Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr 9:3:103429.
doi: 10.1016/j.gimo.2025.103429. eCollection 2025.

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

Eleanor C Broeren  1 , Vanessa N Gitau  1 , Alicia B Byrne  1 , Pamela Ajuyah  1 , Marie B Balzotti  2 , Jonathan S Berg  3 , Krista Bluske  4   5 , B Monica Bowen  6 , Matthew P Brown  4 , Amanda Buchanan  4   7 , Brendan T Burns  4 , Nicole J Burns  4   8 , Anjana Chandrasekhar  4   8 , Aditi Chawla  4 , Jessica X Chong  9   10 , Maya Chopra  11 , Amanda R Clause  4   12 , Marina T DiStefano  1 , Stephanie DiTroia  1 , Marwa A Elnagheeb  3 , Amanda N Girod  1 , Himanshu Goel  13 , Katie L Golden-Grant  4   14 , Thuong Ha  15   16   17 , Ada Hamosh  18 , Jennifer M Huang  5 , Madeline Y Hughes  1 , Saumya S Jamuar  19   20   21 , Sylvia Kam  19   20 , Akanchha Kesari  4 , Ai Ling Koh  19   20 , Rhonda N T Lassiter  5 , Sarah E Leigh  22 , Gabrielle Lemire  1   23   24 , Jiin Ying Lim  19   20 , Alka Malhotra  4 , Hannah R McCurry  1 , Becky Milewski  4   25 , Shahida Moosa  26   27 , Stephen A Murray  28 , Emma H Owens  3 , Elizabeth E Palmer  29 , Brooke C Palus  3 , Mayher J Patel  1 , Revathi Rajkumar  4 , Julie C Ratliff  1 , F Lucy Raymond  30 , Bruno Della Ripa Rodrigues Assis  31 , Samin A Sajan  32   33 , Zinayida Schlachetzki  4   34 , Sarah A Schmidt  4   35 , Zornitza Stark  36   37   38 , Samuel P Strom  4   39 , Julie P Taylor  4 , Courtney Thaxton  3 , Devon L Thrush  5 , Sabrina Toro  3 , Kezang C Tshering  1 , Nicole A Vasilevsky  40 , Bess Wayburn  5 , Ryan F Webb  1 , Anne O'Donnell-Luria  23   1 , Alison J Coffey  41
Affiliations

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

Eleanor C Broeren et al. Genet Med Open. .

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: ClinGen; Gene curation; Gene-disease relationship; Rare disease; Syndromic disorders.

PubMed Disclaimer

Conflict of interest statement

Krista Bluske, Matthew P. Brown, Amanda Buchanan, Brendan T. Burns, Nicole J. Burns, Anjana Chandrasekhar, Aditi Chawla, Amanda R. Clause, Katie L. Golden-Grant, Akanchha Kesari, Alka Malhotra, Revathi Rajkumar, Zinayida Schlachetzki, Julie P. Taylor, Alison J. Coffey are current or former employees and shareholders of Illumina Inc. Krista Bluske, Jennifer M. Huang, Devon L. Thrush, Bess Wayburn are employees of Ambry Genetics. Katie L. Golden-Grant is an employee of Rady Children’s Institute for Genomic Medicine. Saumya S. Jamuar is the cofounder of Global Gene Corporation Pte Ltd. Julie P. Taylor is an employee of Blueprint Genetics (a Quest company). Anne O’Donnell-Luria was a paid consultant for Tome Biosciences, Ono Pharma USA, and Addition Therapeutics and received research funding from Pacific Biosciences. All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Precurations and curations performed from April 2020 to March 2024. A. Summary of lumping and splitting decisions for the 38 precurations performed to date. B. Summary of the final classifications for the 111 approved gene-disease relationship (GDR) classifications to date. C. Summary of mode of inheritance of the 111 approved GDRs to date. D. Summary of final classifications for GDRs across the 5 curation approaches. Approach 1 (38 genes: GDRs most frequently tested in clinical laboratories): 33 Definitive, 1 Strong, 2 Moderate, 2 Limited; Approach 2 (47 genes: GDRs through clinical genome or exome sequencing performed by diagnostic laboratories within the membership of the Syndromic Disorders Gene Curation Expert Panel [SD-GCEP]): 33 Definitive, 4 Strong, 6 Moderate, 5 Limited; Approach 3 (14 genes: new GDRs from research consortia, including National Human Genome Research Institute’s Centers of Mendelian Genomics and GREGoR consortium): 5 Definitive, 3 Strong, 4 Moderate, 2 Limited; Approach 4 (7 genes: GDRs requested by other GCEPs for phenotypes requiring the broad expertise of the SD-GCEP): 4 Definitive, 3 Moderate; Approach 5 (4 genes as of March 2024: syndromic GDRs in GenCC with Strong or Definitive classifications not curated by other GCEPs): 3 Definitive, 1 Strong. GenCC, Gene Curation Coalition; GREGoR, Genomics Research to Elucidate the Genetics of Rare diseases.
Figure 2
Figure 2
Syndromic Disorders Gene Curation Expert Panel curation evidence. A. The number of points awarded for genetic and experimental evidence for each gene represented by the bar height (blue = genetic evidence; green = experimental evidence). Gene-disease relationships (for which no animal model was available) are starred. B. The majority of genes (82%) had an animal model with 92% of sufficient quality and overlap with the human phenotype to be scored in the ClinGen curation framework. C. Mouse models were the predominant model organism scored. GenCC, Gene Curation Coalition.
Figure 3
Figure 3
Gene-disease relationship (GDRs) curated are highly syndromic in nature. HPO higher order terms representing the phenotypic features associated with each disease assertion were graphed by counting the number of HPO terms under each higher order term. For terms that were lumped, HPO terms for all of the assertions were combined and counted. All diseases involved 2 or more organ systems, whereas the majority (88/111 gene-disease relationships, 79.2%) had 5 or more organ systems affected. GenCC, Gene Curation Coalition; HPO, Human Phenotype Ontology.
Figure 4
Figure 4
Exchange and collaboration on gene-disease relationship curations between Syndromic Disorders Gene Curation Expert Panel (GCEP) and other GCEPs to date.
See this image and copyright information in PMC

Update of

  • The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships.
    Broeren E, Gitau V, Byrne A, Ajuyah P, Balzotti M, Berg J, Bluske K, Bowen BM, Brown MP, Buchanan A, Burns B, Burns NJ, Chandrasekhar A, Chawla A, Chong J, Chopra M, Clause A, DiStefano M, DiTroia S, Elnagheeb M, Girod A, Goel H, Golden-Grant K, Ha T, Hamosh A, Huang J, Hughes M, Jamuar S, Kam S, Kesari A, Koh AL, Lassiter R, Leigh S, Lemire G, Lim JY, Malhotra A, McCurry H, Milewski B, Moosa S, Murray S, Owens E, Palmer E, Palus B, Patel M, Rajkumar R, Ratliff J, Raymond FL, Assis BDRR, Sajan S, Schlachetzki Z, Schmidt S, Stark Z, Strom S, Taylor J, Thaxton C, Thrush D, Toro S, Tshering K, Vasilevsky N, Wayburn B, Webb R, O'Donnell-Luria A, Coffey AJ. Broeren E, et al. medRxiv [Preprint]. 2024 Nov 20:2024.11.19.24317561. doi: 10.1101/2024.11.19.24317561. medRxiv. 2024. Update in: Genet Med Open. 2025 Apr 09;3:103429. doi: 10.1016/j.gimo.2025.103429. PMID: 39606380 Free PMC article. Updated. Preprint.

References

    1. Christianson A., Howson C.P., Modell B. March of dimes global report on birth defects. March of Dimes Birth Defects Foundation. https://www.prevencioncongenitas.org/wp-content/uploads/2017/02/Global-r...
    1. Mathews T.J., Driscoll A.K. Vol. 279. NCHS Data Brief; 2017. pp. 1–8. (Trends in infant mortality in the United States, 2005-2014). - PubMed
    1. Chung C.C.Y., Ng N.Y.T., Ng Y.N.C., et al. Socio-economic costs of rare diseases and the risk of financial hardship: a cross-sectional study. Lancet Reg Health West Pac. 2023;34 doi: 10.1016/j.lanwpc.2023.100711. - DOI - PMC - PubMed
    1. Bamshad M.J., Nickerson D.A., Chong J.X. Mendelian gene discovery: fast and furious with no end in sight. Am J Hum Genet. 2019;105(3):448–455. doi: 10.1016/j.ajhg.2019.07.011. - DOI - PMC - PubMed
    1. Clause A.R., Taylor J.P., Rajkumar R., et al. Reactive gene curation to support interpretation and reporting of a clinical genome test for rare disease: experience from over 1,000 cases. Cell Genom. 2023;3(2) doi: 10.1016/j.xgen.2023.100258. - DOI - PMC - PubMed

LinkOut - more resources