Lumping Versus Splitting: How to Approach Defining a Disease to Enable Accurate Genomic Curation

Overview

Journal Cell Genom

Date 2022 Jun 27

PMID 35754516

Authors

Courtney Thaxton

Jennifer Goldstein

Marina DiStefano

Kathleen Wallace

P Dane Witmer

Melissa A Haendel

Ada Hamosh

Heidi L Rehm

Jonathan S Berg

Affiliations

Soon will be listed here.

Abstract

The dilemma of how to categorize and classify diseases has been debated for centuries. The field of medical genetics has historically approached nosology based on clinical phenotypes observed in patients and families. Advances in genomic sequencing and understanding of genetic contributions to disease often provoke a need to reassess these classifications. The Clinical Genome Resource (ClinGen) has developed frameworks to classify the strength of evidence underlying monogenic gene-disease relationships, variant pathogenicity, and clinical actionability. It is therefore necessary to define the disease entity being evaluated, which can be challenging for genes associated with multiple conditions and/or a broad phenotypic spectrum. We therefore developed criteria to guide "lumping and splitting" decisions and improve consistency in defining monogenic gene-disease relationships. Here, we outline the precuration process, the lumping and splitting guidelines with examples, and describe the implications for clinical diagnosis, informatics, and care management.

Citing Articles

Systematic gene-disease relationship (GDR) curation unveils 61 gene-disease associations and highlights the impact on genetic testing.

Zonic E, Ferreira M, Pardo L, Martini J, Rocha M, Aanicai R Genet Med Open. 2024; 1(1):100833.

PMID: 39669245 PMC: 11613557. DOI: 10.1016/j.gimo.2023.100833.

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 medRxiv. 2024; .

PMID: 39606380 PMC: 11601709. DOI: 10.1101/2024.11.19.24317561.

Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping.

Henderson D, Alqahtani A, Chaudhry B, Cook A, Eley L, Houyel L Dis Model Mech. 2024; 17(11).

PMID: 39575509 PMC: 11603121. DOI: 10.1242/dmm.050913.

Assessment of genes involved in lysosomal diseases using the ClinGen clinical validity framework.

Groopman E, Mohan S, Waddell A, Wilke M, Fernandez R, Weaver M Mol Genet Metab. 2024; 143(3):108593.

PMID: 39426251 PMC: 11560485. DOI: 10.1016/j.ymgme.2024.108593.

Phenotypic spectrum of dual diagnoses in developmental disorders.

Ridsdale A, Dickerson A, Chundru V, Firth H, Wright C Am J Hum Genet. 2024; 111(11):2382-2391.

PMID: 39353430 PMC: 11568748. DOI: 10.1016/j.ajhg.2024.08.025.

References

Bagnall R, Molloy L, Kalman J, Semsarian C . Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death. BMC Med Genet. 2014; 15:99. PMC: 4355500. DOI: 10.1186/s12881-014-0099-0. View

Sanbe A, Osinska H, Saffitz J, Glabe C, Kayed R, Maloyan A . Desmin-related cardiomyopathy in transgenic mice: a cardiac amyloidosis. Proc Natl Acad Sci U S A. 2004; 101(27):10132-6. PMC: 454177. DOI: 10.1073/pnas.0401900101. View

Plaza-Menacho I, Burzynski G, De Groot J, Eggen B, Hofstra R . Current concepts in RET-related genetics, signaling and therapeutics. Trends Genet. 2006; 22(11):627-36. DOI: 10.1016/j.tig.2006.09.005. View

Lynch H, Lynch P, Pester J, Fusaro R . The cancer family syndrome. Rare cutaneous phenotypic linkage of Torre's syndrome. Arch Intern Med. 1981; 141(5):607-11. View

Selcen D . Myofibrillar myopathies. Neuromuscul Disord. 2011; 21(3):161-71. PMC: 3052736. DOI: 10.1016/j.nmd.2010.12.007. View

Vatta M, Ackerman M, Ye B, Makielski J, Ughanze E, Taylor E . Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006; 114(20):2104-12. DOI: 10.1161/CIRCULATIONAHA.106.635268. View

Bean L, Funke B, Carlston C, Gannon J, Kantarci S, Krock B . Diagnostic gene sequencing panels: from design to report-a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019; 22(3):453-461. DOI: 10.1038/s41436-019-0666-z. View

Fee D, So Y, Barraza C, Figueroa K, Pulst S . Phenotypic variability associated with Arg26Gln mutation in caveolin3. Muscle Nerve. 2004; 30(3):375-8. DOI: 10.1002/mus.20092. View

Gertler T, Carvill G . : When Neurons Are So Excited, They Just Can't Hide It. Epilepsy Curr. 2019; 19(4):269-271. PMC: 6891829. DOI: 10.1177/1535759719858338. View

10.

Wimmer K, Kratz C, Vasen H, Caron O, Colas C, Entz-Werle N . Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). J Med Genet. 2014; 51(6):355-65. DOI: 10.1136/jmedgenet-2014-102284. View

11.

Biesecker L . Lumping and splitting: molecular biology in the genetics clinic. Clin Genet. 1998; 53(1):3-7. DOI: 10.1034/j.1399-0004.1998.531530102.x. View

12.

Schroder R, Schoser B . Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol. 2009; 19(3):483-92. PMC: 8094720. DOI: 10.1111/j.1750-3639.2009.00289.x. View

13.

Bordeaux M, Forcet C, Granger L, Corset V, Bidaud C, Billaud M . The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease. EMBO J. 2000; 19(15):4056-63. PMC: 306592. DOI: 10.1093/emboj/19.15.4056. View

14.

Stankovic T, Kidd A, Sutcliffe A, McGuire G, Robinson P, Weber P . ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998; 62(2):334-45. PMC: 1376883. DOI: 10.1086/301706. View

15.

Girolami F, Iascone M, Tomberli B, Bardi S, Benelli M, Marseglia G . Novel α-actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study. Circ Cardiovasc Genet. 2014; 7(6):741-50. DOI: 10.1161/CIRCGENETICS.113.000486. View

16.

Gueneau L, Bertrand A, Jais J, Salih M, Stojkovic T, Wehnert M . Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy. Am J Hum Genet. 2009; 85(3):338-53. PMC: 2771595. DOI: 10.1016/j.ajhg.2009.07.015. View

17.

Gazzerro E, Sotgia F, Bruno C, Lisanti M, Minetti C . Caveolinopathies: from the biology of caveolin-3 to human diseases. Eur J Hum Genet. 2009; 18(2):137-45. PMC: 2987183. DOI: 10.1038/ejhg.2009.103. View

18.

Windpassinger C, Schoser B, Straub V, Hochmeister S, Noor A, Lohberger B . An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet. 2008; 82(1):88-99. PMC: 2253986. DOI: 10.1016/j.ajhg.2007.09.004. View

19.

Pelet A, Geneste O, Edery P, Pasini A, Chappuis S, Atti T . Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease. J Clin Invest. 1998; 101(6):1415-23. PMC: 508697. DOI: 10.1172/JCI375. View

20.

Wagnon J, Barker B, Ottolini M, Park Y, Volkheimer A, Valdez P . Loss-of-function variants of in intellectual disability without seizures. Neurol Genet. 2017; 3(4):e170. PMC: 5499976. DOI: 10.1212/NXG.0000000000000170. View