Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease–gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.
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We thank the study families for their enthusiastic participation. This work was supported in part by King Salman Center for Disability Research (FSA). We acknowledge the support of the Saudi Human Genome Program and the Sequencing and Genotyping Core Facilities at KFSRHC. The research by STA reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST).
Conflict of interest
Authors declare no conflict of interest.
A correction to this article is available online at https://doi.org/10.1007/s00439-017-1859-7.
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Figure S1. A) Clinical features of patient with GTF3C3-related ID showing facial asymmetry, bilateral temporal narrowing, epicanthal folds, upslanting palpebral fissures, bulbous nose, and full cheeks. (C) Chromatogram showing skipping of exon10 and partial part of exon11 (PDF 164 kb)
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Anazi, S., Maddirevula, S., Salpietro, V. et al. Expanding the genetic heterogeneity of intellectual disability. Hum Genet 136, 1419–1429 (2017). https://doi.org/10.1007/s00439-017-1843-2