Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

Abstract

Intellectual disability affects about 3% of individuals globally, withB50% idiopathic. We designed an exonic-resolution array targeting all known submicroscopic chromosomal intellectual disability syndrome loci, causative genes for intellectual disability, and potential candidate genes, all genes encoding glutamate receptors and epigenetic regulators. Using this platform, we performed chromosomal microarray analysis on 165 intellectual disability trios (affected child and both normal parents). We identified and independently validated 36 de novo copy-number changes in 32 trios. In all, 67% of the validated events were intragenic, involving only exon 1 (which includes the promoter sequence according to our design), exon 1 and adjacent exons, or one or more exons excluding exon 1. Seventeen of the 36 copy-number variants involve genes known to cause intellectual disability. Eleven of these, including seven intragenic variants, are clearly pathogenic (involving STXBP1, SHANK3 (3 patients), IL1RAPL1, UBE2A, NRXN1, MEF2C, CHD7, 15q24 and 9p24 microdeletion), two are likely pathogenic (PI4KA, DCX), two are unlikely to be pathogenic (GRIK2, FREM2), and two are unclear (ARID1B, 15q22 microdeletion). Twelve individuals with genomic imbalances identified by our array were tested with a clinical microarray, and six had a normal result. We identified de novo copynumber variants within genes not previously implicated in intellectual disability and uncovered pathogenic variation of known intellectual disability genes below the detection limit of standard clinical diagnostic chromosomal microarray analysis.

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

“…Our study reinforces the notion that atypical nested 22q11.2 duplications are associated with a broad phenotypic spectrum, Only symptomatic individuals are included in this table. Central duplications cases included those between LCR22B and LCR22D described in this study, published in the literature (Diehl et al, 2015;Fan et al, 2007;Fernandez et al, 2009;Ou et al, 2008;Pebrel-Richard et al, 2012;Tucker et al, 2014) and within the DECIPHER database with clinical information and one CNV (https://decipher.sanger.ac.uk). Typical proximal duplication cases included those 3 Mb in size between LCR22A and LCR22D (Wenger et al, 2016).…”

“…To date, many individuals have been described with atypical nested 22q11.2 deletions between LCR22B and LCR22D (Clements et al., ; Rump et al., ; Wentzel et al., ). In contrast, very few cases with atypical nested 22q11.2 duplications have been reported (Clements et al., ; Diehl, Mu, Batista, & Gunay‐Aygun, ; Fan et al., ; Fernandez et al., ; Pebrel‐Richard et al., ; Tucker et al., , ). Here, we describe 13 individuals from six families with atypical nested 22q11.2 duplications between LCR22B and LCR22D.…”

TASP1 is deleted in an infant with developmental delay, microcephaly, distinctive facial features, and multiple congenital anomalies

“…4 The technology advancements have allowed the development of higher resolution microarrays that include larger number of probes enabling the detection of smaller deletions and duplications. 5,6 Increasing the resolution has enabled chromosomal microarrays to detect CNVs involving a single gene or part of it. 7 The expanded use of higher resolution microarrays not only allows the diagnosis of single-gene Mendelian disorders, but also provides the opportunity for novel gene discoveries.…”

Epigenetic Developmental Disorders: CHARGE Syndrome, a Case Study

“…To date, such studies indicate that CHD7 mutations are rarely associated with isolated hypogonadotropic hypogonadism and congenital heart disease but not with isolated semicircular canal dysplasia and clefting [16–20]. Other reports point to rare individuals with developmental delay, autism spectrum disorder, or intellectual disability and CHD7 mutations [21–23]. Further biochemical analyses of these newly reported mutations are necessary to establish their effects on CHD7 protein function.…”