Abstract
We reported a neonate presenting with muscle weakness, hypotonia, and joint contractures
since birth. Investigations revealed significantly elevated creatinine-phosphokinase,
abnormal electromyography suggestive of muscle disease and normal magnetic resonance
imaging (MRI) of the brain. Exome sequencing revealed homozygous pathogenic mutations
in LAMA2 (NM_000426.3: c.7881T > G, p.(His2627Gln)) and a heterozygous likely-pathogenic mutation
in COL6A2 (NM_001849.3: c.1970–2A > G). Parental segregation by Sanger sequencing confirmed
a heterozygous carrier state for the LAMA2 variant in both parents, thus confirming the diagnosis of autosomal recessive LAMA2-muscular
dystrophy (LAMA2-MD) in the proband. The COL6A2 variant segregated with the as-yet asymptomatic mother. Musculoskeletal MRI of the
proband at 12 months of age revealed peripheral involvement of the vastii, rectus
femoris, gastrocnemius and the soleus, with relative central sparing, without areas
of fatty infiltration; not serving to distinguish clearly between LAMA-MD and COL6A2-
related disease. Reverse phenotyping of a 27-year-old mother revealed a normal musculoskeletal
MRI and clinically absent red flags. Potential explanations for the heterozygous likely-pathogenic
COL6A2 variant in the proband and the mother include (a) a coexisting diagnosis of autosomal
dominant COL6A2-related myopathy, likely Bethlem myopathy, which has a variable clinical
phenotype and age of onset; (b) a carrier state for autosomal recessive Ullrich congenital
muscular dystrophy; or (c) a heterozygous COL6A2 variant contributing as a synergistic factor along with homozygous LAMA2 mutation. The couple was offered genetic counseling regarding the proband and the
future pregnancies.
Keywords
next-generation sequencing - arthrogryposis - muscle disorders - genetic counseling
- dual diagnosis
