Novel variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability in Iranian consanguineous families

Abstract

Background: Intellectual disability (ID) is a heterogeneous group of neurodevelopmental disorders that is characterized by significant impairment in intellectual and adaptive functioning with onset during the developmental period. Whole-exome sequencing (WES)-based studies in the consanguineous families with individuals affected with ID have shown a high burden of relevant variants. So far, over 700 genes have been reported in syndromic and non-syndromic ID. However, genetic causes in more than 50% of ID patients still remain unclear.Methods: Whole-exome sequencing was applied for investigation of various variants of ID, then Sanger sequencing and in silico analysis in ten patients from five Iranian consanguineous families diagnosed with autosomal recessive neurodevelopmental disorders, intellectual disability, performed for confirming the causative mutation within the probands. The most patients presented moderate-to-severe intellectual disability, developmental delay, seizure, speech problem, high level of lactate, and onset before 10 years. Results:Filtering the data identified by WES, two novel homozygous missense variants in FBXO31 and TIMM50 genes and one previously reported mutation in the CEP290 gene in the probands were found. Sanger sequencing confirmed the homozygote variant's presence of TIMM50 and FBXO31 genes in six patients and two affected siblings in their respective families. Our computational results predicted that the variants are located in the conserved regions across different species and have the impacts on the protein stability. Conclusion:Hence, we provide evidence for the pathogenicity of two novel variants in the patients which will expand our knowledge about potential mutation involved in the heterogeneous disease.

Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50

“…The TIMM50 protein is a pivotal member of the TIM23 complex that is suggested to participate in the import of nearly 60% of the mitochondrial proteome (5,6). Human TIMM50 mutations lead to neurological effects, including mitochondrial epileptic encephalopathy, intellectual disability, seizure disorders like infantile spasms, and severe hypotonia accompanied by 3methylglutaconic aciduria (22)(23)(24)(25)(26)(27). Despite being involved in the import of the majority of the mitochondrial proteome, no study thus far characterized the effects of TIMM50 deficiency on the entire mitochondrial proteome.…”

“…Recently, TIMM50 has generated immense interest in human health research, as mutations in the encoding gene have been linked in geographically and ethnically varied populations to the development of a severe disease characterized by mitochondrial epileptic encephalopathy, developmental delay, optic atrophy, cardiomyopathy, and 3-methylglutaconic aciduria. To date, seven different mutations have been identified in children from ten unrelated families (22)(23)(24)(25)(26)(27).…”

Autosomal recessive variants c.953A>C and c.97-1G>C in NSUN2 causing intellectual disability: a molecular dynamics simulation study of loss-of-function mechanisms

“…All simulations were executed using AMBER 20 ( 54 ) using the same protocol we described elsewhere ( 25 , 55 ). Furthermore, the figures were drawn using Chimera ( 56 ), while structure-based protein multiple sequence alignment of NSUN members ( 1 – 3 , 5 – 8 ) was generated by ESPript ( 57 ).…”

“…In addition to consanguinity, developing countries are also facing the issues of malnutrition, lack of health facilities, unhygienic environment, and cultural deprivation as contributing risk factors of intellectual disability. Furthermore, the recent literature survey has reported over 700 genetic entities involved in syndromic and non-syndromic ID ( 3 ) and are transmitted in an autosomal dominant, recessive, X-Linked, or mitochondrial fashion (Orphanet report). The autosomal recessive inheritance of intellectual disability is relatively rare and accounts for < 12% of cases of intellectual disabilities ( 4 ).…”