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The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease

Eleanor Broeren1, Vanessa Gitau1, Alicia Byrne1

  • 1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States.

Medrxiv : the Preprint Server for Health Sciences
|November 28, 2024
PubMed

Insights

The ClinGen Syndromic Disorders Expert Panel curated 111 gene-disease relationships for 100 genes, classifying 78 as definitive. This work enables clinical testing for rare genetic syndromes.

Area of Science:

  • Genetics
  • Genomic Medicine
  • Rare Diseases

Background:

  • Clinical Genome Resource (ClinGen) Gene Curation Expert Panels (GCEPs) traditionally focused on organ-specific or phenotype-specific disorders.
  • An unmet need existed for expert curation of genes associated with syndromic disorders, which often affect multiple organ systems.

Purpose of the Study:

  • To establish the ClinGen Syndromic Disorders GCEP (SD-GCEP) to address the need for syndromic disorder gene curation.
  • To apply ClinGen's established framework for evaluating the clinical validity of genes linked to rare syndromic conditions.

Main Methods:

  • Evaluated 111 gene-disease relationships (GDRs) involving 100 genes associated with syndromic disorders.
  • Performed 38 precurations to clarify if disorders represented a spectrum or distinct entities, leading to gene reclassification.
  • Classified the clinical validity of GDRs into Definitive, Strong, Moderate, and Limited categories based on available evidence.

Main Results:

  • Reviewed 111 GDRs for 100 genes, classifying 78 as Definitive, 9 as Strong, 15 as Moderate, and 9 as Limited.
  • Reclassified 38 genes: 14 consolidated into single disease entities, and 24 split into separate entities (11 curated by SD-GCEP).
  • Confirmed that all evaluated syndromic disorders affected at least two organ systems, with 79.2% affecting five or more.

Conclusions:

  • The SD-GCEP successfully addresses a critical gap in gene curation for syndromic disorders.
  • This curation facilitates the inclusion of genes for syndromic conditions in clinical genetic testing.
  • Efforts support keeping pace with the rapid discovery of new genetic syndromes and their associated genes.
Abstract

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