JAG2

Inheritance Pattern: AR

Disease ID:MONDO:0030456

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0030456

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

JAG2 encodes jagged canonical Notch ligand 2, one of several ligands that activate Notch and related receptors. JAG2 was first reported in relation to autosomal recessive limb girdle muscular dystrophy in 2021 (Coppens et al., PMID: 33861953). Among the 27 patients from 16 families described to date, symptom onset ranges from infancy to adolescence/young adulthood. Muscle weakness is typically progressive with lower extremity and proximal dominance; loss of ambulation occurs in a subset of individuals. Reduced or absent deep tendon reflexes are common, and serum CK is normal or mildly elevated. Muscle biopsy findings are primarily dystrophic but may also include myopathic features. Additional features observed in some patients include scoliosis, joint contractures, ptosis and mild facial weakness, muscle atrophy or hypertrophy, cardiac features, asymptomatic moderate respiratory muscle weakness, intellectual disability or global developmental delay, speech delay, and autism spectrum disorder. Eighteen variants (13 missense, 1 in-frame indel, 1 nonsense, 2 frameshift, and 1 large deletion) reported in 16 probands in three publications (PMID: 33861953, 34878394, 39121631) are included in this curation. Co-segregation of JAG2 variants in affected family members was observed in multiple families, including three with at least three affected individuals. The mechanism of pathogenicity appears to be loss of function. However, additional investigation is needed as the effects of missense variants on gene function have not yet been determined, and many missense variants were identified in a homozygous state, often in consanguineous families. This gene-disease relationship is also supported by experimental evidence, including altered Notch pathway gene expression in patient muscle tissue and murine myoblasts following shRNA-mediated JAG2 knockdown as well as age-related locomotor decline in Drosophila following RNAi-mediated downregulation of Serrate (JAG2 ortholog)-dependent Notch signaling in adult muscle progenitors (PMID: 33861953, 39121631). In summary, there is moderate evidence supporting the relationship between JAG2 and autosomal recessive limb girdle muscular dystrophy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies GCEP on August 13, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0030456

Submitter: PanelApp Australia