RT Journal Article SR Electronic T1 The First Korean Siblings With Adult-Onset 4H Leukodystrophy Related to Nonsynonymous POLR3B Mutations JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e667 DO 10.1212/NXG.0000000000000667 VO 8 IS 3 A1 Yang, Hui-Jun A1 Park, Gyeongmin A1 Nam-Goong, Il Seong A1 Ahn, Jun-Woo A1 Weon, Young Cheol YR 2022 UL http://ng.neurology.org/content/8/3/e667.abstract AB Objectives 4H leukodystrophy is a rare autosomal recessive hypomyelinating disorder characterized by several combinations of motor dysfunction, abnormal dentition, and ophthalmic and endocrine abnormalities. To date, only a single Korean case report of pediatric leukodystrophy caused by the POLR1C sequence variation has been published, while there are no reports on the POLR3B, POLR3A, or POLR3K variants.Methods Genetic tests of Korean sibling pairs with primary amenorrhea due to normosmic isolated hypogonadotropic hypogonadism and cognitive or behavioral symptoms were performed by whole-exome sequencing (WES). The WES results were validated by direct Sanger sequencing.Results We identified biallelic variations in the POLR3B gene of p.Tyr685* and p.Tyr746Cys, which have not been associated with 4H leukodystrophy. Both sequence variants lie in the hybrid-binding domain of the protein RPC2. The protein structure analysis predicted that cysteine substitution of the phylogenetically conserved amino acid tyrosine can cause destabilization.Discussion The siblings reported are the first POLR3B-related hypomyelinating leukodystrophy cases in Korea. Our report expands the mutational spectrum of 4H leukodystrophy and suggests that it is mandatory to consider its diagnostic possibility in adult patients presenting with primary amenorrhea and mild cognitive or behavioral symptoms.