Submission Details

The relationship between POMGNT1 and autosomal recessive myopathy caused by variation in POMGNT1 (muscular dystrophy-dystroglycanopathy types 3A (congenital with brain and eye anomalies) and 3B (congenital with mental retardation) included)), has been evaluated using the ClinGen Clinical Validity Framework as of August, 2020. The gene is also associated with Muscular dystrophy-dystroglycanopathy (limb-girdle), type 3C, and referred to as LGMD2O and LGMD R15 POMGNT1-related in the literature (PMID: 30055862). However, the two individuals reported with the LGMD phenotype do not meet the LGMD GCEP's phenotype criteria. Therefore, the LGMD phenotype, although potentially part of the spectrum, has not been described in individuals with POMGNT1 variants. The association myopathy caused by variation in POMGNT1 was made using case-level and experimental data. The POMGNT1 gene is located on chromosome 1p34.1 and encodes multiple transcript variants. The commonly referred transcript (NM_017739.3) is 2.7 kb long with 22 exons encoding a 660-amino acid protein. More than 100 pathogenic variants reported in humans with autosomal recessive myopathy caused by variation in POMGNT1 are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. Myopathy caused by variation in POMGNT1 encompasses a spectrum of phenotypes including severe forms with muscle-eye-brain disease, Walker-Warburg syndrome and muscular dystrophy dystroglycanopathy with intellectual disability. Patients often show an elevated serum creatine kinase and progressive muscle weakness. POMGNT1 has been reported in association with autosomal recessive myopathy caused by variation in POMGNT1 as early as 2001 by Yoshida et al (PMID: 11709191).

OMIM entities: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 3; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 3; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3; Retinitis pigmentosa 76.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities may be lumped into one disease entity, autosomal recessive myopathy caused by variation in POMGNT1. However, the patients with an asserted LGMD phenotype do not meet the GCEP-specific LGMD phenotype criteria and therefore are not scored. Similarly, individuals with isolated retinitis pigmentosa are not scored.

Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 4 publications (PMID: 11709191, 12588800, 12788071, 22419172). POMGNT1 variants are also reported in patients with isolated Retinitis Pigmentosa without other syndromic features (PMID: 26908613). These probands are noted but not scored in this curation. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.

The mechanism for disease is expected to be biallelic loss of function.

Summary of Experimental Data (5.5 points): This gene-disease relationship is supported by animal models, expression studies, functional assays and rescue evidence. POMGNT1 catalyzes the transfer of N-acetylglucosamine to O-mannose of alpha-dystroglycan and interacts with other proteins in the glycosylation pathway of alpha-dystroglycan in skeletal muscle (PMID: 16584074, 17034757, 17869517, 23454088). POMGNT1 is expressed ubiquitously, including the retinal photoreceptors and brain, localizing to the Golgi complex and the nucleus (PMID: 27375352). Mouse models with POMGNT1 knocked out recapitulate the human muscle-eye-brain disease phenotype (PMID: 16458488, 23454088, 19114101).

In summary, the gene-disease relationship between POMGNT1 and myopathy caused by variation in POMGNT1 is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on August 11, 2020 (SOP Version 7).