Ann Lab Med 2017; 37(6): 516-521  
A Unique Mutational Spectrum of MLC1 in Korean Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts: p.Ala275Asp Founder Mutation and Maternal Uniparental Disomy of Chromosome 22
Sun Ah Choi, M.D.1, Soo Yeon Kim, M.D.1, Jihoo Yoon, M.D.2, Joongmoon Choi, M.D.2, Sung Sup Park, M.D.2,3, Moon-Woo Seong, M.D.2,3, Hunmin Kim, M.D.4, Hee Hwang, M.D.4, Ji Eun Choi, M.D.5, Jong Hee Chae, M.D1, Ki Joong Kim, M.D.1, Seunghyo Kim, M.D.6, Yun-Jin Lee, M.D.7, Sang Ook Nam, M.D.7, and Byung Chan Lim, M.D.1
Department of Pediatrics1, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul; Department of Laboratory Medicine2, Seoul National University Hospital, Seoul National University College of Medicine, Seoul; Biomedical Research Institute3, Seoul National University Hospital, Seoul; Department of Pediatrics4, Seoul National University Bundang Hospital, Seongnam; Department of Pediatrics5, Seoul National University Boramae Medical Center, Seoul; Department of Pediatrics6, Jeju National University Hospital, Jeju National University School of Medicine, Jeju; Department of Pediatrics7, Pusan National University Children’s Hospital, Pusan National University College of Medicine, Yangsan, Korea
Correspondence to: Moon-Woo Seong
Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: +82-2-2072-4180 Fax: +82-2-747-0359 E-mail: mwseong@snu.ac.kr
Co-corresponding author: Byung Chan Lim
Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: +82-2-2072-2364 Fax: +82-2-743-3455 E-mail: prabbit7@snu.ac.kr
Received: January 13, 2017; Revised: March 18, 2017; Accepted: June 25, 2017; Published online: November 1, 2017.
© The Korean Society for Laboratory Medicine. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: Megalencephalic leukoencephalopathy with subcortical cysts, MLC1, Founder effect, Korean, Uniparental disomy


This Article

e-submission

Archives

Indexed/Covered by