Congenital Muscular Dystrophy-Dystroglycanopathy (MDDGA1) in a Consanguineous Family with Compound Heterozygous Mutations of the POMT1 Gene and Variable Clinical Severity

Background/Purpose: Congenital muscular dystrophies-dystroglycanopathies with brain and eye anomalies (MDDGA) are genetically heterogeneous autosomal recessive disorders with characteristic brain and eye malformations and congenital muscular dystrophy. We report on a consanguineous family with two sisters with MDDGA1 in which homozygosity mapping failed to elucidate the causal mutation.

Methods: Brain and muscle MRI were performed. Linkage analysis based on informative microsatellite markers, whole exome sequencing and data analysis were applied.

Results: We report on two female patients (P1, P2) from a consanguineous family who presented in early infancy with generalized muscle hypotonia and primary microcephaly. Brain MRI revealed different degrees of hypoplasia of the cerebellar vermis and a hypoplastic corpus callosum. P1 needed a PEG because of pronounced dysphagia at the age of eight years and P2 developed a cardiomyopathy at the age of four years. Muscle biopsy analysis (P1) revealed a muscular dystrophy with reduced expression of α-dystroglycan in immunoblot analyses. Muscle MRI and linkage analyses failed to elucidate a candidate gene. Applying whole exome sequencing identified a compound heterozygous POMT1 gene mutation, which segregate with the phenotype in the pedigree.

Conclusion: The phenotype (P1, P2) is in line with the phenotypic spectrum of POMT1 mutations. Compound heterozygosity of disease-causing mutations is not generally anticipated in consanguineous marriages; thus, these mutations typically elude conventional homozygosity mapping. Population genetic studies have recently raised the proposal that compound heterozygosity in consanguineous marriages, should be taken heed of by considering population sub-structure and factors as well.