POGLUT1 was first reported in relation to autosomal recessive limb-girdle muscular dystrophy-21 (LGMDR21) in 2016 (Servián-Morilla et al., PMID: 27807076). LGMDR21 is typically characterized by young-adult onset of slowly progressive proximal upper and lower limb muscle weakness and atrophy. Additional phenotypes such as scapular winging, calf pseudohypertrophy, and contractures have been reported. A unique feature of "inside to outside" fatty degeneration has been observed in muscle biopsy in reported probands.
Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two separate disease entities for autosomal recessive limb-gridle muscular dystrophy-21 (OMIM: 617232) and dominant Dowling-Degos disease 4 (OMIM: 615696). Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data.
Summary of Case Level Data: 10.8 POINTS. Variants in this gene have been reported in at least 9 probands in 2 publications (PMIDs: 31897643, 27807076). Variants in this gene segregated with disease in 1 additional family members in Family 1 (PMID: 31897643). Primary mechanism of disease associated is loss of function as reported in the literature (PMID: 27807076).
Summary of Experimental Data: 1 POINT. This gene-disease association is also supported by functional alteration in non-human cells (PMID: 29634421). A model constructed using C2C12 cultured mouse myoblasts demonstrated that POGLUT1 knockdown reduced Notch signaling, affecting key regulators of myogenic differentiation, including PAX7 decrease and MYOD increase. The perturbed Pax7/MyoD expression balance led to a premature myogenic differentiation and an increase in myotube size. This finding was pronounced in in response to strong POGLUT1 downexpression. Considering the proposed disease mechanism for LGMD is biallelic loss-of-function leading to reduced Notch signalling that affects skeletal muscle formation and regeneration, the functional alteration evidence seems to support the gene-disease relationship.
In summary, there is definitive evidence to support the relationship between POGLUT1 and autosomal recessive limb-girdle muscular dystrophy-21. 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 the meeting date of February 8th, 2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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