AUTHOR=Liu Yi-Dan , Tan Dan-Dan , Song Dan-Yu , Fan Yan-Bin , Fu Xiao-Na , Ge Lin , Wei Wei , Xiong Hui TITLE=Uniparental disomy for chromosome 1 with POMGNT1 splice-site variant causes muscle-eye-brain disease JOURNAL=Frontiers in Genetics VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1170089 DOI=10.3389/fgene.2023.1170089 ISSN=1664-8021 ABSTRACT=

POMGNT1, encoding protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1, is one of the genes responsible for dystroglycanopathy (DGP), which includes multiple phenotypes such as muscle-eye-brain disease (MEB), congenital muscular dystrophy with intellectual disability, and limb-girdle muscular dystrophy Here, we report a case of MEB that is the result of a homozygous variant of POMGNT1 that is revealed through uniparental disomy (UPD). An 8-month-old boy was admitted with mental and motor retardation, hypotonia, esotropia, early onset severe myopia, and structural brain abnormalities. A panel testing of genetic myopathy-related genes was used to identify a homozygous c.636C>T (p.Phe212Phe) variant in exon 7 of POMGNT1 in the patient, a heterozygous c.636C>T variant in the father, and the wild type in the mother. Quantitative polymerase chain reaction (q-PCR) revealed no abnormal copy numbers in exon 7. Trio-based whole-exome sequencing (trio-WES) revealed a possible paternal UPD on chromosome 1 of the patient. Chromosomal microarray analysis (CMA) revealed a 120,451 kb loss of heterozygosity (LOH) on 1p36.33-p11.2, encompassing POMGNT1, and a 99,319 kb loss of heterozygosity on 1q21.2-q44, which indicated UPD. Moreover, RNA sequencing (RNA-seq) verified that the c.636C>T variant was a splice-site variant, leading to skipping of exon 7 (p.Asp179Valfs*23). In conclusion, to the best of our knowledge, we present the first case of MEB caused by UPD, providing valuable insights into the genetic mechanisms underlying this condition.