The clinical significance of small copy number variants in neurodevelopmental disorders.
J Med Genet
; 51(10): 677-88, 2014 Oct.
Article
em En
| MEDLINE
| ID: mdl-25106414
ABSTRACT
BACKGROUND:
Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500â kb has not been well elucidated in a clinical context.METHODS:
By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500â kb in a cohort of 714 patients with undiagnosed NDDs.RESULTS:
We detected 96 rare CNVs <500â kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130â kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear.CONCLUSIONS:
These results verify the diagnostic relevance of genome-wide rare CNVs <500â kb, which were found pathogenic in â¼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Deficiências do Desenvolvimento
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Variações do Número de Cópias de DNA
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article