# The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the clinical validity of 111 gene-disease relationships

## TL;DR

This paper describes a new expert panel that evaluates genes linked to rare syndromic disorders, improving clinical testing and understanding of complex genetic conditions.

## Contribution

The paper introduces a dedicated panel for curating genes associated with syndromic disorders, addressing a gap in clinical genetic testing.

## Key findings

- 111 gene-disease relationships were curated, with 78 classified as Definitive and 15 as Moderate.
- 38 precurations led to 14 genes being grouped into one disease and 24 split into distinct entities.
- Most curated gene-disease relationships involved five or more organ systems.

## Abstract

The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders Gene Curation Expert Panel (SD-GCEP) was formed to address an unmet need.

The SD-GCEP applied ClinGen’s framework to evaluate the clinical validity of genes associated with rare syndromic disorders. A total of 111 gene-disease relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated.

From April 2020 through March 2024, 38 precurations were performed on genes with multiple disease relationships and were reviewed to determine if the disorders were part of a spectrum or distinct entities. A total of 14 genes were lumped into a single disease entity, and 24 were split into separate entities, of which 11 were curated by the SD-GCEP. A full review of 111 GDRs for 100 genes followed, with 78 classified as Definitive, 9 as Strong, 15 as Moderate, and 9 as Limited, highlighting cases in which further data are needed. All diseases involved 2 or more organ systems, whereas the majority (88/111 GDRs, 79.2%) had 5 or more organ systems affected.

The SD-GCEP addresses a critical gap in gene curation efforts, enabling inclusion of genes for syndromic disorders in clinical testing and contributing to keeping pace with the rapid discovery of new genetic syndromes.