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.
Highlights
Intellectual disability (ID) is a common neurodevelopmental disorder with an onset of cognitive impairment before the age of 18 years[1,2,3] and is characterized by significant limitations in intellectual functioning and adaptive behavior.[1]
We enrolled a cohort of 121 ID families with a likely autosomal recessive inheritance pattern mostly from the rural areas of Punjab, Sindh, Baluchistan, Khyber Pakhtoon Khawa and Northern areas
Pathogenic variants identified in previously reported autosomal recessive ID (ARID) genes We identified 34 predicted pathogenic variants in 32 genes previously associated with ID or related neurodevelopmental disorders (Tables 1 and 3a; Supplementary Figures S3 and S6)
Summary
Intellectual disability (ID) is a common neurodevelopmental disorder with an onset of cognitive impairment before the age of 18 years[1,2,3] and is characterized by significant limitations in intellectual functioning and adaptive behavior.[1]. The other half of ID cases has a genetic etiology, such as chromosomal abnormalities or mutations in specific genes.[3,5]. De novo heterozygous mutations and genomic copy number changes account for the majority of ID cases.[7] In contrast, recessive ID appears to be more common in consanguineous populations. By 2006, only three genes, CC2D1A, CRBN and PRSS12 had been associated with ARID.[8,9,10] After 2006, research studies involving highly inbred populations from North Africa, the Middle East and South East Asia, Department of Otorhinolaryngology—Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA or Professor H van Bokhoven, Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, PO BOX 9101, Nijmegen 6500 HB, The Netherlands or Professor S
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