Submission Details

The relationship between POMT1 and POMT1-related myopathies, (including Congenital muscular dystrophy – POMT1-related, Muscle eye brain-POMT1-related and LGMD-POMT1-related) inherited in the autosomal recessive pattern, has been evaluated using the ClinGen Clinical Validity Framework as of July, 2021. This association was made using case-level and experimental data. The POMT1 gene is located on chromosome 9q34.13 and encodes multiple transcript variants. The commonly referred transcript in the literature (NM_007171.4) is 3.1 kb long with 20 exons encoding a 747-amino acid protein. The MANE select transcript, however, is NM_001077365.2, and has been referred in this curation. At least 70 pathogenic variants reported in humans with autosomal recessive Muscular Dystrophy Dystroglycanopathy are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. POMT1-related myopathies encompasses a spectrum of phenotypes including severe forms asserted in the literature as Walker-Warburg syndrome and congenital muscular dystrophy with or without intellectual disability and milder forms of limb-girdle muscular dystrophy with or without intellectual disability. LGMD patients often show an elevated serum creatine kinase and progressive muscle weakness. POMT1 has been reported in association with autosomal recessive POMT1-related myopathies as early as 2002 by Beltrán-Valero de Bernabé et al (PMID: 12369018). The first association with the LGMD phenotype was made in 2005 by Balci et al (PMID: 15792865). In curating evidence from the literature, several individuals who were reported to have an LGMD presentation were evaluated if they met the LGMD GCEP-specified phenotype criteria. A few probands (n=5) reported in PMIDs: 22549409, 31311558, 20065251 and 25088310 meet the LGMD phenotype definition specified by the LGMD GCEP.

Summary of Case Level Data (12 points): The association is seen in at least 21 probands in 11 publications (PMID: 15792865, 12369018, 27193224, 28157257, 25088310, 22549409, 28403181, 20065251, 15792865, 31311558, & 1787820). 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. Milder phenotypes have been proposed to arise due to hypomorphic variants.

Summary of Experimental Data (4 points): This gene-disease relationship is supported by animal models, expression studies, and functional assays. POMT1 product is an O-mannosyltransferase that catalyzes the transfer of O-mannose to alpha-dystroglycan and needs to interacts with the product of POMT2 to form a complex for its emzymatic function (PMID: 16698797). Pathogenic variants in POMT1 result in loss of POMT activity that can be assayed in patient cells as well experimental systems (PMID: 15522202). POMT1 is expressed ubiquitously, but during embryogenesis, it is found in neuronal tissues, including neural tube and eye, somites, and limb-bud mesenchyme (PMID: 15383666). Mice with homozygous knock out of POMT1 die early in embryogenesis, but loss of alpha-dystroglycan is eveident in these embryos. Similar loss of alpha-dystroglycan is also noted in fruit flies (PMID: 18385336).

In summary, the POMT1-autosomal recessive POMT1-related myopathies gene-disease relationship 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 ... (SOP Version 7).

OMIM entities: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 1; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1.

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. The LGMD GCEP recommended using the term, POMT1-related myopathies instead of the term, muscular dystrophy-dystroglycanopathy.