Ann Lab Med.  2017 Nov;37(6):516-521. 10.3343/alm.2017.37.6.516.

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

• 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

• KMID: 2425993
• DOI: http://doi.org/10.3343/alm.2017.37.6.516

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.

Keyword

Megalencephalic leukoencephalopathy with subcortical cysts; MLC1; Founder effect; Korean; Uniparental disomy

MeSH Terms

Alleles
Chromosomes, Human, Pair 22*
Comparative Genomic Hybridization
Exons
Founder Effect
Haplotypes
Humans
Leukoencephalopathies*
Loss of Heterozygosity
Megalencephaly
Mothers
Seizures
Uniparental Disomy*

Figure

• 

  Fig. 1 Pedigree and MLC1 mutational analysis of Patient 1. (A) Pedigree of Patient 1 and the c.337_353del17insG mutation status in her family. Direct Sanger sequencing revealed that c.337_353 del17insG mutation was homozygous in the patient and heterozygous in the mother. The father did not harbor this mutation. (B) Loss of heterogeneity spanning chromosome 22q11.22-q13.33 (Chr22: 23279752-51103692, hg19) was predicted by the CGH plus SNP array.Abbreviations: wt, wild type; m, mutant; CGH, comparative genomic hybridization; SNP, single nucleotide polymorphism.

• 

  Fig. 2 Results of haplotype analysis in the five families. Families of Patient 1-5 are presented as a number accordingly.

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