Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare, recessively inherited neurological condition frequently involving insensitivity to pain. The subtype, HSAN2A, results from ...mutations in the gene WNK1. We identified a consanguineous Pakistani family with three affecteds showing symptoms of HSANII. We performed microarray genotyping, followed by homozygosity-by-descent (HBD) mapping, which indicated several significant HBD regions, including ~6 Mb towards the terminus of chromosome 12p, spanning WNK1. Simultaneously, we performed whole exome sequencing (WES) on one of the affected brothers, and identified a homozygous 1 bp insertion variant, Chr12:978101dupA, within exon 10. This variant, confirmed to segregate in the family, is predicted to truncate the protein (NM_213655.4:c.3464delinsAC; p.(Thr1155Asnfs*11) and lead to nonsense-mediated mRNA decay of the transcript. Previous studies of congenital pain insensitivity/HSANII in Pakistani families have identified mutations in SCN9A. Our study identified a previously unreported WNK1 mutation segregating with congenital pain insensitivity/HSANII in a Pakistani family.
With its high rate of consanguineous marriages and diverse ethnic population, little is currently understood about the genetic architecture of autism spectrum disorder (ASD) in Pakistan. Pakistan has ...a highly ethnically diverse population, yet with a high proportion of endogamous marriages, and is therefore anticipated to be enriched for biallelic disease-relate variants. Here, we attempt to determine the underlying genetic abnormalities causing ASD in thirty-six small simplex or multiplex families from Pakistan. Microarray genotyping followed by homozygosity mapping, copy number variation analysis, and whole exome sequencing were used to identify candidate. Given the high levels of consanguineous marriages among these families, autosomal recessively inherited variants were prioritized, however de novo/dominant and X-linked variants were also identified. The selected variants were validated using Sanger sequencing. Here we report the identification of sixteen rare or novel coding variants in fifteen genes (ARAP1, CDKL5, CSMD2, EFCAB12, EIF3H, GML, NEDD4, PDZD4, POLR3G, SLC35A2, TMEM214, TMEM232, TRANK1, TTC19, and ZNF292) in affected members in eight of the families, including ten homozygous variants in four families (nine missense, one loss of function). Three heterozygous de novo mutations were also identified (in ARAP1, CSMD2, and NEDD4), and variants in known X-linked neurodevelopmental disorder genes CDKL5 and SLC35A2. The current study offers information on the genetic variability associated with ASD in Pakistan, and demonstrates a marked enrichment for biallelic variants over that reported in outbreeding populations. This information will be useful for improving approaches for studying ASD in populations where endogamy is commonly practiced.
In a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in ...apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygosity-by-descent (HBD) mapping were unsuccessful. However, following an assumption of locus heterogeneity, a reiterative HBD approach in concert with whole exome sequencing (WES) was employed. We identified a known disease-linked mutation in the polymicrogyria gene, ADGRG1, in two affected members. In the remaining two (living) affected members, HBD mapping cross-referenced with WES data identified a single biallelic frameshifting variant in the gene encoding retinol dehydrogenase 14 (RDH14). Transcription data indicate that RDH14 is expressed in brain, but not in retina. Magnetic resonance imaging for the individuals with this RDH14 mutation show no signs of polymicrogyria, however cerebellar atrophy was a notable feature. RDH14 in HEK293 cells localized mainly in the nucleoplasm. Co-immunoprecipitation studies confirmed binding to the proton-activated chloride channel 1 (PACC1/TMEM206), which is greatly diminished by the mutation. Our studies suggest RDH14 as a candidate for autosomal recessive ID and cerebellar atrophy, implicating either disrupted retinoic acid signaling, or, through PACC1, disrupted chloride ion homeostasis in the brain as a putative disease mechanism.
Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This mutation results in a ...tissue-specific reduction of ELP1 protein, with the lowest levels in the central and peripheral nervous systems (CNS and PNS, respectively). FD patients exhibit complex neurological phenotypes due to the loss of sensory and autonomic neurons. Disease symptoms include decreased pain and temperature perception, impaired or absent myotatic reflexes, proprioceptive ataxia, and progressive retinal degeneration. While the involvement of the PNS in FD pathogenesis has been clearly recognized, the underlying mechanisms responsible for the preferential neuronal loss remain unknown. In this study, we aimed to elucidate the molecular mechanisms underlying FD by conducting a comprehensive transcriptome analysis of neuronal tissues from the phenotypic mouse model TgFD9; Elp1
. This mouse recapitulates the same tissue-specific ELP1 mis-splicing observed in patients while modeling many of the disease manifestations. Comparison of FD and control transcriptomes from dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC) showed significantly more differentially expressed genes (DEGs) in the PNS than the CNS. We then identified genes that were tightly co-expressed and functionally dependent on the level of full-length ELP1 transcript. These genes, defined as ELP1 dose-responsive genes, were combined with the DEGs to generate tissue-specific dysregulated FD signature genes and networks. Within the PNS networks, we observed direct connections between Elp1 and genes involved in tRNA synthesis and genes related to amine metabolism and synaptic signaling. Importantly, transcriptomic dysregulation in PNS tissues exhibited enrichment for neuronal subtype markers associated with peptidergic nociceptors and myelinated sensory neurons, which are known to be affected in FD. In summary, this study has identified critical tissue-specific gene networks underlying the etiology of FD and provides new insights into the molecular basis of the disease.
The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental ...disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.
PIDD1 encodes p53-Induced Death Domain protein 1, which acts as a sensor surveilling centrosome numbers and p53 activity in mammalian cells. Early results also suggest a role in DNA damage response ...where PIDD1 may act as a cell-fate switch, through interaction with RIP1 and NEMO/IKKg, activating NF-κB signaling for survival, or as an apoptosis-inducing protein by activating caspase-2. Biallelic truncating mutations in CRADD-the protein bridging PIDD1 and caspase-2-have been reported in intellectual disability (ID), and in a form of lissencephaly. Here, we identified five families with ID from Iran, Pakistan, and India, with four different biallelic mutations in PIDD1, all disrupting the Death Domain (DD), through which PIDD1 interacts with CRADD or RIP1. Nonsense mutations Gln863* and Arg637* directly disrupt the DD, as does a missense mutation, Arg815Trp. A homozygous splice mutation in the fifth family is predicted to disrupt splicing upstream of the DD, as confirmed using an exon trap. In HEK293 cells, we show that both Gln863* and Arg815Trp mutants fail to co-localize with CRADD, leading to its aggregation and mis-localization, and fail to co-precipitate CRADD. Using genome-edited cell lines, we show that these three PIDD1 mutations all cause loss of PIDDosome function. Pidd1 null mice show decreased anxiety, but no motor abnormalities. Together this indicates that PIDD1 mutations in humans may cause ID (and possibly lissencephaly) either through gain of function or secondarily, due to altered scaffolding properties, while complete loss of PIDD1, as modeled in mice, may be well tolerated or is compensated for.
Antidepressants (ADs) play a valuable role in treating the depressive episodes of bipolar disorder. However, 14% of these individuals taking ADs experience AD-associated mania (AAM) within a few ...weeks of starting treatment. Numerous studies have suggested potential clinical and genetic risk factors. We aimed to conduct a comprehensive systematic review and meta-analysis that integrates the past literature with the recent studies and identifies important predictors for AAM.
The review was limited to experimentally designed studies that contain the relevant search terms in PubMed and PsychInfo. After removing studies that were in discordance with our criteria, the review included 24 reports examining clinical risk factors and 10 investigating genetic risk factors. Our meta-analysis was conducted on 5 clinical risk factors, each of which had at least 4 articles with extractable data.
The only clinical factors in the literature that have been shown to be more indicative of AAM risk are AD monotherapy and tricyclic ADs. Among genetic factors, the serotonin transporter gene polymorphism may play a minor role in AAM. Our meta-analysis provided support for the number of prior depressive episodes.
Prevention of AAM may be served by early detection of recurrent depression episodes. Further large-scale longitudinal studies are required to determine the underpinnings of AAM.
Intellectual disability (ID) is a phenotypically and genetically heterogeneous disorder.
In this study, genome wide SNP microarray and whole exome sequencing are used for the variant identification ...in eight Pakistani families with ID. Beside ID, most of the affected individuals had speech delay, facial dysmorphism and impaired cognitive abilities. Repetitive behavior was observed in MRID143, while seizures were reported in affected individuals belonging to MRID137 and MRID175.
In two families (MRID137b and MRID175), we identified variants in the genes CCS and ELFN1, which have not previously been reported to cause ID. In four families, variants were identified in ARX, C5orf42, GNE and METTL4. A copy number variation (CNV) was identified in IL1RAPL1 gene in MRID165.
These findings expand the existing knowledge of variants and genes implicated in autosomal recessive and X linked ID.
The genetic dissection of autism spectrum disorders (ASD) has uncovered the contribution of de novo mutations in many single genes as well as de novo copy number variants. More recent work also ...suggests a strong contribution from recessively inherited variants, particularly in populations in which consanguineous marriages are common. What is also becoming more apparent is the degree of pleiotropy, whereby mutations in the same gene may have quite different phenotypic and clinical consequences. We performed whole exome sequencing in a group of 115 trios from countries with a high level of consanguineous marriages. In this paper we report genetic and clinical findings on a proband with ASD, who inherited a biallelic truncating pathogenic/likely pathogenic variant in the gene encoding voltage-gated sodium channel X alpha subunit, SCN10A (NM_006514.2:c.937G>T:(p.Gly313*)). The biallelic pathogenic/likely pathogenic variant in this study have different clinical features than heterozygous mutations in the same gene. The study of consanguineous families for autism spectrum disorder is highly valuable.
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