Identification of Two Novel LAMA2 Mutations in a Chinese Patient with Congenital Muscular Dystrophy.

Jing Zhou,Dingyuan Ma,Jianxin Tan,Jian Cheng,Yuguo Wang,Zhengfeng Xu,Jingjing Zhang,Gang Liu,Chunyu Luo

doi:10.3389/fgene.2018.00043

Abstract

Merosin-deficient CMD type 1A (MDC1A), caused by mutations of laminin subunit alpha 2 (LAMA2), is a predominant subtype of congenital muscular dystrophy (CMD). Herein, we described a Chinese patient with MDC1A who was admitted to hospital 17 days after birth because of marasmus and feeding difficulties. Mutations were identified by targeted capture and next generation sequencing (NGS) and further confirmed by Sanger sequencing. Paternity was confirmed by short tandem repeat analysis. Physical examination showed malnutrition, poor suck and appendicular hypotonia. Her serum CK levels were 2483 and 1962 U/L at 2 and 4 months of age, respectively. Brain magnetic resonance imaging performed at 1 month of age presented hyperintensity on T2-weighted images, T1-weighted images in parietal and occipital lobes, and diffusion-weighted image (DWI) as well as hypointensity on fluid attenuated inversion recovery (FLAIR) image; however, the cerebellum and corpus arenaceum were normal. At 7 months of age, delayed developmental milestones were observed, and she failed to turn her body over and raise her head up. A point mutation (c.1782+2T > G) and a frameshift duplication (c.8217dupT) in the LAMA2 gene were identified by targeted capture and NGS and further confirmed by Sanger sequencing. Moreover, genotyping with multiple short tandem repeat markers confirmed paternity to demonstrate that the point mutation is de novo. The frameshift duplication (c.8217dupT), inherited from her mother, was predicted to cause a substitution of Pro (P) to Ser (S) at the 2740th amino-acid residue and generate a prematurely truncated protein. The in silico analysis suggests that the mutation (c.1782+2T > G) may lead to aberrant splicing of LAMA2. Our case further confirms the heterogeneous clinical spectrum of MDC1A and presents two novel LAMA2 mutations to expand the mutation spectrum of MDC1A.

Highlights

The congenital muscular dystrophies (CMDs) are a highly heterogeneous group of neuromuscular disorders with preferentially autosomal recessive inheritance (Philpot et al, 1995)
We report a Chinese patient with Merosin-deficient CMD type 1A (MDC1A) carrying two novel mutations in the laminin subunit alpha 2 (LAMA2) gene
We identified a heterozygous point mutation (c.1782+2T > G) and a heterozygous frameshift duplication (c.8217dupT) in the LAMA2 gene, which were further confirmed by Sanger sequencing (Figure 2)

Summary

Introduction

The congenital muscular dystrophies (CMDs) are a highly heterogeneous group of neuromuscular disorders with preferentially autosomal recessive inheritance (Philpot et al, 1995). We report a Chinese patient with MDC1A carrying two novel mutations in the LAMA2 gene. Our in silico analysis suggests that one of the mutations is likely to cause aberrant splicing of LAMA2. We identified a heterozygous point mutation (c.1782+2T > G) and a heterozygous frameshift duplication (c.8217dupT) in the LAMA2 gene (reference sequence: NM_000426.3), which were further confirmed by Sanger sequencing (Figure 2).

Results

Conclusion