Clinical Significance of De Novo and Inherited Copy-Number Variation

• Published in: Human mutation Vol. 34; no. 12; pp. 1679 - 1687
• Main Authors: 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, Pfundt, Rolph, de Leeuw, Nicole, de Vries, Bert B.A.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.12.2013; Hindawi Limited
• Subjects: Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; Adolescent; Child; Child, Preschool; Chromosome Mapping; CNV; Computational Biology - methods; copy number variation; DNA Copy Number Variations; Female; Genetic Association Studies; genotype-phenotype; human phenotype ontology; Humans; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Male; Phenotype; Polymorphism, Single Nucleotide; SNP; CNV; human phenotype ontology; SNP; copy number variation; genotype-phenotype
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22442

ABSTRACT 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. DNA samples from 5,531 patients with ID/MCA were analyzed with a 250K SNP array for detection of copy number variants (CNVs). Comparison of phenotype features of patients with de novo (yellow), inherited (red), and without CNVs (blue) showed that severe phenotypes, including abnormal head circumference and organ malformations, were enriched in patients with de novo CNVs, both in comparison to patients without CNVs as well as patients with inherited CNVs. Remarkably, patients with inherited CNVs had significantly more facial dysmorphisms and a higher De Vries score (measure of clinical severity) compared with patients without CNVs, suggesting that the milder clinical features can also be related to the presence of inherited CNVs.