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

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