Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Abstract

4Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

“…We compared the list of 350 genes emerging from MTAG with a list of 621 genes known to cause autosomal dominant or autosomal recessive Mendelian disorders featuring intellectual disability (Harripaul et al, 2017; Vissers et al, 2016). As shown in Table 1, a total of 23 genes identified by MTAG appeared on this list, representing a 2-fold enrichment over chance (hypergeometric probability p=0.001).…”

“…We compared the list of genes resulting from the MTAG analysis (including all genes within GWS SNP loci, as well as GWS genes identified with MAGMA) with a list of 621 genes known to cause autosomal dominant or autosomal recessive Mendelian disorders featuring intellectual disability; this list is primarily derived from a recent comprehensive review (Vissers et al, 2016), supplemented by a subsequent large-scale study of consanguineous multiplex families (Harripaul et al, 2017). A total of 193 autosomal dominant genes were identified, and a total of 413 autosomal recessive genes were identified.…”

Effect of inbreeding on intellectual disability revisited by trio sequencing

“…This has been confirmed by large‐scale, high‐throughput sequencing in consanguineous families with two or more intellectually disabled children (see Ref. and refs therein): between the first and the most recent study of this kind, the percentage of multiplex families with mutations in known ARID genes has only risen from one‐third to about one half while the number of known ARID genes has increased from about a dozen to about 800 today …”

“…In a recent study of the British Deciphering Developmental Defects (DDD) project, whole‐exome sequencing (WES) identified bi‐allelic (recessive) mutations in 3.6% of the patients with developmental disorders (DD) and European ancestry, compared to 49.9% DNMS in known DD genes. To date, no comparable molecular data have been published for countries where PC is common, because most sequencing studies performed in Iran, Turkey, Saudi Arabia or Pakistan focused on recessive gene defects and were not designed to capture DNM (eg,), did not quantify consanguinity or autozygosity, or were simply too small.…”

Investigating the child with intellectual disability

“…Although autosomal‐recessive genes appear to play a minor role at a population level, consanguineous relationships are an important exception. When the parents are related, 90% of diagnoses revealed by WES are autosomal recessive, reinforcing the appropriateness of advising a 25% risk of recurrence in this setting.…”