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Intellectual disability affects about 3% of individuals globally, with∼50% 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 copy-number 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.

A large-scale sequencing screen of X-linked synaptic genes in individuals with autism spectrum disorder (ASD) or schizophrenia (SCZ), two common neurodevelopmental disorders, identified many variants most of which have no easily predictable effect on gene function. In this report, we evaluated the impact of these rare missense and silent variants on gene splicing. For this purpose, we used complementary in silico analyses, in vitro minigene-based assays and RNA prepared from lymphoblastoid cells derived from patients with these mutations. Our goal was to identify the variants which might either create or disrupt an acceptor splice site, a donor splice site or an exonic splicing enhancer, thus leading to aberrant splicing that could be involved in the pathogenesis of ASD or SCZ. We identified truncating mutations in distinct X-linked gamma-aminobutyric acid A (GABAA) receptor subunit-encoding genes, GABRQ and GABRA3, in two different families. Furthermore, missense and silent variants in nuclear RNA export factor 5 and histone deacetylase 6 were shown to partially disrupt the protein. While genes from the GABAergic pathway have previously been thought to be involved in the pathophysiology of ASD, this is the first report of ASD patients with truncating mutations in GABA receptors genes.

Heterozygous in-frame mutations (p.E2207del and p.R2308_M2309dup) in the α-II subunit of spectrin (SPTAN1) were recently identified in two patients with intellectual disability (ID), infantile spasms (IS), hypomyelination, and brain atrophy. These mutations affected the C-terminal domain of the protein, which contains the nucleation site of the α/β spectrin heterodimer. By screening SPTAN1 in 95 patients with idiopathic ID, we found a de novo in-frame mutation (p.Q2202del) in the same C-terminal domain in a patient with mild generalized epilepsy and pontocerebellar atrophy, but without IS, hypomyelination, or other brain structural defects, allowing us to define the core phenotype associated with these C-terminal SPTAN1 mutations. We also found a de novo missense variant (p.R566P) of unclear clinical significance in a patient with non-syndromic ID. These two mutations induced different patterns of aggregation between spectrin subunits in transfected neuronal cell lines, providing a paradigm for the classification of candidate variants.

STXBP1 (Munc18-1) is a component of the machinery involved in the fusion of secretory vesicles to the presynaptic membrane for the release of neurotransmitters. De novo missense mutations in STXBP1 were recently reported in patients with Ohtahara syndrome, a form of encephalopathy with severe early-onset epilepsy. In addition, sequencing of the coding region of STXBP1 in 95 patients with non-syndromic intellectual disability (NSID) revealed de novo truncating mutations in two patients who also showed severe non-specific epilepsy, suggesting that STXBP1 disruption has the potential of causing a wide spectrum of epileptic disorders in association with intellectual disability. Here, we report on the mutational screening of STXBP1 in a different series of 50 patients with NSID and the identification of a novel de novo truncating mutation (c.1206delT/ p.Y402X) in a male with NSID, but surprisingly with no history of epilepsy. This is the first report of a patient with a truncating mutation in STXBP1 that does not show epilepsy, thus, expanding the clinical spectrum associated with STXBP1 disruption.