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Ann Lab Med. 2017 Nov;37(6):516-521. English. Original Article. https://doi.org/10.3343/alm.2017.37.6.516
Choi SA , Kim SY , Yoon J , Choi J , Park SS , Seong MW , Kim H , Hwang H , Choi JE , Chae JH , Kim KJ , Kim S , Lee YJ , Nam SO , Lim BC .
Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea. prabbit7@snu.ac.kr
Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea. mwseong@snu.ac.kr
Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.
Department of Pediatrics, Seoul National University Boramae Medical Center, Seoul, Korea.
Department of Pediatrics, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Korea.
Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University College of Medicine, Yangsan, Korea.
Abstract

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited disorder characterized by infantile-onset macrocephaly, slow neurologic deterioration, and seizures. Mutations in the causative gene, MLC1, are found in approximately 75% of patients and are inherited in an autosomal recessive manner. We analyzed MLC1 mutations in five unrelated Korean patients with MLC. METHODS: Direct Sanger sequencing was used to identify MLC1 mutations. A founder effect of the p.Ala275Asp variant was demonstrated by haplotype analysis using single-nucleotide polymorphic (SNP) markers. Multiple ligation-dependent probe amplification (MLPA) and comparative genomic hybridization plus SNP array were used to detect exonic deletions or uniparental disomy (UPD). RESULTS: The most prevalent pathogenic variant was c.824C>A (p.Ala275Asp) found in 7/10 (70%) alleles. Two pathogenic frameshift variants were found: c.135delC (p.Cys46Alafs*12) and c.337_353delinsG (p.Ile113Glyfs*4). Haplotype analysis suggested that the Korean patients with MLC harbored a founder mutation in p.Ala275Asp. The p.(Ile113Glyfs*4) was identified in a homozygous state, and a family study revealed that only the mother was heterozygous for this variant. Further analysis of MLPA and SNP arrays for this patient demonstrated loss of heterozygosity of chromosome 22 without any deletion, indicating UPD. The maternal origin of both chromosomes 22 was demonstrated by haplotype analysis. CONCLUSIONS: This study is the first to describe the mutational spectrum of Korean patients with MLC, demonstrating a founder effect of the p.Ala275Asp variant. This study also broadens our understanding of the mutational spectrum of MLC1 by demonstrating a homozygous p.(Ile113Glyfs*4) variant resulting from UPD of chromosome 22.

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