Genotype-phenotype correlation in congenital muscular dystrophies with defective O-glycosylation of #CHR:alpha_LOWER#-dystroglycan

Aims: Congenital muscular dystrophies with defective O-glycosylation of α-dystroglycan (dystroglycanopathies) are a heterogeneous group of autosomal-recessive diseases with a broad clinical spectrum ranging from Walker-Warburg syndrome (WWS) to limb girdle muscular dystrophy (LGMD). The aim of this study is to characterize genotype and phenotype of patients with confirmed dystroglycanopathy diagnosed in our genetic laboratory in the past 9 years.

Methods: Evaluation of the patients' medical reports and MR imaging. Linkage analysis and stepwise sequence analysis of POMT1, POMT2, POMGnT1, Fukutin, FKRP, LARGE, and ISPD.

Results: A total of 51 patients from 45 families with mutations confirming defective O-glycosylation were identified. Homozygous or compound heterozygous mutations were found in POMT1 (16 families), POMGnT1 (13), FKRP (5), Fukutin (4), LARGE (1), and ISPD (1). Only one mutation was recognized in five cases (POMGnT1: 2; FKRP: 2; LARGE: 1). Seventeen patients from 12 families were referred to us with the clinical diagnosis of WWS; in this cohort, mutations were predominantly identified in POMT1 (7/12 families) and only one family with mutations in POMGnT1, FKRP, FKTN, LARGE, and ISPD. Interestingly, among WWS patients with POMT1 mutation, exclusively truncating mutations were found. In all three WWS families with two or more affected offspring, a uniformly severe clinical presentation was observed. POMGnT1 mutations in our cohort uniformly resulted in muscle eye brain disease (12 families) or WWS. In 10 patients from 9 families, the diagnosis of LGMD2K was confirmed by identification of POMT1 mutations. A rather uniform LGMD2K phenotype with proximal muscle weakness and mental retardation was observed in six families homozygous for the POMT1 mutation Ala200Pro.

Conclusion: In our cohort, mutations were predominantly identified in POMT1 and POMGnT1. Our data support a genotype-phenotype correlation for POMT1 with truncating mutations resulting in WWS. Clinically well characterized families without identified mutation will now be included in genome-wide studies to identify further candidate genes involved in dystroglycanopathies.