Recurrent copy number variations as risk factors for autism spectrum disorders: analysis of the clinical implications

Abstract

Chromosomal microarray analysis (CMA) is currently considered a first-tier diagnostic assay for the investigation of autism spectrum disorders (ASD), developmental delay and intellectual disability of unknown etiology. High-resolution arrays were utilized for the identification of copy number variations (CNVs) in 195 ASD patients of Greek origin (126 males, 69 females). CMA resulted in the detection of 65 CNVs, excluding the known polymorphic copy number polymorphisms also found in the Database of Genomic Variants, for 51/195 patients (26.1%). Parental DNA testing in 20/51 patients revealed that 17 CNVs were de novo, 6 paternal and 3 of maternal origin. The majority of the 65 CNVs were deletions (66.1%), of which 5 on the X-chromosome while the duplications, of which 7 on the X-chromosome, were rarer (22/65, 33.8%). Fifty-one CNVs from a total of 65, reported for our cohort of ASD patients, were of diagnostic significance and well described in the literature while 14 CNVs (8 losses, 6 gains) were characterized as variants of unknown significance and need further investigation. Among the 51 patients, 39 carried one CNV, 10 carried two CNVs and 2 carried three CNVs. The use of CMA, its clinical validity and utility was assessed.

Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features

“…To date, only two interstitial deletion CNVs involving TRIP12 [MIM 604506], encoding a member of the HECT domain E3 ubiquitin ligases family, have been reported in the literature: a de novo ~ 5.4 Mb CNV deletion on 2q36.2q36.3 has been identified in an individual with severe intellectual disability (ID), multiple renal cysts, and dysmorphic features (Doco-Fenzy et al 2008) and a de novo ~ 60 kb deletion involving FBXO36 and the first non-coding exon of TRIP12 has been described in a subject with an autistic spectrum disorder (Pinto et al 2014). An ~ 180 kb CNV duplication encompassing FBXO36 and the 5′ portion of TRIP12 has been reported in an individual with macrocephaly (Figure 1a) (Oikonomakis et al 2016). Recently, four TRIP12 de novo single nucleotide variants have been identified amongst 64 autism spectrum disorders (ASDs) candidate genes re-sequenced in 5,979 individuals; two missense and two truncating variants were detected in individuals with ASDs and ID, ranging from mild to moderate severity (O’Roak et al 2014).…”

Clinical and Molecular Characteristics of Mitochondrial Dysfunction in Autism Spectrum Disorder

“…Although it has been estimated that the genetic etiology of ASD may account for up to 40% of cases [ 83 , 84 ] and whole exome sequencing (WES) and chromosomal microarray analysis (CMA) studies have reported yields up to 30% [ 85 ] and 26% [ 86 ], respectively, separate clinical studies have failed to confirm this high rate of genetic disorders in children with ASD. For example, a study from Canada found that 9.3% and 8.4% of children with ASD received a molecular diagnosis using WES and CMA, respectively, resulting in only 15.8% of children with ASD receiving a molecular diagnosis [ 84 ].…”

Chromosomal microarray analysis in a cohort of underrepresented population identifies SERINC2 as a novel candidate gene for autism spectrum disorder

“…However, it is difficult to directly compare such diagnostic yields among studies due to the use of different inclusion criteria for diagnostic yields. Some studies report diagnostic yields from only pathogenic CNVs 4 , 8 , 11 , 13 – 18 , 20 , 22 , 24 , 26 , 28 , 29 , 32 , while others include combined pathogenic CNVs and likely pathogenic CNVs 10 , 23 , 25 , 30 or combined pathogenic CNVs and VOUS 12 , 19 , 21 , 27 . In addition, previous studies have had different inclusion criteria for participating patients and used various microarray platforms with different resolutions.…”