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.
Highlights
Hypomyelinating leukodystrophies (HLDs) are a specific group of leukodystrophies characterized by an unchanged pattern of deficient myelination on MRI scans at least 6 months apart in a child between the ages of 1–2 years [1, 2]
Twenty core pedigrees in this study were a portion of our HLDs cohort with 205 cases clinically diagnosed with HLDs, collected at Peking University First Hospital (Beijing, China)
Regression, ataxia, and other brain abnormalities were observed in a few patients
Summary
Hypomyelinating leukodystrophies (HLDs) are a specific group of leukodystrophies characterized by an unchanged pattern of deficient myelination on MRI scans at least 6 months apart in a child between the ages of 1–2 years [1, 2]. HLDs are genetically and clinically diverse, but have a prominent commonality: motor ability is affected in most HLDs patients, often as ataxia with cerebellar signs. The prototype of HLD1 is Pelizaeus–Merzbacher disease (PMD [MIM: 312080]) due to variants in the myelin protein proteolipid protein 1 (PLP1 [MIM: 300401]). Before we started our research, 15 disease-causing genes related to HLDs, have been defined in OMIM. In our HLDs cohort in China, out of 205 cases, genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes diagnostically solved 155 cases (~75%). 20 pedigrees, from the remaining 50 unresolved cases, underwent trio-based whole-exome sequencing (WES) to uncover their genetic data are not publicly available due to privacy and ethical etiology
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