Dataset Information

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability.

ABSTRACT: Intellectual disability (ID) has become very common and is an extremely heterogeneous disorder, where the patients face many challenges with deficits in intellectual functioning and adaptive behaviors. A single affected family revealed severe disease phenotypes such as ID, developmental delay, dysmorphic facial features, postaxial polydactyly type B, and speech impairment. DNA of a single affected individual was directly subjected to whole exome sequencing (WES), followed by Sanger sequencing. Data analysis revealed a novel biallelic missense variant (c.1511G>C; p.(Trp504Ser)) in the ALKBH8 gene, which plays a significant role in tRNA modifications. Our finding adds another variant to the growing list of ALKBH8-associated tRNA modifications causing ID and additional phenotypic manifestations. The present study depicts the key role of the genes associated with tRNA modifications, such as ALKBH8, in the development and pathophysiology of the human brain.

SUBMITTER: Waqas A

PROVIDER: S-EPMC9096442 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability.

Waqas Ahmed A Nayab Anam A Shaheen Shabnam S Abbas Safdar S Latif Muhammad M Rafeeq Misbahuddin M MM Al-Dhuayan Ibtesam S IS Alqosaibi Amany I AI Alnamshan Mashael M MM Sain Ziaullah M ZM Habib Alaa Hamed AH Alam Qamre Q Umair Muhammad M Saqib Muhammad Arif Nadeem MAN

Frontiers in genetics 20220428

Intellectual disability (ID) has become very common and is an extremely heterogeneous disorder, where the patients face many challenges with deficits in intellectual functioning and adaptive behaviors. A single affected family revealed severe disease phenotypes such as ID, developmental delay, dysmorphic facial features, postaxial polydactyly type B, and speech impairment. DNA of a single affected individual was directly subjected to whole exome sequencing (WES), followed by Sanger sequencing. D ...[more]

PMID: 35571055

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Project description:ObjectiveHeterozygous variants in KCNQ2 or, more rarely, KCNQ3 genes are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical presentation and course, genetic transmission, and prognosis. While familial forms mostly include benign epilepsies with seizures starting in the neonatal or early-infantile period, de novo variants in KCNQ2 or KCNQ3 have been described in sporadic cases of early-onset encephalopathy (EOEE) with pharmacoresistant seizures, various age-related pathological EEG patterns, and moderate/severe developmental impairment. All pathogenic variants in KCNQ2 or KCNQ3 occur in heterozygosity. The aim of this work was to report the clinical, molecular, and functional properties of a new KCNQ3 variant found in homozygous configuration in a 9-year-old girl with pharmacodependent neonatal-onset epilepsy and non-syndromic intellectual disability.MethodsExome sequencing was used for genetic investigation. KCNQ3 transcript and subunit expression in fibroblasts was analyzed with quantitative real-time PCR and Western blotting or immunofluorescence, respectively. Whole-cell patch-clamp electrophysiology was used for functional characterization of mutant subunits.ResultsA novel single-base duplication in exon 12 of KCNQ3 (NM_004519.3:c.1599dup) was found in homozygous configuration in the proband born to consanguineous healthy parents; this frameshift variant introduced a premature termination codon (PTC), thus deleting a large part of the C-terminal region. Mutant KCNQ3 transcript and protein abundance was markedly reduced in primary fibroblasts from the proband, consistent with nonsense-mediated mRNA decay. The variant fully abolished the ability of KCNQ3 subunits to assemble into functional homomeric or heteromeric channels with KCNQ2 subunits.SignificanceThe present results indicate that a homozygous KCNQ3 loss-of-function variant is responsible for a severe phenotype characterized by neonatal-onset pharmacodependent seizures, with developmental delay and intellectual disability. They also reveal difference in genetic and pathogenetic mechanisms between KCNQ2- and KCNQ3-related epilepsies, a crucial observation for patients affected with EOEE and/or developmental disabilities.

Dataset Information

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability.

Publications

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability.

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