :

BCL11B related disorder, also known as intellectual developmental disorder with speech delay, dysmorphic facies, and T cell abnormalities (IDDSFTA; OMIM 618092) syndrome, is mainly characterised by developmental delay (DD) and intellectual disability (ID), ranging from mild to severe, and immunological abnormalities. To date 17 individuals with BCL11B variants have been described in literature.

The aims of this study are first to better delineate the clinical phenotype, as well as the neuropsychological profile, and the brain MRI characteristics; and, second, to study the epigenetic signatures in a cohort of individuals with BCL11B intragenic pathogenic variants. This work will conduct to a MD thesis of a clinical resident geneticist in France.

Physician that will participate will fill an Excel sheet regarding the clinical and neuropsychological assessment. We will be also happy to have either CD-ROM or a link to have access to the brain MRI data as well as a DNA sample with a minimum 0.5ug of peripheral blood genomic DNA. We will gather the DNA in Montpellier genetic lab (Dr Mouna BARAT) and send the batch to the Dr Sadikovic’ lab.

Coordinating clinician/researchers:

  • Pr David GENEVIEVE, MD, PhD

Institution :

Genetic Department for rare disease and personalised medicine

Arnaud de VILLENEUVE Hospital

371 Doyen G Giraud Avenue

34000 Montpellier

Contact :

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : Yes (but only epigenetic data)

Resampling of patients : No

Linked to a translational/basic research project? No

10/12/2020 – Phenotypic delineation of patients with bi-allelic CDK10 mutations (Al Kaissi syndrome)

Targeted gene(s)/phenotype under study :

  • CDK10 (OMIM 603464)
  • Phenotype: intra uterine growth retardation – Postnatal growth retardation with low weight and small head circumference – Intellectual disability, moderate to severe – Hypotonia – Thin corpus callosum – Dysmorphic facial features – Naevus flammeus – Hand anomalies – Atrial septal defect – Characteristics spinal segmentation defects – orthopaedic anomalies
  • AL KAISSI Syndrome (OMIM 617694)  

Abstract :

Up to now only 10 patients from 6 unrelated families have been reported in the literature with bi allelic variants in CDK10. Main clinical features are developmental delay, pre and postnatal growth retardation with microcephaly, dysmorphic facial features, skin abnormalities (with angioma or neavus flammeus of the glabella), hand anomalies (mainly clinodactyly), anomalies of the corpus callosum and quite characteristics anomalies of the cervical vertebrae.

We have identified 4 new patients from France and Netherlands with compound heterozygous or homozygous variants in the CDK10 gene.

We would like to constitute an European cohort in order to better describe this rare syndrome.

Coordinating clinician/researchers:

  • Dr Elise SCHAEFER
  • Dr Juliette PIARD
  • Manon CHRETIEN (Resident)

Institution :

  • HAUTEPIERRE Hospital – 67200 Strasbourg – FRANCE
  • SAINT-JACQUES  Hospital – 25030 Besançon – FRANCE

Contact :

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : No

Linked to a translational/basic research project? No

02/12/2020 – Search for patients with a deletion of the first 2 non-coding exons of the RAI1 gene

Targeted gene(s)/phenotype under study :

  • Gene: RAI1 (OMIM * 607642)

Abstract :

RAI1 is a gene involved in Smith-Magenis syndrome, with a phenotype that includes intellectual disability, recognisable morphologic traits, and sleep disorders. We describe a new phenotype, related to the deletion of the first two non-coding exons of RAI1 and we are collecting patients with a deletion of the first 2 non-coding exons in order to better describe the phenotype and confirm the pathophysiological mechanism.

Coordinating clinician/researchers:

  • Dr Colin Estelle and Tessarech Marine

Institution :

Angers University Hospital

Contact :

marine.tessarech@chu-angers.fr

escolin@chu-angers.fr

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : Yes

Linked to a translational/basic research project? Yes

30/11/2020 – FOREIGN (FOSL2-related signs)

Targeted gene(s)/phenotype under study :

  • Gene: FOSL2

Abstract :

We would like better delineate the clinical spectrum and natural history of a new syndrome linked to the FOSL2 This new phenotype is characterised by specific morphological anomalies, growth retardation and a neurodevelopmental disorder.

In the 5 cases already identified throughout Europe, a de novo variation was found out in a coding region of the FOSL2 gene (NM_005253.3).

Coordinating clinician/researchers:

  • Pr Koen DEVRIENDT
  • Dr Laurent PASQUIER

Institution :

UZ Leuven

Herestraat 49, 3000

Leuven, Belgium

and,

CHU Rennes

2 rue Henri Le Guilloux

Rennes, France

Contact :  

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : No

Resampling of patients : Yes

Linked to a translational/basic research project? In progress

30/11/2020 – Search for patients with biallelic variants in genes implicated in the ufmylation pathway

Targeted gene(s)/phenotype under study :

  • Gene: UBA5, UFM1, UFC1, UFL1 and MRE11 (OMIM # 617132, # 617899, # 618076, # 604391)

Abstract :

The covalent attachment of the ubiquitin-fold modifier1 (UFM1) to a target protein, also named ufmylation, is a recently identified ubiquitin-like post-translational modification, ubiquitously expressed. Similarly to ubiquitination, ufmylation requires a series of enzymes referred to as E1 activating enzyme (UBA5), E2 conjugating enzyme (UFC1), and E3 ligase (UFL1) to transfer UFM1 to its targets. The molecular and cellular functions of UFMylation remains poorly understood. Biallelic variants in UBA5, UFM1 and UFC1 have been involved in neurodevelopmental disorders with often early encephalopathy, hypomyelination, acquired microcephaly, movement disorders or spasticity, thus pointing the importance of this pathway for the brain development.

Recently publications showed that ufmylation of the nuclease MRE11 regulate ATM activation and double strand break repair.

We are collecting patients with biallelic variants in UBA5, UFM1, UFL1, UFC1 and MRE11 (even patients who have already been published) to further describe the phenotype and to identify the molecular and cellular determinants regulated by the UFM1 pathway.

Coordinating clinician/researchers:

  • Dr Estelle Colin
  • Dr Christophe Lachaud

Institution :

Medical Genetic Department

Angers University Hospital

Angers, France

and,

CR1 CNRS

Inserm UMR1068, CNRS UMR7258, Université U105, Institut Paoli Calmettes

Marseille, France

Contact :  

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : N

Resampling of patients : Y

Linked to a translational/basic research project? Y

24/11/2020 – KMT2B-related disorders without dystonia

Targeted gene(s)/phenotype under study :

  • Gene: KMT2B 

Abstract :

KMT2B encodes a lysine-specific histone methyltransferase which catalyzes methylation to the fourth lysine residue of histone H3 (H3K4). So far, de novo loss-of-function and damaging missense variants in KMT2B have mainly been found in individuals with early-onset dystonia (#OMIM 617284), although about 20% of patient present not with a dystonic phenotype but rather with a neurodevelopmental disorder (NDD)  (Faundes et al., 2018, Cif et al., 2020). It is currently unclear whether dystonia develops later among the NDD individuals.

Our study aims to delineate the phenotypic and genetic spectrum associated with NDD patients without dystonia and, in collaboration with, the groups of Tjitske Kleefstra and Rosanna Weksberg from Radboudumc, the Netherlands and the SickKids hospital, Canada, respectively, investigate the molecular bases of KMT2B-associated disorders, by performing DNA methylation analyses in samples extracted from peripheral blood of the dystonic and non-dystonic individuals.

Coordinating clinician/researchers:

  • Dr Antonio Vitobello
  • Dr Estelle Colin
  • Dr Anne-Sophie Denommé-Pichon   

Institution :

Centre Hospitalier Universitaire Dijon Bourgogne

Inserm 1231 GAD team

Dijon, France

Contact :  

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : If Necessary

Resampling of patients : If Necessary

Linked to a translational/basic research project? If Necessary

19/11/2020 – Neurodevelopmental disease and brain abnormalities due to YWHAE loss-of-function variants

Targeted gene(s)/phenotype under study :

  • Gene: YWHAE

Abstract :

The Miller-Dicker syndrome is caused by a heterozygous deletion of the LIS1 and YWHAE genes in the 17p13.3 region. In 2003, Toyo-oka et al. presented evidence that the gene whose deletion is responsible for most severe Miller-Dieker cases is YWHAE. Since then, several patients with 17q13.3 deletions involving YWHAE have been reported and presented with developmental delay and cerebral abnormalities.

To this day, YWHAE loss-of-function is supposed to be pathogenic but the gene is not reported as clearly morbid yet and the associated phenotype is still not defined.

On the basis of several cases with variants in YWHAE and of the creation of a mouse model suggesting a role for YWHAE in neurodevelopmental disease, we welcome additional cases to further delineate the phenotype.

Coordinating clinician/researchers:

Laurence Faivre and Anne-Sophie Denommé-Pichon

Institution :

Genetics of Developmental Disorders

Dijon Bourgogne University Hospital

Inserm UMR 1231 GAD team, Bâtiment B3

15 boulevard Maréchal Delattre de Tassigny

21070 Dijon Cedex, France

Contact :  

laurence.faivre@chu-dijon.fr

anne-sophie.denomme-pichon@u-bourgogne.fr

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : N

Resampling of patients : N

Linked to a translational/basic research project? N

16/11/2020 – Search for patients with de novo variants in DCAF15

Targeted gene(s)/phenotype under study :

  • Gene: DCAF15
  • OMIM #  or ORPHA code: This gene has no registration with OMIM/ ORPHA
  • Phenotype: The phenotype of the 3 patients identified so far is very similar and includes common dysmorphic facial features, severe neurodevelopmental delay, arthrogryposis, congenital CNS malformations, visual impairment and hearing loss, among others.
  • Disorder under study: syndromic neurodevelopmental disorder

Abstract :

We have a cohort of 3 patients with a similar syndromic neurodevelopmental disorder and the same variant in DCAF15 gene. This is a variant without allelic frequency described in gnomAD and with constraint metrics that indicate that it might be intolerant to protein-truncating and missense variations. Dcaf15 gene expression data in mice tissues show a ubiquitous expression pattern, which might be compatible with a malformative syndrome.  This gene is a substrate-recognition component of a cullin-4-RING E3 ubiquitin-protein ligase complex that possibly mediates ubiquitination and degradation of cohesin subunits SMC1A and SMC3.

The phenotype of the 3 patients identified so far is very similar and includes common dysmorphic facial features, severe neurodevelopmental delay, arthrogryposis, congenital CNS malformations, visual impairment and hearing loss, among others.

In all three cases the presumptive diagnosis was similar and all of them had previous extensive genetic studies with normal result, being the variant in this gene the only candidate.

Coordinating clinician/researchers:

  • Dr. Sixto García-Miñaúr
  • Dr. Antonio Vitobello
  • Dr. María Palomares

Institution :

– INGEMM, Institute of Medical and Molecular Genetics

Hospital Universitario La Paz

Madrid-Spain

– Centre Hospitalier Universitaire Dijon Bourgogne

Inserm 1231 GAD team

Dijon, France

Contact :  

sixto.garciamin@gmail.com

maria.palomares@salud.madrid.org

Antonio.Vitobello@u-bourgogne.fr

  

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples : N

Resampling of patients : N

Linked to a translational/basic research project? Y

12/11/2020 – KLHL11 pathogenic variant in patients with lichen planus, abnormalities of the nails and tumour proneness

Targeted gene(s)/phenotype under study :

  • KLHL11 (OMIM 619078)

Abstract :

Lichen planus (LP) is a chronic inflammatory disorder affecting the skin, oral/genital mucosa, and scalp. LP has been associated with numerous systemic entities such as metabolic syndrome, diabetes mellitus, hypertension, thyroid dieseases, psychosomatic, chronic liver and gastrointestinal diseases.

We present a two-generation family with six people affected by LP in which dystrophic alterations in the nails are also associated and cancer of the tongue and other locations in two of them. Other relatives also died with cancer. The clinical findings segregate from parents to affected children suggesting an autosomal dominant inheritance. WES studies have been carried out in affected and healthy people in the family, identifying a variant in the KLHL11 gene that perfectly segregates with the clinical findings. The variant does not appear in the control population databases gnomADexomes, gnomADgenomas, Kaviar, 1000G, ESP). There are no disorders associated with this gene to date.

The KLHL11 gene belongs to the Kelch-like gene family (KLHL) and encodes a group of proteins that possess a BTB / POZ domain, a BACK domain, and five to six KELCH motifs. The full function of KLHL11 is not known, but several KLHL proteins bind to the E3 ligase cullin3 that are involved in ubiquitination. Other KLHL genes are responsible for Mendelian diseases and have been associated with cancer. KELCH-type proteins usually form homodimers, the detected variant in the present family could affect this interaction between KELCH monomers.

Coordinating clinician/researchers: Pablo Lapunzina

Institution :

INGEMM, Institute of Medical and Molecular Genetics

Hospital Universitario La Paz

Madrid-Spain

Contact :   plapunzina@ciberer.es    

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : Y
  • Resampling of patients : Y
  • Linked to a translational/basic research project? N

10/11/2020 – Phenotype-genotype study of TAF2

Targeted gene(s)/phenotype under study :

  • TAF2/Mental retardation, autosomal recessive 40 (OMIM 615599)

Abstract :

We are collecting patients with intellectual disability and biallelic (homozygous or compound heterozygous) variants in TAF2 in order to better describe the phenotype and the variants

Coordinating clinicians/researchers: Marion Lesieur, Boris Keren

Institution :

Genetic Department,

Pitié-Salpêtrière Hospital,

Paris, France

Contact :   marion.lesieur@aphp.fr  ,  boris.keren@aphp.fr       

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project? N

09/11/2020 – Phenothype-Genotype relationships in 3q29-microduplication syndrome

Targeted gene(s)/phenotype under study :

  • chromosome 3q29 duplication (OMIM 611936); BDH1 (OMIM 603063)

Abstract :

3q29 microduplication syndrome is a rare genetic condition resulted from a 1.6 Mb duplication on the long arm (q) of chromosome 3. These patients presented with health problems in the first year of life as feeding problems, low gain of weight, hypotonia and respiratory distress; developmental delay and learning disability, gastrointestinal problems, seizures, and social interaction defect. 3-Hydroxybutyrate Dehydrogenase 1 (BDH1) gene encodes a member of the short-chain dehydrogenase/reductase gene family. This protein forms a homotetrameric lipid-requiring enzyme of the mitochondrial membrane and has a specific requirement for phosphatidylcholine for optimal enzymatic activity. The encoded protein catalyzes the interconversion of acetoacetate and (R)-3-hydroxybutyrate, the two major ketone bodies produced during fatty acid catabolism. BDH1 has been implicated in aging and Alzheimer’s disease, and may be responsible for ketone body metabolism within the brain.

We have identified a 3q29 microduplication syndrome in a 9-year-old-male resulted from two microduplications including the genes XXYLT1, ACAP2, and BDH1. Psychomotor delay and Autism-Spectrum-Disorder were the main features. Minimal overlapping region with other cases reported in literature includes only the gene BDH1.

Published reports on 3q29 microduplication syndrome are limited; therefore, the aim of this study is to collect clinical data on additional patients with a 3q29 microduplication syndrome and to analyse the link between the genotype and the phenotype and to determine the minimal critical region. This will aid in expanding our current knowledge on this syndrome, on the genes responsible for this disease and delineating associated phenotypes. This study could add important informations about which genes are responsible for psychomotory neurodevelopmental delay.

Coordinating clinicians/researchers:  Alessandra Ferrarini

Institution :

Service of Medical Genetics,

Italian Hospital of Lugano and University of Lugano,

6900 Lugano, Switzerland (CH)

Contact :   alessandra.ferrarini@eoc.ch

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project? Y

02/11/2020 – De novo missense variants in EIF3I cause a novel neurodevelopmental disorder with midline brain defects and skeletal abnormalities.

Targeted gene(s)/phenotype under study :

  • EIF3I (OMIM * 603911)

Abstract :

All stages of the eukaryotic canonical translation initiation on a 5’-capped mRNA are highly coordinated and require a set of eukaryotic initiation factors (eIFs), including eIF1, eIF1A, eIF2, eIF3, eIF4B, eIF4F, eIF5, and eIF5B. The largest and most complex initiation factor is eIF3, consisting of 12 subunits (a-m) in humans and essential during all stages of translation initiation. The i subunit, encoded by EIF3I, is the most conserved subunit and supports basic functions of the whole eIF3 complex. Aside from being a protein scaffold for the formation of initiation complexes, eIF3i drives the specialized translation of specific mRNAs. Furthermore, it is involved in the regulation of PI3K-Akt signaling cascade through a direct interaction with Akt1. Through whole exome sequencing, we identified de novo missense variants in EIF3I in several individuals presenting with a novel neurodevelopmental disorder characterized by intellectual disability, variable midline brain defects, and skeletal features. We have ongoing functional studies aiming to investigate the effects of EIF3I variants on the translation initiation and eIF3-driven specialized regulation, as well as their functional consequences on the modulation of Akt activity. These data most likely support the association between EIF3I variants and a novel neurodevelopmental disorder.

We look forward to including additional patients harboring missense EIF3I variants and displaying a similar phenotype in our collaborative research study.

Coordinating clinicians/researchers:  Marcello Scala, Valeria Capra

Institution :

University of Genoa, Department of Neurosciences,

Genoa, Italy; IRCCS Istituto Giannina Gaslini, Department of Neurology,

Genoa, Italy.

Contact :   marcelloscala87@gmail.com, valeriacapra@gaslini.org    

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project? Y

28/10/2020 – Implication of missense variants in the NSD1 gene in Sotos-like phenotype

Targeted gene(s)/phenotype under study :

  • NSD1 gene (OMIM #606681)

Abstract :

Non-sens mutations in the NSD1 gene cause SOTOS Syndrome 1 (OMIM #117550) , characterized by overgrowth with advanced bone age, an unusual face with large skull, acromegalic features and pointed chin, occasional brain anomalies and seizures, and impaired intellectual development.

We found a missense mutation in the NSD1 gene  in a boy with overgrowth syndrome, slight impaired intellectual development  but without the characteristic dysmorphy, a sort of “Sotos-like” syndrome.

We would like to ascertain these sort of variants in  the NSD1 gene as causative of this type of phenotype from other similar cases.

Coordinating clinicians/researchers:  Pr. Brigitte GILBERT-DUSSARDIER

Institution :

Medical Genetics,

Development Anomalies Expert Center,

Universitary Hospital,

Poitiers, France

Contact : brigitte.gilbert-dussardier@chu-poitiers.fr       

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project? N

27/10/2020 – CAMK2A-related neurodevelopmental disorder – description of the clinical and neurological phenotype

Targeted gene(s)/phenotype under study :

  • Calcium/Calmodulin Dependent Protein Kinase II Alpha – CAMK2A (OMIM: 114078)

Abstract :

CAMK2A encodes one of the four subunits of Calcium/Calmodulin Dependent Protein Kinase II, a multisubunit serine/threonine kinase highly expressed in the brain with important roles in synaptic plasticity, learning and memory. Heterozygous CAMK2A variants cause autosomal dominant mental retardation-53 (OMIM #617798).

We have identified a heterozygous pathogenic missense CAMK2A variant in a 3-year-old girl with a complex neurodevelopmental disorder associated with global developmental delay, hypotonia, absent speech and epilepsy.

Published reports on CAMK2A-related neurodevelopmental disorder variants are exceptionally limited (Kury et al., 2017; Akita et al., 2018; Chia et al., 2018); therefore, the aim of this study is to collect clinical and molecular data on additional patients with rare CAMK2A variants. This will aid in expanding our current knowledge on this gene, further delineating associated phenotypes, and ultimately assisting in the clinical diagnosis and management of patients. The analysis could potentially lead to further functional studies.

Coordinating clinicians/researchers:  Dr. George A. Tanteles

Institution :

Clinical Genetics Clinic

The Cyprus Institute of Neurology and Genetics

Ayios Dometios 2371, Nicosia, Cyprus

Contact : gtanteles@cing.ac.cy

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project? Potential studies could be performed

26/10/2020 – Osteopathia striata with cranial sclerosis – A further insight

Targeted gene(s)/phenotype under study :

  • AMER1

Abstract :

Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked disorder due to AMER1 mutations. Males present a severe form which is usually lethal before birth. Female patients show macrocephaly, cleft palate, mild learning disabilities, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae alongside other systemic anomalies.

There are about one hundred cases described in the literature.

We are looking to form a European cohort to bring further insight into OSCS and we already have 5 patients from France.

Coordinating clinicians/researchers:  DOCO-FENZY Martine

Institution : 

Genetic department,

CHU de REIMS

Reims, France

Contact : mdocofenzy@chu-reims.fr ; hthorn@chu-reims.fr

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project?

20/10/2020 – Expanding the phenotype related to de novo missense variants in HNRNPH2

Targeted gene(s)/phenotype under study :

  • HNRNPH2 (OMIM # 300610)

Abstract :

De novo missense variants in HNRNPH2 have been recently reported in association with Bain type syndromic X-linked intellectual disability (OMIM #300986). To date, only 10 patients (7 females and 3 males) have been described presenting with severe developmental delay and intellectual disability, hypotonia, feeding difficulties and some facial dysmorphism. Additional neurological phenotype consisted of developmental regression, microcephaly, cerebellar anomalies and behavioral anomalies.

All but one variants cluster within the same domain encoding nuclear localization signal (NLS) of HNRPNPH2 and a mutational hotspot was found in the aminoacid 206, affected in 8 out of 10 patients. The exact physiopathologic mechanism related to missense mutations is currently unknown.

We found a novel de novo missense variant in HNRNPH2 in a female patient. We expand the phenotype with unreported clinical manifestations. We aim to collect other clinical and molecular data to further delineate the phenotype and to perform some functional analysis such as X chromosome inactivation and cDNA expression studies.

Coordinating clinicians/researchers:  Stéphanie Moortgat and Isabelle Maystadt

Institution : 

Department of Human Genetics

Institut de Pathologie et de Génétique

IPG, Gosselies, Belgium

Contact : stephanie.moortgat@ipg.be

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : Y
  • Resampling of patients : If necessary in some cases
  • Linked to a translational/basic research project?

05/10/2020 – A novel X-linked syndromic neurodevelopmental disorders associated with WDR44 pathogenic variants

Targeted gene(s)/phenotype under study :

  • WDR44 (OMIM # or ORPHA code not available)

Abstract :

By trio-based exome sequencing, we identified a missense variant (c.2291C>T(p.Ser764Phe)) in the X-linked WDR44 gene, in a male patient with intellectual disability, mild microcephaly, structural brain anomalies, congenital heart defects, kidney cysts, cryptorchidism, musculoskeletal anomalies (talipes equinovarus, congenital hip dysplasia, increased CPK and joint hypermobility) and low platelet. Through collaborations, we have collected additional cases with similar phenotype, harbouring either missense or nonsense variants in WDR44.

WDR44, also known as Rabphillin11, is thought to be involved in endosomal and vesicle recycling through the interaction with a small G protein (Rab11p), a key regulators of intracellular membrane trafficking. Recently, WDR44 depletion has been shown to promote Rabin8 preciliary trafficking and ciliogenesis-initiating events at the mother centriole.

We have ongoing functional studies in patients-derived fibroblasts to show a possible ciliogenesis defect and assess the dynamic interaction with Rab11. Lastly, we aim to investigate the impact of the WDR44 variants in a zebrafish model.

These data likely support the evidence of a novel X-linked neurodevelopmental disorder linked to WDR44 variants. We look for other patients with WDR44 variants sharing similar clinical features.

Coordinating clinicians/researchers:  Andrea Accogli and Valeria Capra   

Institution : 

Medical Genetics,

Instituto G.Gaslini,

Genoa, Italy

Contact :  andreaaccogli@gaslini.org   and  valeriacapra@gaslini.org

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples :
  • Resampling of patients : N
  • Linked to a translational/basic research project?

29/09/2020 – RAB10: a candidate gene for a severe neurodevelopmental syndrome

Targeted gene(s)/phenotype under study :

  • RAB10 (612672)

Abstract :

By trio-based exome sequencing, we identified a de novo missense variant in RAB10 gene p.Thr23Ile in a patient with microcephaly, corpus callosum agenesis, hypotonia, severe developmental delay, and epilepsy. The variant was not present in Gnomad and was predicted to be deleterious by in-silico analyses. Additionally, RAB10 gene is significantly depleted of missense variants. RAB proteins are small GTPases that cycle between an active (GTP-bound) and inactive  (GDP-bound) state.  RAB proteins are involved in intracellular trafficking and synaptic function and mutations in RAB proteins (RAB18, RAB39B, RAB11B) have been associated with neurodevelopmental disorders.

Interestingly, the missense p.Thr23Ile variant in RAB10 detected in our patient affects an highly conserved amino acid residue that is well known to affect GTP/GDP binding. Dominant-negative GDP-locked (p.Thr23Asn) RAB10 mutant indeed is known to result in abnormalities of the endoplasmic reticulum dynamics affecting dendritic growth.

Coordinating clinicians/researchers: Nicola Brunetti-Pierri      

Institution :

Federico II University

Department of Translational Medicine

Naples, Italy

Contact : brunetti@tigem.it

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples :
  • Resampling of patients : N
  • Linked to a translational/basic research project?

29/09/2020 – B4GALT5 as potential candidate gene for a novel sphingolipid disorder.

Targeted gene(s)/phenotype under study :

  • B4GALT5 (604016)

Abstract :

By trio-based exome sequencing, we identified compound heterozygous missense variants in B4GALT5 gene (p.Gly274Arg, p.Arg173His) in a patient with bilateral cataracts, intellectual disability, hypermobility joints and marfanoid habitus.

The p.Gly274Arg variant is present in 1/251,428 in GnomAD controls while the variant p.Arg173His is absent in GnomAD. The gene is sensitive to either missense variants and to loss-of-function variants. B4GALT5 encodes for B4GalT5 enzyme involved in sphingolipid metabolism, allowing the conversion of glucosyl-ceramide to lactosyl-ceramide, which is then transformed into ganglioside GM3.

The sphingolipids profile in the proband showed high levels of glucosyl-ceramide while low levels of  lactosyl-ceramide and ganglioside GM3 were detected supporting a B4GalT5 deficiency. These data might support a novel condition associated to B4GalT5 deficiency and we are looking for other patients sharing clinical features and variants in B4GALT5.

Coordinating clinicians/researchers: Nicola Brunetti-Pierri      

Institution :

Federico II University

Department of Translational Medicine

Naples, Italy

Contact : brunetti@tigem.it

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples :
  • Resampling of patients : N
  • Linked to a translational/basic research project?

24/09/2020 – Clinical and molecular characterization of a novel MYCN related syndrome – A mirror phenotype and molecular of the Feingold syndrome.

Targeted gene(s)/phenotype under study :

  • MYCN  (OMIM #164840) Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome spectrum

Abstract :

We identified a de novo variant in MYCN, in a foetus with a mirror phenotype of the Feingold syndrome. To date, only one patient (post-natal) has been described, with a similar mirror phenotype (PMID: 30573562). It suggests a gain-of-function mechanism, rather than a loss-of-function as described in the Feingold syndrome.

Therefore, we are collecting, already identified variants in MYCN , localized between amino-acids 50 and 70, in patients within the megalencephaly polymicrogyrya polydactyly hydrocephalus spectrum (MPPH), and negative for another molecular cause.

We have the possibility to perform functional assay on the identified MYCN variant with the collaborators from the initial publication, whom we are working with.

Coordinating clinicians/researchers: Dr. Frederic Tran-Mau-Them     

Institution :

UF6254 Innovation en Diagnostic Genomique des Maladies Rares

CHU Dijon,

France

Contact : Frederic.tran-mau-them@u-bourgogne.fr

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : Y if necessary (by the inclusion centre)
  • Resampling of patients : N
  • Linked to a translational/basic research project? Y (collaboration with a Japanese team on functional assay)

27/08/2020 – SCA2 in children

Targeted gene(s)/phenotype under study :

  • ATXN2  (OMIM #183090)

Abstract :

Spinocerebellar ataxia type 2 (SCA2) is a cerebellar degeneration due to expansions of CAG repeats in ATXN2 that may further expand during meiosis, which gives rise to familial cases with affected children (well-known anticipation phenomenon). Although being known for about 25 years, the clinical involvement in children is far from being fully described. Most young patients have been reported as single cases or familial cases.

We aim at describing/analysing the first clinical series of children with SCA2 to report the full spectrum of the disease. We previously analysed the phenotype and genotype/phenotype correlation of 27 children with SCA7, our article will soon be available (Eur J Neurol).

Until now, we collected 12 children with SCA2 and wish to at least double this number. We will recruit retrospectively and prospectively all children aged 0-15 years old with a proved SCA2. We will collect clinical/radiological/molecular by sending you a table. If you are interested, you can contact either Dr. Maissa Bah or Dr. Cyril Mignot.

Coordinating clinicians/researchers: Cyril Mignot and Maïssa BAH     

Institution :

Département de Génétique

Hôpital Trousseau et Groupe Hospitalier Pitié-Salpêtrière

Paris, France

Contact : cyril.mignot@aphp.fr  and  bah.maissa@gmail.com

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project? N

19/08/2020 – Functional studies of variants in RBM10

Targeted gene(s)/phenotype under study :

  • RBM10 (OMIM 300080)

Abstract :

Loss of function variants in RBM10 are well known to cause TARP-syndrome, a severe X-linked recessive syndrome with malformations, global developmental delay, and early death of affected males. Missense variants in the RBM10-gene have so far not been proven to be pathogenic. We have collected a cohort of families with RBM10-variants – missense variants, splice variants and loss of function variants – and we are conducting a PhD study of the genotype-phenotype correlation and supporting functional studies.

We welcome further cases of rare variants in the RBM10-gene – all types of variants are included.

Coordinating clinician/researcher: Christina Fagerberg

Institution :

Department of Clinical Genetics

Odense University Hospital

Odense, Denmark

Contact : christina.fagerberg@rsyd.dk

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : Y
  • Linked to a translational/basic research project? Y

17/08/2020 – Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant

Targeted gene(s)/phenotype under study :

  • CLCN7 – without osteopetrosis

Abstract :

Individuals with loss-of-function CLCN7 variants in known to develop autosomal recessive or autosomal dominant osteopetrosis. Recently Nicoli et al, however, described two children with the identical pathogenic de novo variant in CLCN7 showing cutanous albinism, delayed myelination and development, organomegaly, enteropathy and hypopigmentation, but no osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children.

We now have an additional case of an adult patient with a similar phenotype and a de novo CLCN7 variant. To further confirm the phenotype of this new syndrome we welcome additional cases.

Coordinating clinician/researcher: Lilian Bomme Ousager

Institution :

Department of Clinical Genetics

Odense University Hospital

Odense, Denmark

Contact : lilian.bomme.ousager@rsyd.dk

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project?

Expanding the phenotypic spectrum of the ZNF292- Associated neurodevelopmental disorder

Targeted gene(s)/phenotype under study :

  • ZNF292

Abstract :

Loss-of-function variants in the zinc finger protein 292 (ZNF292) gene have recently been described to cause a neurodevelopmental disorder characterized by developmental delay, intellectual disability and a variety of syndromic features (article by Mirzaa GM et al., 2020, Genetics in Medicine). Our aim is to expand the knowledge on this disorder by describing the phenotypic spectrum of additional patients with variants in the ZNF292 gene as well as studying the inheritance mode of this syndrome.

Coordinating clinician/researcher: Miriam Bertrand

Institution :

Institute of Medical Genetics and Applied Genomics,

University of Tübingen,

72076 Tübingen, Germany

Contact : miriam.bertrand@med.uni-tuebingen.de

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project?

06/07/2020 – CHAMP1 Clinical Spectrum (MRD40 – OMIM 616579)

Targeted gene(s)/phenotype under study :

  • CHAMP1

Abstract :

A very small number of patients have been reported with heterozygous LOF variants in CHAMP1 (Tanaka 2016, Isidor 2016, Hempel 2015). CHAMP1 is involved in spindle assembly checkpoint, which assures proper kinetochore-microtubule attachment of all chromosomes prior to anaphase. LOF causes e.a. abnormal spindle orientation and formation of multipolar spindles. The patients present with hypotonia and joint laxity, microcephaly, moderate to severe intellectual disability with absent or very poor speech acquisition, and variable dysmorphism with, epicanthal folds, upslanting palpebral fissures, tented upper lip, everted lower lip and pointed chin. Mild brain atrophy, cerebellar cortical dysplasia and delayed myelination are seen. Departing from 2 local patients, we aim at building an European cohort of CHAMP1 patients, in order to better delineate the clinical spectrum, the neurodevelopmental profile and developmental brain anomalies, considering interactions of CHAMP1 with several MCPH genes.

Coordinating clinician: Pr Alain Verloes

Institution: 

Department of Clinical Genetics

APHP Robert Debré University Hospital

75019 Paris

France

Contact: alain.verloes@aphp.fr

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: N

Resampling of patients: N

Linked to a translational/basic research project? N

26/06/2020 – Syntelencephaly cohort

Targeted gene(s)/phenotype under study : Syntelencephaly

Abstract :

We are currently collecting clinical and brain MRI data of patients with syntelencephaly, the aim is to provide novel insight into the correlation of the brain MRI with the neurological symptoms, neurodevelopment and genotype-phenotype correlations. As syntelencephaly is a very rare form of holoprosencephaly, your collaboration would be of great help, thanks a lot!

Coordinating clinician/researcher: Dr. Alinoë Lavillaureix

Institution :

  • Department of Clinical Genetics, CHU Rennes, France

Contact : Alinoe.lavillaureix@chu-rennes.fr

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project?

23/06/2020 – QRICH1 related disorders

Targeted gene(s)/phenotype under study : QRICH1

Abstract :

De novo pathogenic variants of QRICH1 (Glutamine-rich protein 1, OMIM #617387) has recently been described in five patients (Ververi et al. 2018; Lui et al. 2019). The variants have been associated with developmental delay and intellectual disability, mild facial dysmorphism and chondrodysplasia in some cases. Through Gene Matcher (Genematcher.org) we have now identified 19 further patients with QRICH1-variants. Currently, we are in the process of defining the phenotype-genotype spectrum of QRICH1-related disorders in the patient cohort (a total of 24 including the published cases) and preparing a manuscript. We welcome further cases to this study to reach a better understanding of this rare disorder. We aim to close inclusion of further cases 15th July 2020.

Coordinating clinician/researcher: Zeynep Tümer

Institution :

Kennedy Center,

Department of Clinical Genetics,

Copenhagen University Hospital, Rigshospitalet,

Copenhagen, Denmark

Contact : tumer@regionh.dk

Specific requirements beyond clinical data and genotype data sharing:

  • Re-analysis of DNA samples : N
  • Resampling of patients : N
  • Linked to a translational/basic research project?

22/06/2020 – Further delineate the clinical and molecular spectrum of recessive pathogenic SLC6A9 variants

Targeted gene(s)/phenotype under study : 

  • SLC6A9

Abstract :

Up to date 6 patients have been reported with recessive pathogenic SLC6A9 variants, responsible for Glycine transporter 1 encephalopathy (OMIM# 617301; glycine encephalopathy with normal serum glycine, GLYT1 transporter dysfunction, and nonketotic hyperglycinemia). Patients present with neonatal respiratory failure, inital hypotonia followed by limb hypertonia, severe developmental delay, arthrogryposis, startle like responses to noise or tactile stimulation and similar dysmorphic features. CSF levels of glycine are mildly elevated in these patients, whereas serum glycine levels are normal.

We have recently identified 3 novel patients from 2 unrelated families with pathogenic SLC6A9 recessive variants and consistent phenotype. With the help of GeneDx, another patient has been identified. We aim to find more families to collect clinical and molecular data, pictures, cerebral imaging, biochemical results, in order to publish a new series of patients to further delineate this genetic disease.

Coordinating clinician: Dr Sandra WHALEN

Institution: 

Clinical Genetics Departement

APHP – Armand Trousseau Hospital

26 Avenue du Dr Arnold Netter

75012 Paris -France

Contact: sandra.whalen@aphp.fr

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: N

Resampling of patients: N

Linked to a translational/basic research project? N

22/06/2020 – IQSEC2-related phenotype

Targeted gene(s)/phenotype under study : 

  • IQSEC2

Abstract :

: IQSEC2 is a new gene related to an X-linked intellectual disability, characterized by a highly variable phenotype partially overlapping Rett syndrome. To date the mechanisms underlying this broad clinical variability are not fully understood both in male and female patients. The aim of this study is to collect clinical and molecular data of patients harbouring a mutation in IQSEC2 gene in order to better define the clinical wide spectrum of IQSEC2 gene related phenotype.

Coordinating clinician: Pr Alessandra Renieri

Institution: U.O.C. Genetica Medica, Università di Siena – Dipartimento di Biotecnologie Mediche; Azienda Ospedaliera
Universitaria Senese – Ospedale Santa Maria alle Scotte
Viale Mario Bracci, 53100 SIENA, ITALY

Contact: alessandra.renieri@unisi.it

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: N

Resampling of patients: N

Linked to a translational/basic research project? N

09/06/2020 – Neurodevelopmental delay associated with KDM6B gene variants: description of the clinical and neurological phenotype

Targeted gene(s)/phenotype under study : 

  • KDM6B

Abstract :

It has been described recently that variations in the KDM6B gene cause a neurodevelopmental disorder characterized by motor and speech delay of variable severity, often associated with mild facial peculiarities and skeletal anomalies (article by Stolerman ES et al., 2019, American Journal of Medical Genetics). Our goal is to expand the knowledge on this syndrome, and in particular on its neurological features, by collecting clinical information on novel patients diagnosed with KDM6B defects. At present, we cannot anticipate whether future research might be able to develop specific therapeutic strategies. In the short term, however, collecting and studying clinical data from new patients is expected to result in an earlier diagnosis and a better, specifically tailored assistance for individuals affected by this condition.

We would like to gather the clinical data, the brain MRI CDs and the EEGs in order to see whether there is a neuroradiological and EEG phenotype.

For the moment the protocol is available only in Italian, but the English version will be issued as soon as possible. The recruitment form is bi-lingual, in Italian and in English.

Coordinating clinician: Dr Livia Garavelli

Institution:

AUSL Reggio-Emilia

Dipartimento  Materno-Infantile

AUSL IRCCS  Arcispedale S.Maria Nuova

Viale Risorgimento, 80

42123-Reggio Emilia ITALY

Contact: livia.garavelli@ausl.re.it

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: N

Resampling of patients: N

Linked to a translational/basic research project? Y

26/05/2020 – Search for patients with Pai/OAFNS syndrome

Targeted gene(s)/phenotype under study : 

  • Pai/OAFNS syndrome, ideally after negative exome

Abstract :

The Solve-RD project is aiming at identifying genes in diseases resistant to exome sequencing. Pai and OAFNS are overlapping syndromes, belonging to the unsolvable cohorts in solve-RD, taking into account that exomes have remained negative in a number of patients. Multiomics are proposed to identify the molecular bases of these entities. New samples are required, including blood, urine and saliva of the proband and parents, and ideally tissue of affected area if available.

Coordinating clinician: Pr Laurence FAIVRE

Institution: CHU Dijon  (France)

Contact: laurence.faivre@chu-dijon.fr

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: N

Resampling of patients: Y

Linked to a translational/basic research project? Y, Solve-RD

05/05/2020 – YY1 related disorder : clinical phenotype, neuropsychological profile, brain MRI characteristics and epigenetic signatures

Targeted gene(s)/phenotype under study : 

  • Gene YY1, Orphanet number: 506358, OMIM: 600013; Gabriele-de-Vries syndrome OMIM: 617557
  • Clinical phenotype
  • Neuropsychological study based on WISC/WAIS standard tests
  • Brain MRI characteristic
  • Epigenetic signature on blood DNA samples in collaboration with Bekim SADICOVIK (London CANADA)

YY1 related disorder, also known as Gabriele-de-Vries syndrome, is mainly characterised by developmental delay (DD) and intellectual disability (ID), ranging from mild to severe, and neuroimaging abnormalities.

The aims of this study are first to better delineate the clinical phenotype, as well as the neuropsychological profile, and the brain MRI characteristics; and, second, to study the epigenetic signatures in a cohort of individuals with YY1 intragenic pathogenic variants. This work will conduct to a MD thesis of a clinical geneticist resident in France.

We will happy to collaborate with physician from the ERN ITHACA consortium.

Physician will fill an Excel sheet regarding the clinical and neuropsychological assessment. We will be also happy to have either CD-ROM or a link to have access to the brain MRI data as well as a DNA sample with a minimum 0.5ug of peripheral blood genomic DNA. We will gather the DNA in Montpellier genetic lab (Dr Mouna BARAT) and send the batch to the Dr Sadikovic’ lab.

Between 2019 and 2020, we have already recruited data from individuals with YY1 pathogenic variants from several European and American genetic centres.

Coordinating clinician: Pr David GENEVIEVE, MD, PhD

Institution: Genetic Department for rare disease and personalised medicine

Arnaud de VILLENEUVE Hospital : 371 Doyen G Giraud Avenue  34000 Montpellier

Contact: d-genevieve@chu-montpellier.fr

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: Y

Resampling of patients: N

Linked to a translational/basic research project? N

05/05/2020 – CDK13 related disorder : clinical phenotype, neuropsychological profile, brain MRI characteristics and epigenetic signatures

Targeted gene(s)/phenotype under study : 

Ideally patients with the triad, including:

  • Gene CDK13, no Orphanet number, OMIM : 663309 CHDFIDD disorder OMIM : 617360
  • Clinical phenotype better delineation
  • Neuropsychological study based on WISC/WAIS standard tests
  • Brain MRI characteristic
  • Epigenetic signature on blood DNA samples in collaboration with Bekim SADICOVIK (London CANADA)

CDK13 related disorder, also known as CHDFIDD disorder, is mainly characterised by developmental delay (DD) and intellectual disability (ID), ranging from mild to severe, and and visceral malformations.

The aims of this study are first to better delineate the clinical phenotype, as well as the neuropsychological profile, and the brain MRI characteristics; and, second, to study the epigenetic signatures in a cohort of individuals with YY1 intragenic pathogenic variants. This work will conduct to a work for genetic degree of a clinical geneticist resident in France.

We will happy to collaborate with physician from the ERN ITHACA consortium.

Physician will fill an Excel sheet regarding the clinical and neuropsychological assessment. We will be also happy to have either CD-ROM or a link to have access to the brain MRI data as well as a DNA sample with a minimum 0.5ug of peripheral blood genomic DNA. We will gather the DNA in Montpellier genetic lab (Dr Mouna BARAT) and send the batch to the Dr Sadikovic’ lab.

Coordinating clinician: Pr David GENEVIEVE, MD, PhD

Institution: Genetic Department for rare disease and personalised medicine

Arnaud de VILLENEUVE Hospital : 371 Doyen G Giraud Avenue  34000 Montpellier

Contact: d-genevieve@chu-montpellier.fr

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: Y

Resampling of patients: N

Linked to a translational/basic research project? N

05/05/2020 – Search for patients with Wildervanck syndrome

Targeted gene(s)/phenotype under study : 

Ideally patients with the triad, including:

    • cervical vertebral fusion (Klippel-Feil anomaly)
    • bilateral abducens palsy with retracted eyes (Duane syndrome)
    • congenital hearing loss (perceptive and/or transmission)

The Solve-RD project is aiming at identifying genes in diseases resistant to exome sequencing. Genome analyses are proposed in a cohort of patients with Wildervank syndrome. If DNA is available, there is no need for resampling. Patients with the triad are missing and your collaboration will be highly appreciated. You can also contact us if only two of the three typical signs are available.

Coordinating clinician:  Pr Laurence Faivre

Institution:  CHU Dijon/France

Contact: laurence.faivre@chu-dijon.fr

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: Y

Resampling of patients: N

Linked to a translational/basic research project? Y

28/04/2020 – Understanding the New BRD4-related Syndrome

Targeted gene(s)/phenotype under study :  BRD4-related Cornelia de Lange-like syndrome

To date, only four patients have been reported in the literature with BRD4 point mutations. However, a small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.12 deletions overlapping BRD4, since nine patients are described. Interestingly, they share a characteristic phenotype including growth retardation, microcephaly, intellectual disability, cardiac defects and a facial dysmorphism suggestive of Cornelia de Lange-like spectrum disorder. To characterize this new syndrome with a cohort study, we are collecting new patients with BRD4 point mutations or deletions of the region 19:15347647-15443356, GrCH37. This collaborative study will contribute to a better delineation of the clinical spectrum associated with BRD4, while providing sufficient clinical and molecular data to investigate clinically relevant genotype-phenotype correlations.

Coordinating clinician:  Dr Guillaume Jouret

Institution:  National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg

Contact: Guillaume.Jouret@lns.etat.lu

Specific requirements beyond clinical data and genotype data sharing:

Re-analysis of DNA samples: N

Resampling of patients: N

Linked to a translational/basic research project? N

Networking support scheme (nss)

The objective of the ejp-rd’s networking support scheme (nss) is to encourage the knowledge sharing on rare diseases and rare cancers between healthcare professionals, researchers and patients.

This call also aims to enable and/or increase the participation of traditionally under-represented european countries in new and existing research networks.

The programme will provide financial support to applicants to foster the organisation of workshops or conferences on new or existing/expanding research networks to strengthen collaborations and to enable the exchange of knowledge.

These workshops or conferences must focus on innovative research and solutions, and on strengthening collaborations between different stakeholders. The number of participants is not limited, but the maximum budget that can be requested is eur 30 000.

The call for applications is open continuously. More information here