The clinical significance of small copy number variants in neurodevelopmental disorders

Abstract

BackgroundDespite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context.MethodsBy high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1–500 kb in a cohort of 714 patients with undiagnosed NDDs.ResultsWe detected 96 rare CNVs <500 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 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear.ConclusionsThese results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions.

Clinical relevance of small copy-number variants in chromosomal microarray clinical testing

“…14,15 It maps to the 5p region that is deleted in Cri du Chat syndrome and has been implicated in developmental delay, intellectual disability, autism, and schizophrenia. 7,16,17 Patient 13167 was noted to have a 145-kb deletion that encompasses exon 2 of CTNND2 (Figure 1b) together with a recurrent 15q11.2 BP1-BP2 microduplication. This 13-month-old boy presented with central and obstructive sleep apnea, mild developmental delay, and partial complex seizures.…”

“…Recent efforts have been made to understand the role of these small, nonrecurrent CNVs in neurodevelopmental disorders. [7][8][9] In this study we evaluate the role of these small, nonrecurrent CNVs (<500 kb) in a cohort of 4,417 patients referred to our lab to determine the overall significance of these CNVs in patients undergoing CMA clinical testing for developmental Submitted Purpose: The 2010 consensus statement on diagnostic chromosomal microarray (CMA) testing recommended an array resolution ≥400 kb throughout the genome as a balance of analytical and clinical sensitivity. In spite of the clear evidence for pathogenicity of large copynumber variants (CNVs) in neurodevelopmental disorders and/or congenital anomalies, the significance of small, nonrecurrent CNVs (<500 kb) has not been well established in a clinical setting.…”

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

“…The literature supports this observation on the basis of historic CdCS studies, as well as more recent observations, in that duplication of 5 0 CTNND2 and deletion of the 3 0 portion of the gene in a CdCS patient is hypothesized to result in amelioration of the cognitive phenotype [Sardina et al, 2014]. Small exonic deletions of CTNND2 have also been reported in individuals with low normal IQ and learning problems with or without autistic features or developmental delay [Asadollahi et al, 2014]. In addition, a recent study identified that deleterious variants in the CYFIP1, DLG1, PLXNA3, and CTNND2 genes are enriched in severely affected patients in female-enriched multiplex families (FEMFs) with severe autism and demonstrated the loss-of-function effect of CTNND2 in autism and neurodevelopment by in vivo and in vitro functional analyses [Turner et al, 2015].…”

Can genetic research motivate parents to pursue genomic testing for children with autism spectrum disorder?

“…Professionals involved with this project can analyze a bank of test results recorded from patients to identify previously unidentified mutated genes which may contribute to the cause of ASD and other genetic disorders [5,6]. By identifying and recording new candidate genes, the genetic causes that underlie ASD can be more accurately described and better understood [16]. Thus far, the collection of this data has been useful in detecting and describing new CNVs, which can ultimately influence future diagnosis and treatment [17,18].…”