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Clinical significance of de novo and inherited copy-number variation

Vulto-van Silfhout, Anneke T., Hehir-Kwa, Jayne Y., van Bon, Bregje W. M., Schuurs-Hoeijmakers, Janneke H M., Meader, Stephen, Hellebrekers, Claudia J. M., Thoonen, Ilse J. M., de Brouwer, Arjan P. M., Brunner, Han G., Webber, Caleb ORCID:, Pfundt, Rolph, de Leeuw, Nicole and De Vries, Bert B. A. 2013. Clinical significance of de novo and inherited copy-number variation. Human Mutation 34 (12) , pp. 1679-1687. 10.1002/humu.22442

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Copy‐number variations (CNVs) are a common cause of intellectual disability and/or multiple congenital anomalies (ID/MCA). However, the clinical interpretation of CNVs remains challenging, especially for inherited CNVs. Well‐phenotyped patients (5,531) with ID/MCA were screened for rare CNVs using a 250K single‐nucleotide polymorphism array platform in order to improve the understanding of the contribution of CNVs to a patients phenotype. We detected 1,663 rare CNVs in 1,388 patients (25.1%; range 0–5 per patient) of which 437 occurred de novo and 638 were inherited. The detected CNVs were analyzed for various characteristics, gene content, and genotype–phenotype correlations. Patients with severe phenotypes, including organ malformations, had more de novo CNVs (P < 0.001), whereas patient groups with milder phenotypes, such as facial dysmorphisms, were enriched for both de novo and inherited CNVs (P < 0.001), indicating that not only de novo but also inherited CNVs can be associated with a clinically relevant phenotype. Moreover, patients with multiple CNVs presented with a more severe phenotype than patients with a single CNV (P < 0.001), pointing to a combinatorial effect of the additional CNVs. In addition, we identified 20 de novo single‐gene CNVs that directly indicate novel genes for ID/MCA, including ZFHX4, ANKH, DLG2, MPP7, CEP89, TRIO, ASTN2, and PIK3C3.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley
ISSN: 1059-7794
Date of Acceptance: 30 August 2013
Last Modified: 09 Nov 2022 09:27

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