Balkan Journal of Medical Genetics

A NOVEL SPLICE-SITE MUTATION ON THE MLC1 GENE LEADING TO EXON 9 SKIPPING AND MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS IN A TURKISH PATIENT
Türkyılmaz A1,*, Ünver O2, Ekinci G3, Türkdoğan D2
*Corresponding Author: Ayberk Türkyılmaz, M.D., Department of Medical Genetics, Marmara University School of Medicine, Fevzi Çakmak Quarter Muhsin Yazıcıoğlu Street No. 10 Üst Kaynarca, Pendik, İstanbul, Turkey. Tel: +90-505-812-0334. Fax: +90-216-625-4545. E-mail: ayberkturkyilmaz@gmail.com
page: 89

DISCUSSION

Megalencephalic leukoencephalopathy is a rare disorder, two phenotypes are observed in MLC. The classic phenotype of MLC is characterized by early-onset macrocephaly, mild motor developmental delay, seizures, ataxia, spasticity, and sometimes extrapyramidal findings; and generally mild mental regression. An improving phenotype of MLC has similar clinical features but these findings recover in time [1]. The diagnosis of MLC is established in individuals with typical clinical and brain MRI findings [3]. Description of homozygous mutations in the MLC1 or HEPACAM genes can prove the diagnosis of classic phenotype of MLC. Identification of a heterozygous HEPACAM pathogenic variant can establish the diagnosis of MLC with improving phenotype [4]. Our case was diagnosed on the basis of the classic phenotype’s clinical and radiological features including macrocephaly, mild motor developmental delay, bilateral, diffuse, symmetric structural white matter abnormalities, relatively sparing the cerebellum and bilateral subcortical temporal cysts. In the molecular study, a novel homozygous splicesite variant (NM_015166: c.768+2T>C) in intron 9 of the MLC1 gene was identified (Figure 2). The present variant has not been previously reported in population studies (ESP, ExAC, 1000G, and gnomAD). His father and mother were heterozygous. In silico analysis using Human Splicing Finder (HSF) and Mutation Taster was supportive of pathogenicity. According to the HSF prediction, the splice-site c.768+2T>C mutation most probably affecting splicing via alteration of the wild type donor splice site. For determination of the novel splice-site mutation’s effect, the exons 7-11 of MLC1 cDNA were amplified. Only a mutated single band (403 bp) appeared in the patient, but in his parents, a 460 bp wild-type and 403 bp mutated bands were detected. The Sanger sequencing of polymerase chain reaction (PCR) products showed that the 403 bp mutated allele matched the deletion of exon 9 in the MLC1 gene (Figure 3). In conclusion, cDNA analysis showed that the splice-site c.768+2T>C mutation gave rise to exon 9 skipping. In summary, we report the novel homozygous splicesite mutation in the MLC1 gene causing a classic phenotype of MLC. Functional effect of the splice-site mutation was explained by cDNA analysis and was contributed to the literature. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. (if applicable)

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