Submission Details

PAX7 is located on chromosome 1 at 1p36.13 and encodes the paired box 7 protein, which is a transcription factor. Though not the phenotype that is being curated here, PAX7 was first reported in 2017 in relation to an autosomal recessive neurodevelopmental condition with seizures in a pair of consanguineous siblings with a homozygous extended splice donor variant predicted to impact the last exon of isoform 3 only (Proskorovski-Ohayon et al., 2017, PMID: 28779497). We are curating the phenotype reported in 2019, where PAX7 was associated with autosomal recessive congenital myopathy with myasthenic-like onset, in a cohort of five patients from four consanguineous families with features including hypotonia, skeletal muscle atrophy, progressive scoliosis, and mild dysmorphic features (Feichtinger et al., 2019, PMID: 31092906). Additional features found in some patients included congenital contractures, growth deficiency, respiratory insufficiency and ptosis. These individuals generally presented at or shortly after birth, displayed a progressive myopathy and were not reported to have intellectual disability. The mechanism of disease is reported to be loss of function. Four variants were reported in a homozygous state (2 stop-gain, 1 splice acceptor, 1 missense) in five individuals (PMID: 31092906). Notably, all of these variants are located within the paired box (PD) domain, which is present in all three human isoforms of PAX7. This gene disease association is further supported by expression studies performed in mice which demonstrate the upregulation of PAX7 expression in quiescent satellite cells following satellite cell activation following muscle stimulation or trauma (PMIDs: 11030621, 24065826, 31092906). Additionally, PAX7- deficient mouse models recapitulate several aspects of the reported phenotype including postnatal myopathy, impaired motor skills, growth deficiency and malformation of the maxilla and nose (PMID: 8631261, 11030621). Tissue specific knock-out of PAX7 in mouse myoblasts has been shown to result in depletion of satellite cells and defective myogenesis following injury with cardiotoxin (PMID: 24065826). In summary, there is moderate evidence to support the association of PAX7 with autosomal recessive congenital myopathy with myasthenic-like onset. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated as Moderate by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date September 18th, 2020 as per SOP v7. It was reevaluated on March 31st, 2024. This record underwent an update in scoring to be consistent with SOP v10. No new evidence has been reviewed or added. As a result of this reevaluation, the classification did not change.