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.

Genetic basis of neurodevelopmental disorders in 103 Jordanian families

“…Pathogenic variants in homologs of PUS3 also have a strong impact on human physiology. Bi‐allelic pathogenic variants in PUS1 cause myopathy and sideroblastic anemia, sometimes with neuronal involvement, while bi‐allelic loss of function of PUS7 has been described in individuals with non‐syndromic intellectual disability and severe microcephaly . Taken all these finding together we consider PUS3 as a strong new candidate gene for intellectual disability.…”

“…In 1.9% of cases we could identify good candidate variants pending further investigation (yellow) while the rest of the cases is still under investigation (red). B, 52.5% of the detected variants were truncating, for example, stop gain or frameshift (red), 10% of the variants were splice with neuronal involvement, 51,52 while bi-allelic loss of function of PUS7 has been described in individuals with nonsyndromic intellectual disability and severe microcephaly 53,54. Taken all these finding together we consider PUS3 as a strong new candidate gene for intellectual disability.…”

INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family

“…ES using genomic DNA sample from one affected member of family LUCC15 was performed as described previously. 10 To evaluate the protein evolutionary sequence conservation Clustal omega multiple sequence alignment (http://www.ebi.ac.uk/Tools/msa/clustalo/) was used. The Phyre2 server (http://www.sbg.bio.ic.ac.uk/phyre2/html/ page.cgi?id=index) was used for protein 3D structure.…”

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

“…In several published cohorts consisting of predominantly consanguineous ARID families from the Middle East and Pakistan (number of families ranging from 18 to 337), detection rates of putatively causal variants from NGS studies range from 37 to 90% and an aggregate of 327 novel or candidate ARID genes were identified (Najmabadi et al 2011; Yavarna et al 2015; Charng et al 2016; Megahed et al 2016; Riazuddin et al 2017; Anazi et al 2017; Reuter et al 2017; Harripaul et al 2017; Monies et al 2017; Hu et al 2018). …”