Uniparental disomy unmasks a homozygous mutation of POMGNT1 in a case of muscle-eye-brain disease

Introduction: POMGNT1, encoding protein O-mannose beta-1,2-N-acetylglucosaminyltransferase, is one of the genes responsible for dystroglycanopathy (DGP), which includes muscle-eye-brain disease (MEB) and other phenotypes. Here, we report a case of MEB due to a homozygous mutation in POMGNT1 unmasked by uniparental disomy (UPD). Case Presentation: The patient, an 8-month-old boy, was admitted for “mental and motor retardation”. He raised his head unsteadily at 4-month-old. He could not roll over or sit without support at 8 months. Physical examination found esotropia, hypotonia, and muscle weakness with the muscle strength of limbs between level 3 to level 3+, predominantly proximal. Serum creatine kinase was 1799 IU/L. Brain magnetic resonance imaging showed white matter abnormal signal, a flat brainstem, and cerebellar hypoplasia. Trio-based whole-exome sequencing identified a homozygous variant c.636C>T (p.Phe212Phe) in exon7 of POMGNT1 in the patient, a heterozygous variant c.636C>T in the father, and wild type in the mother. Quantitative polymerase chain reaction found no abnormal copy number in exon 7. Chromosomal microarray analysis revealed a 99319 kb loss of heterozygosity (LOH) on 1q21.2-q44 and a 120451 kb LOH on 1p36.33-p11.2 encompassing POMGNT1, which indicated UPD. RNAseq verified that the variant c.636C>T was a splice-site mutation. Discussion: UPD is defined as two copies of a chromosome derived from one parent. The two copies can be maternal (UPDmat) or paternal (UPDpat). The case in the present study is the first case of DGP caused by UPDpat. Conclusion: In this study, our findings indicated that UPDpat could lead to MEB.