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

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.

A novel de�novo variant of LAMA2 contributes to merosin deficient congenital muscular dystrophy type 1A: Case report

“…The majority of reported genetic variations of MDC1A are homozygous or compound heterozygous variants (6,7). De novo variations in contrast are not common events and only a few have been reported in patients with MDC1A (8)(9)(10).…”

Identification of a compound heterozygous missense mutation in LAMA2 gene from a patient with merosin‐deficient congenital muscular dystrophy type 1A

“… 6 , 10 Moreover, de novo mutations are the rare events and a few have been reported in MDC1A patients. 11 , 12 …”

“…The early diagnosis of MDC1A is based on high serum concentrations of CK, deficiency of merosin in skin or muscle biopsy, alterations in white matter on brain, and clinical examination. 11 Previous studies reported the efficiency of whole‐exome sequencing (WES) for the molecular diagnosis of the congenital muscular dystrophy. 13 , 14 However, use of WES method is not cost‐effective in patients with clinical overlap.…”

Whole Exome Sequencing as a Diagnostic Tool for Unidentified Muscular Dystrophy in a Vietnamese Family

“…Diagnosis of LAMA2 -related muscular dystrophy is based on clinical findings, elevated serum creatine kinase, abnormal white matter signal on T2-weighted MRI, complete or partial laminin α2 subunit on IHC staining of muscle, and biallelic mutation of the LAMA2 gene [ 18 ]. Molecular diagnosis of LAMA2 -related muscular dystrophy provides the advantage of avoiding invasive muscle biopsy [ 19 , 20 ] and allows determination of the inheritance pattern. DNA testing is performed for other family members when the mutation in the proband is known.…”