GPR126: A novel candidate gene implicated in autosomal recessive intellectual disability.

Intellectual disability (ID), a genetically and clinically heterogeneous disorder, affects 1%-3% of the general population and is a major health problem, especially in developing countries and in populations with a high frequency of consanguineous marriage. Using whole exome sequencing, a homozygous missense variation (c.3264G>C, p.

Biallelic missense variants in ZBTB11 can cause intellectual disability in humans.

Exploring genes and pathways underlying intellectual disability (ID) provides insight into brain development and function, clarifying the complex puzzle of how cognition develops. As part of ongoing systematic studies to identify candidate ID genes, linkage analysis and next-generation sequencing revealed Zinc Finger and BTB Domain Containing 11 (ZBTB11) as a novel candidate ID gene. ZBTB11 encodes a little-studied transcription regulator, and the two identified missense variants in this study are predicted to disrupt canonical Zn2+-binding residues of its C2H2 zinc finger domain, leading to possible altered DNA binding.

Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.

Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here, we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.

Exome Sequencing and Linkage Analysis Identified Novel Candidate Genes in Recessive Intellectual Disability Associated with Ataxia.

Background: Intellectual disability (ID) is a neuro-developmental disorder which causes considerable socio-economic problems. Some ID individuals are also affected by ataxia, and the condition includes different mutations affecting several genes.

Methods: We used whole exome sequencing (WES) in combination with homozygosity mapping (HM) to identify the genetic defects in five consanguineous families among our cohort study, with two affected children with ID and ataxia as major clinical symptoms.

Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.

New evidence for the role of calpain 10 in autosomal recessive intellectual disability: identification of two novel nonsense variants by exome sequencing in Iranian families.

Background: Knowledge of the genes responsible for intellectual disability, particularly autosomal recessive forms, is rapidly expanding. Increasing numbers of the gene show great heterogeneity and supports the hypothesis that human genome may contain over 2000 causative genes with a critical role in brain development.

Methods: Since 2004, we have applied genome-wide SNP genotyping and next-generation sequencing in large consanguineous Iranian families with intellectual disability, to identify the genes harboring disease-causing mutations.

Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems.

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.

High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations.

During the past years, significant advances have been made in our understanding of the development of the human brain, and much of this knowledge comes from genetic studies of disorders associated with abnormal brain development. We employed array-comparative genomic hybridization (CGH) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic epilepsy.

Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability.

We have used genome-wide genotyping to identify an overlapping homozygosity-by-descent locus on chromosome 9q34.3 (MRT15) in four consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability (NS-ARID) and one in which the patients show additional clinical features. Four of the families are from Pakistan, and one is from Iran.

A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation in a consanguineous Iranian family.

The genetic basis of autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to suspect that the number of underlying gene defects may well go beyond 1,000. To date, however, only less than 10 genes have been implicated in non-specific/non-syndromic ARMR (NS-ARMR). As part of an ongoing systematic study aiming to identify further ARMR genes, we investigated a consanguineous family with three patients with NS-ARMR.

Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots.

Mental retardation (MR) has a worldwide prevalence of around 2% and is a frequent cause of severe disability. Significant excess of MR in the progeny of consanguineous matings as well as functional considerations suggest that autosomal recessive forms of MR (ARMR) must be relatively common. To shed more light on the causes of autosomal recessive MR (ARMR), we have set out in 2003 to perform systematic clinical studies and autozygosity mapping in large consanguineous Iranian families with non-syndromic ARMR (NS-ARMR).

Genetics of early onset cognitive impairment.

Intellectual disability (ID) is the leading socio-economic problem of health care, but compared to autism and schizophrenia, it has received very little public attention. Important risk factors for ID are malnutrition, cultural deprivation, poor health care, and parental consanguinity. In the Western world, fetal alcohol exposure is the most common preventable cause.

Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation.

ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe.

A novel mutation in the DLG3 gene encoding the synapse-associated protein 102 (SAP102) causes non-syndromic mental retardation.

We have identified a novel splice site mutation (IVS6-1G > A) in the disc-large homolog 3 (DLG3) gene, encoding the synapse-associated protein 102 (SAP102) in one out of 300 families with moderate to severe non-syndromic mental retardation. SAP102 is a member of the neuronal membrane-associated guanylate kinase protein subfamily comprising SAP97, postsynaptic density (PSD)95, and PSD93, which interacts with methyl-D-aspartate receptor and associated protein complexes at the postsynaptic density of excitatory synapses. DLG3 is the first mental retardation gene directly linked to glutamate receptor signalling and trafficking, increasingly recognised as a central mechanism in the regulation of synaptic formation and plasticity in brain and cognitive development.

Fragile X syndrome screening of families with consanguineous and non-consanguineous parents in the Iranian population.

Fragile X syndrome is the most common form of inherited mental retardation (MR). It is caused by the expansion of CGG triplet repeats in the fragile X mental retardation 1 (FMR1) gene. In mentally retarded males, the frequency of fragile X syndrome is approximately 2-3 percent, but little is known about its proportion in mentally retarded patients from countries where parental consanguinity is common.

An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4.

We report on three siblings with a novel mental retardation (MR) syndrome who were born to distantly related Iranian parents. The clinical problems comprised severe MR, cataracts with onset in late adolescence, kyphosis, contractures of large joints, bulbous nose with broad nasal bridge, and thick lips. Two patients also had uni- or bilateral iris coloboma.

A defect in the TUSC3 gene is associated with autosomal recessive mental retardation.

Recent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into the thousands. To date, however, only four genes have been implicated in nonsyndromic ARMR (NS-ARMR): PRSS12 (neurotrypsin), CRBN (cereblon), CC2D1A, and GRIK2. As part of an ongoing systematic study aiming to identify ARMR genes, we investigated a large consanguineous family comprising seven patients with nonsyndromic ARMR in four sibships.

MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.

Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan-Herndon-Dudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features.

Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome.

We have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosity mapping we identified one region with a significant LOD score on chromosome 9(p24.2-24.

A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation.

Nonsyndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked forms, but, in contrast to the latter, they are still largely unexplored. Here, we report a complex mutation in the ionotropic glutamate receptor 6 gene (GRIK2, also called "GLUR6") that cosegregates with moderate-to-severe nonsyndromic autosomal recessive mental retardation in a large, consanguineous Iranian family.

Genomic structure, chromosome mapping and expression analysis of the human AVIL gene, and its exclusion as a candidate for locus for inflammatory bowel disease at 12q13-14 (IBD2).

Chronic inflammatory bowel disease is a multifactorial disorder with two major clinical forms, Crohn's disease and ulcerative colitis. One of the potential susceptibility loci for inflammatory bowel disease (IBD2) was localized at 12q13-14 in the vicinity of the deoxyribonucleic acid marker D12S83 by linkage analysis. A candidate susceptibility gene for IBD2 in this region is the AVIL gene.