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[Preprint]. 2024 Nov 20:2024.11.19.24317561.
doi: 10.1101/2024.11.19.24317561.

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

Eleanor Broeren  1 , Vanessa Gitau  1 , Alicia Byrne  1 , Pamela Ajuyah  1 , Marie Balzotti  2 , Jonathan Berg  3 , Krista Bluske  4   5 , B Monica Bowen  6 , Matthew P Brown  4 , Amanda Buchanan  7 , Brendan Burns  4 , Nicole J Burns  4   8 , Anjana Chandrasekhar  4   8 , Aditi Chawla  4 , Jessica Chong  9   10 , Maya Chopra  11 , Amanda Clause  4   12 , Marina DiStefano  1 , Stephanie DiTroia  1 , Marwa Elnagheeb  3 , Amanda Girod  1 , Himanshu Goel  13 , Katie Golden-Grant  4   14 , Thuong Ha  15   16   17 , Ada Hamosh  18 , Jennifer Huang  5 , Madeline Hughes  1 , Saumya Jamuar  19   20   21 , Sylvia Kam  19   20 , Akanchha Kesari  4 , Ai Ling Koh  19   20 , Rhonda Lassiter  5 , Sarah Leigh  22 , Gabrielle Lemire  1   23   24 , Jiin Ying Lim  19   20 , Alka Malhotra  4 , Hannah McCurry  1 , Becky Milewski  4   25 , Shahida Moosa  26   27 , Stephen Murray  28 , Emma Owens  3 , Emma Palmer  29 , Brooke Palus  3 , Mayher Patel  1 , Revathi Rajkumar  4 , Julie Ratliff  1 , F Lucy Raymond  30 , Bruno Della Ripa Rodrigues Assis  31 , Samin Sajan  32   33 , Zinayida Schlachetzki  4   34 , Sarah Schmidt  4   35 , Zornitza Stark  36   37   38 , Samuel Strom  4   39 , Julie Taylor  4 , Courtney Thaxton  3 , Devon Thrush  5 , Sabrina Toro  3 , Kezang Tshering  1 , Nicole Vasilevsky  40 , Bess Wayburn  5 , Ryan 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 Broeren et al. medRxiv. .

Update in

  • The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the clinical validity of 111 gene-disease relationships.
    Broeren EC, Gitau VN, Byrne AB, Ajuyah P, Balzotti MB, Berg JS, Bluske K, Bowen BM, Brown MP, Buchanan A, Burns BT, Burns NJ, Chandrasekhar A, Chawla A, Chong JX, Chopra M, Clause AR, DiStefano MT, DiTroia S, Elnagheeb MA, Girod AN, Goel H, Golden-Grant KL, Ha T, Hamosh A, Huang JM, Hughes MY, Jamuar SS, Kam S, Kesari A, Koh AL, Lassiter RNT, Leigh SE, Lemire G, Lim JY, Malhotra A, McCurry HR, Milewski B, Moosa S, Murray SA, Owens EH, Palmer EE, Palus BC, Patel MJ, Rajkumar R, Ratliff JC, Raymond FL, Della Ripa Rodrigues Assis B, Sajan SA, Schlachetzki Z, Schmidt SA, Stark Z, Strom SP, Taylor JP, Thaxton C, Thrush DL, Toro S, Tshering KC, Vasilevsky NA, Wayburn B, Webb RF, O'Donnell-Luria A, Coffey AJ. Broeren EC, et al. Genet Med Open. 2025 Apr 9;3:103429. doi: 10.1016/j.gimo.2025.103429. eCollection 2025. Genet Med Open. 2025. PMID: 40496713 Free PMC article.

Abstract

Purpose: The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels (GCEPs) have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders GCEP (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. 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. 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 where further data are needed. All diseases involved two or more organ systems, while the majority (88/111 GDRs, 79.2%) had five 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.

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Conflict of interest statement

Conflict of Interest K.B., M.P.B., B.T.B., N.J.B., An.C., Ad.C., A.R.C, K.L.G., A.K., A.M., R.R., Z.Sc., J.P.T., A.J.C. are current or former employees and shareholders of Illumina Inc. K.B., J.M.H., D.L.T., B.W. are employees of Ambry Genetics. K.L.G. is an employee of Rady Children’s Institute for Genomic Medicine. SSJ is the co-founder of Global Gene Corporation Pte Ltd. J.P.T is an employee of Blueprint Genetics (a Quest company). AODL was a paid consultant for Tome Biosciences, Ono Pharma USA, and Addition Therapeutics and receives 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 - 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 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 five 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 SD-GCEP): 33 Definitive, 4 Strong, 6 Moderate, 5 Limited; Approach 3 (14 genes - new GDRs from research consortia including NHGRI’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.
Figure 1.
Figure 1.. Precurations and curations performed from April 2020 - 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 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 five 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 SD-GCEP): 33 Definitive, 4 Strong, 6 Moderate, 5 Limited; Approach 3 (14 genes - new GDRs from research consortia including NHGRI’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.
Figure 2.
Figure 2.. SD-GCEP 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). GDRs where 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.
Figure 2.
Figure 2.. SD-GCEP 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). GDRs where 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.
Figure 3.
Figure 3.. 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 two or more organ systems, while the majority (88/111 GDRs, 79.2%) had five or more organ systems affected.
Figure 4.
Figure 4.
Exchange and collaboration on GDR curations between SD-GCEP and other GCEPs to date.
See this image and copyright information in PMC

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