Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability

Abstract

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.

Figure 1

(a) Protein–protein interactions of novel candidates in different pathways. Novel candidate genes either directly interact with known intellectual disability (ID) genes (in blue) or through other genes (in gray) in the pathway. (b) Molecular functions of novel candidate genes (in red) for ID are indicated. Genes are involved in various cellular processes by activating, inhibiting and interacting with other molecules and are part of protein complexes. PowerPoint slide

Figure 2

Co-expression of novel intellectual disability (ID) candidate genes was evaluated using RNA-seq data from the BrainSpan Atlas. (a) Gene pairs were defined as connected if the absolute value of the Pearson’s correlation coefficient is >0.8 for their expression levels in different brain region (frontal cortex, temporal–parietal, sensory–motor and sub-cortical) and different developmental stage (fetal, infancy to late childhood and adolescence to adulthood). Connections of co-expression genes at three development stages and four brain regions were plotted. Dotted lines indicate numbers of connections (edges) in networks created using target genes. Histograms represent distributions of the numbers of edges in 10 000 simulated networks using a similar number of random genes. *Represents the significance enrichment with P less than adjusted P-value. (b) Co-expression of novel ID candidate genes during embryonic developmental stages for the same four brain regions. PowerPoint slide

Figure 3

Overview of the results of genetic studies in 121 consanguineous Pakistani families segregating recessive intellectual disability (ID) phenotype. PowerPoint slide