Penetrance, variable expressivity and monogenic neurodevelopmental disorders.

de Masfrand, Servane; Cogné, Benjamin; Nizon, Mathilde; Deb, Wallid; Goldenberg, Alice; Lecoquierre, François; Nicolas, Gaël; Bournez, Marie; Vitobello, Antonio; Mau-Them, Frédéric Tran; le Guyader, Gwenaël; Bilan, Frédéric; Bauer, Peter; Zweier, Christiane; Piard, Juliette; Pasquier, Laurent; Bézieau, Stéphane; Gerard, Bénédicte; Faivre, Laurence; Saugier-Veber, Pascale; ... (2024). Penetrance, variable expressivity and monogenic neurodevelopmental disorders. European journal of medical genetics, 69, p. 104932. Elsevier 10.1016/j.ejmg.2024.104932

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PURPOSE

Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance.

METHOD

From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study.

RESULTS

We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with de novo variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2 and RERE. Grandparents have been tested in 6 families, and each time the variant was confirmed de novo in the healthy carrier parent.

CONCLUSION

Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Human Genetics

UniBE Contributor:

Zweier, Christiane Gertrud

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1878-0849

Publisher:

Elsevier

Language:

English

Submitter:

Pubmed Import

Date Deposited:

11 Mar 2024 16:19

Last Modified:

18 Jun 2024 00:13

Publisher DOI:

10.1016/j.ejmg.2024.104932

PubMed ID:

38453051

Uncontrolled Keywords:

Incomplete penetrance Intellectual disability Monogenic Neurodevelopmental disorder

BORIS DOI:

10.48350/194034

URI:

https://boris.unibe.ch/id/eprint/194034

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