B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype–phenotype associations in the muscular dystrophy-dystroglycanopathies

Reza Maroofian, Moniek Riemersma, Lucas T. Jae, Narges Zhianabed, Marjolein H. Willemsen, Willemijn M. Wissink-Lindhout, Michèl A. Willemsen, Arjan P. M. de Brouwer, Mohammad Yahya Vahidi Mehrjardi, Mahmoud Reza Ashrafi, Benno Kusters, Tjitske Kleefstra, Yalda Jamshidi, Mojila Nasseri, Rolph Pfundt, Thijn R. Brummelkamp, Mohammad Reza Abbaszadegan, Dirk J. Lefeber, Hans van Bokhoven

The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2. The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes. In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.