4Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.
Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.
The novel coronavirus disease 2019 (COVID-19) is a global pandemic. Although the main clinical manifestations of the COVID-19 infection have confined to the respiratory system, there is some evidence suggesting the neuro-invasive potential of the COVID-19. There are limited reports of Guillain–Barré syndrome (GBS) as a peripheral nervous system complication of COVID-19 infection. We described four patients with COVID-19 infection who developed acute polyneuropathy with a final diagnosis of Guillain–Barré syndrome. COVID-19 may have the potential to invade the peripheral nervous system. GBS, as one of the critical neurological complications of COVID-19, could be considered as a post-infectious event.
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.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.
Guillain–Barré syndrome (GBS) is a neurological disorder accompanied by several neurological signs and symptoms including progressive weakness and diminished or decreased reflexes. GBS was reported as one of the several neurological complications in MERS-CoV and SARS-CoV outbreaks. Several studies have reported GBS as a neurological complication in recent COVID-19 outbreak. We report on the case of a 55-years -old female who was hospitalized with dyspnea, dry cough, and myalgia. She developed Acute Motor & Sensory Axonal Neuropathy (AMSAN), a rare variant of GBS signs and symptoms including decreased muscle strength and pinprick sensation in both lower extremities during her hospitalization.
Background: Pathogenic mutations in TRAPPC9 are associated with autosomal recessive Intellectual Disability (ID), a major public health issue that affects about 1-3% of children worldwide. Method: Clinical evaluation, magnetic resonance imaging, peripheral blood karyotype, Multiplex ligation-dependent probe amplification (MLPA), array CGH, and whole-exome sequencing were used to characterize etiology in three patients from two unrelated consanguineous families of Iranian descent with intellectual disability. Results: Whole-exome sequencing showed two novel homozygous nonsense mutations (c.937C>T) in exon 3 and (c.3103C>T) in exon 19 of TRAPPC9 (NM_031466.7) in two unrelated consanguineous families.
Conclusion:The two novel variants found in TRAPPC9 caused truncated protein and clinical manifestations such as ID, developmental delay, microcephaly, and brain abnormalities in three patients.
Evidence suggests that the relationship between arsenic metabolism and diseases, including metabolic syndrome, is complex. The aim of this study was to evaluate the different types of arsenic methylation and its association with metabolic syndrome in an arsenic endemic area. A cross-sectional study was conducted on 132 subjects from Shahid-Abad Village, Qazvin province, Iran (arsenic endemic area). Demographic characteristics, metabolic syndrome, and urinary arsenic species, including iAs (inorganic arsenic), MMA (monomethylarsonic acid), and DMA (dimethylarsinic acid) were measured for all patients and their relationship was analyzed by appropriate statistical methods. In this study, 34.5% of the participants had metabolic syndrome. The decrease in %MMA, increase in %DMA and increase in secondary methylation index (DMA/MMA) were associated with increased risk of metabolic syndrome (p<0.05). We did not find any association between the incidence of metabolic syndrome with primary methylation index (MMA/iAs) and %iAs (p>0.05). This study showed that the prevalence of metabolic syndrome was significantly higher in people with metabolic syndrome than in the general population. A closer examination revealed that the secondary methylation index is related to the metabolic syndrome and its components. Given the higher prevalence of cardiovascular disease and diabetes in patients with metabolic syndrome, it is necessary to change the pathogenesis of the disease using comprehensive management methods for decreasing patient complications.
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