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.

The first Turkish family with a novel biallelic missense variant of the ALKBH8 gene: A study on the clinical and variant spectrum of ALKBH8‐related intellectual developmental disorders

“…The ALKBH8-related intellectual developmental disorder was first identified by Monies et al in (Maddirevula et al, 2022;Monies et al, 2019;Saad et al, 2021;Waqas et al, 2022). Of the 12 cases detected with a variant of the ALKBH8 gene, 12 (100%) had facial dysmorphism, 8 (66%) had seizures, 7 (58%) had epilepsy, 5 (41%) had cranial anomaly, and 1 (8%) had cardiac anomaly (Table 1).…”

“…Subsequently, Saad et al reported two siblings from an Egyptian family in 2021; Maddirevula et al reported two patients from a Yemeni family in 2022; and Waqas et al reported one case from a Pakistani family in 2022. All patients included in the literature showed signs of facial dysmorphic features, global developmental delay, and intellectual impairment (Maddirevula et al, 2022; Monies et al, 2019; Saad et al, 2021; Waqas et al, 2022). Of the 12 cases detected with a variant of the ALKBH8 gene, 12 (100%) had facial dysmorphism, 8 (66%) had seizures, 7 (58%) had epilepsy, 5 (41%) had cranial anomaly, and 1 (8%) had cardiac anomaly (Table 1).…”

“…To date, five variations of the ALKBH8 gene (one nonsense, two frameshift, and two missense) have been identified in the literature (Maddirevula et al, 2022; Monies et al, 2019; Saad et al, 2021; Waqas et al, 2022) (Figure S3). All detected variations were located in the 12th, or last, exon of the gene and in the C‐terminal MTase domain of the ABH8 protein (Figure S4).…”

“…Signs of intellectual disability and facial dysmorphic findings were noted in all cases. Two different missense variants were revealed to be linked to the disease phenotype in two families, whereas truncating variants were detected in the majority (75%) of the cases as well (Maddirevula et al, 2022; Monies et al, 2019; Saad et al, 2021; Waqas et al, 2022).…”

Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the CNTNAP1 and ADGRG1 genes

“…The selected structure was optimized through 1000 steps of steepest‐decent 13 and 1000 steps of conjugate‐gradient 14 minimization by UCSF Chimera, version 1.11, 15 through the AMBER ff14SB force field (https://pubs.acs.org/doi/10.1021/acs.jctc.5b00255). The 3D Structure of mutated protein was generated by MODELLER, version 9.19 16 . MODELLER helps to predict 3D structure of proteins by meeting spatial restraints 17 .…”