Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing

Abstract

Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.

A synonymous variant contributes to a rare Wiedemann-Rautenstrauch syndrome complicated with mild anemia via affecting pre-mRNA splicing

“…Except for missense, nonsense, frameshifting, and mutations disrupting canonical splicing sites, there were 10 intronic mutations to affect pre-mRNA splicing of POLR3A ( Hiraide et al, 2020 ), such as c.645 + 312C > T ( Hiraide et al, 2020 ), c.1048 + 5G > T ( Minnerop et al, 2017 ), c.1770 + 5G > C ( Yan et al, 2021 ), c.1771-6C > G ( Rydning et al, 2019 ; Wu et al, 2019 ), c.1771-7C > G ( Minnerop et al, 2017 ), c.1909 + 22G > A ( Minnerop et al, 2017 ; Morales-Rosado et al, 2020 ), c.1909 + 18G > A ( Lessel et al, 2018 ), c.2003 + 18G > A ( Bernard et al, 2011 ), c.3337-5 T > A ( Lessel et al, 2018 ; Wambach et al, 2018 ), c.3337-11 T > C ( Wambach et al, 2018 ). Among them, c.1909 + 22G > A was the most commonly reported mutations.…”

FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder

“…[2005]004. Patients were sequenced and analysed as described previously (Yan et al , 2021), with sequencing performed by Joy Oriental Co. (Beijing, China).…”

SOX10: 20 years of phenotypic plurality and current understanding of its developmental function

“…We have worked on SOX10 since its characterisation, both in the research and clinical context, and have only once found an exception to each of these rules. With the increasing number of mutations described, it appears that there may be a second, rare spot of mutations in the dimerisation domain (three variations reported in four independent cases, creating or removing valines at residues 76, 79 and 80), although functional tests are required to reach a definitive conclusion91 92 (online supplemental table 1).…”