Identifying Genes Responsible for Intellectual Disability in Consanguineous Families

Iqbal, Zafar; Bokhoven, Hans van

doi:10.1159/000360539

Cited by 31 publications

(22 citation statements)

References 113 publications

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“…The rate of consanguineous marriages is 38% in Iran, 13 , 14 over 40% in several Middle Eastern countries 15 and above 50% in Pakistan. 16 The elevated level of endogamy in Pakistan has led to the increased prevalence of genetic disorders, including ARID, with an average of 1.1 cases of severe ID and 6.2 cases of mild ID per 100 live births. 17 The present study is designed to identify pathogenic gene mutations that cause ARID in the highly inbred population of Pakistan.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Identification of additional variants and understanding their impact on gene function will not only improve genetic counseling of affected families, but will furthermore advance understanding of molecular networks involved in cognitive processes, which may result in studying treatment and therapy of cognitive impairment in the future. 15,32 …”

Section: Aimp1 Variants-recessive Intellectual Disability Z Iqbal Et Almentioning

confidence: 99%

“…14 A recent review suggests that ARID is not rare, and in outbred populations as many as 13-24% of ID may be due to AR genes, 13 and identifying the underlying genetic cause is an important issue in clinical genetics. 15 Consanguineous marriages, for which there is cultural preference in many countries including Iran, Pakistan and Syria, are an important risk factor for ARID and other congenital disorders, 15 resulting in a significant excess of ID in offsprings of consanguineous marriages. 14,[16][17][18] In the present study, we report on two consanguineous families with novel missense variants in AIMP1 that co-segregated with the ID phenotype.…”

Section: Introductionmentioning

confidence: 99%

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

et al. 2015

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AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p. (Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.

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“…Intellectual disability (ID), the most common clinical presentation, is a serious neurodevelopmental disorder characterized by significant limitations in intellectual functioning and adaptive behavior, having an age of onset before 18 (reviewed by Schalock and Luckasson 2015). ID is relatively common with a prevalence that can reach 3.6 % (Delobel-Ayoub et al 2015) with a higher frequency expected in inbred populations (Shamia et al 2015;Iqbal and van Bokhoven 2014). The advances in Intellectual Disability gene discovery have identified many causative genes, but about half of cases do not have a known etiology (Ellison et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

et al. 2016

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Intellectual disability is a heterogeneous disease with many genes and mutations influencing the phenotype. Consanguineous families constitute a rich resource for the identification of rare variants causing autosomal recessive disease, due to the effects of inbreeding. Here, we examine three consanguineous Arab families, recruited in a quest to identify novel genes/mutations. All the families had multiple offspring with non-specific intellectual disability. We identified homozygosity (autozygosity) intervals in those families through SNP genotyping and whole exome sequencing, with variants filtered using Ingenuity Variant Analysis (IVA) software. The families showed heterogeneity and novel mutations in three different genes known to be associated with intellectual disability. These mutations were not found in 514 ethnically matched control chromosomes. p.G410C in WWOX, p.H530Y in RARS2, and p.I69F in C10orf2 are novel changes that affect protein function and could give new insights into the development and function of the central nervous system.

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Identifying Genes Responsible for Intellectual Disability in Consanguineous Families

Cited by 31 publications

References 113 publications

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

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

Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

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