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

Abstract

IntroductionIntellectual disability (ID) is a clinically and genetically heterogeneous disorder. It drastically affects the learning capabilities of patients and eventually reduces their IQ level below 70.MethodsThe current genetic study ascertained two consanguineous Pakistani families suffering from autosomal recessive intellectual developmental disorder-5 (MRT5). We have used exome sequencing followed by Sanger sequencing to identify the disease-causing variants.Results and discussionGenetic analysis using whole exome sequencing in these families identified two novel mutations in the NSUN2 (NM_017755.5). Family-A segregated a novel missense variant c.953A>C; p.Tyr318Ser in exon-9 of the NSUN2. The variant substituted an amino acid Tyr318, highly conserved among different animal species and located in the functional domain of NSUN2 known as “SAM-dependent methyltransferase RsmB/NOP2-type”. Whereas in family B, we identified a novel splice site variant c.97-1G>C that affects the splice acceptor site of NSUN2. The identified splice variant (c.97-1G>C) was predicted to result in the skipping of exon-2, which would lead to a frameshift followed by a premature stop codon (p. His86Profs*16). Furthermore, it could result in the termination of translation and synthesis of dysfunctional protein, most likely leading to nonsense-mediated decay. The dynamic consequences of NSUN2 missense variant was further explored together with wildtype through molecular dynamic simulations, which uncovered the disruption of NSUN2 function due to a gain in structural flexibility. The present molecular genetic study further extends the mutational spectrum of NSUN2 to be involved in ID and its genetic heterogeneity in the Pakistani population.

Statistical Mechanics Metrics in Pairing and Parsing In Silico and Phenotypic Data of a Novel Genetic NFκB1 (c.T638A) Variant

“…In yet another instance, both in silico and in vitro functional analyses of a TGFBR2 VUS with a clinical diagnosis of Marfan syndrome confirmed the pathology of the variant and suggested the diagnosis of a very similar syndrome, Loeys-Dietz syndrome [52]. Molecular modeling has been shown to be of use in analyzing single variants alone [53], multiple variants in one gene [52,[54][55][56][57][58], and multiple genes in one disease [59]. Interestingly, molecular modeling has also been of use in visualizing the interaction between different variants of SARS-CoV2 and the human ACE2 receptor [60,61].…”

A novel variant in NSUN2 causes intellectual disability in a Chinese family

“…In 2012, Khan et al provided the first report of mutations in the NSUN2 gene of three unrelated, affected individuals with neurodevelopmental disability, microcephaly, short stature and growth restriction [7]. A total of 30 patients with NSUN2-intellectual disability syndrome have since been reported [6][7][8][9][10][11][12][13][14][15][16][17]. The clinical presentation of these subjects with NSUN2 deficiency includes facial dysmorphism, microcephaly, short stature, ID, growth restriction, language impairment, hypotonia and delayed puberty.…”

“…A total of 17 variants were observed, of which loss-offunction variants (LoF; including non-sense variants, splicing variants and frameshifts ) were the most common type (Table S1)\ [6][7][8][9][10][11][12][13][14][15][16][17]. We compared the phenotypes of five patients with homozygous missense variants and 26 patients with homozygous loss-of-function variants (Table 1).…”

“…Recently, 16 loss-of-function (LoF) NSUN2 mutations were identified in 30 patients with intellectual disability/developmental delay (ID/DD) and growth retardation. These mutations included seven frameshift variants, three nonsense variants, two missense variants and three splicing variants [1,[7][8][9][10][11][12][13][14][15][16][17] (Fig. 1A).…”

Molecular insight into CREBBP and TANGO2 variants causing intellectual disability

“…Worldwide, one in every 100 people is diagnosed with intellectual impairment, marked by significant difficulties in intellectual functioning and adaptive behavior, and typically manifests before the age of 18 years. 1 A definitive intellectual disability (ID) is diagnosed when an IQ test of a person reveals a score of 70 or below. 2 ID has a wide range of severities (mild, moderate, severe and profound) and can be isolated or in association with other congenital abnormalities or neurological malformations, such as epilepsy, sensory impairment and autism spectrum disorders.…”