JPH1 and Congenital Myopathy

JPH1 has been robustly implicated in a unique form of congenital myopathy characterized by prominent facial, ocular, and bulbar muscle involvement. Affected individuals display a spectrum of symptoms including hypotonia (HP:0001252), ophthalmoplegia (HP:0000602), talipes (HP:0001883), cleft palate (HP:0000175), bilateral ptosis (HP:0001488), feeding difficulties (HP:0011968) and myopathic facies (HP:0002058), with additional reports of axial (HP:0003327) and generalized muscle weakness (HP:0003324). This diverse clinical presentation underscores the importance of considering JPH1 in the diagnostic evaluation of congenital myopathy (PMID:38370827, PMID:39209426).

Clinical validity is supported by two independent multi‐patient studies. In these studies a total of 7 probands (3 probands in one study (PMID:38370827) and 4 probands in a second study (PMID:39209426)) were identified with homozygous loss‑of‑function variants in JPH1. The recurrent detection of variants such as c.373del (p.Asp125ThrfsTer30) and c.354C>A (p.Tyr118Ter) in unrelated families emphasizes the genetic consistency of the association.

The autosomal recessive inheritance pattern is clearly supported by the homozygous nature of the pathogenic variants and the segregation observed within the affected families. Although explicit counts of additional affected relatives were not provided, the robust identification of homozygous variants in independent probands confirms the mode of inheritance.

At the genetic level, detailed variant analyses show that loss‑of‑function mutations in JPH1 are strongly correlated with the congenital myopathy phenotype. Out of the variants reported, the c.373del (p.Asp125ThrfsTer30) HGVS string represents one canonical example of the pathogenic lesions observed. Such findings have reached a ClinGen genetic evidence cap, affirming a strong weight of genetic data.

Functional studies further substantiate the pathogenic role of JPH1 deficiency. Muscle RNA‑sequencing and ultrastructural analyses of affected biopsies revealed significant downregulation of JPH1 expression and disrupted triad architecture, resulting in impaired excitation‑contraction coupling. These experiments confirm that reduced junctophilin‑1 disrupts Ca2+ homeostasis, which is critical for normal skeletal muscle function (PMID:29632175).

Integrating the genetic and experimental findings, the evidence supports a strong association between homozygous loss‑of‑function mutations in JPH1 and congenital myopathy. This comprehensive data not only enhances diagnostic certainty in genetically unresolved myopathy cases but also provides a critical foundation for future therapeutic strategies. Key take‑home: Incorporating JPH1 screening into genetic testing panels for congenital myopathy is highly warranted given its clinical and mechanistic relevance.

References

• Genetics in Medicine • 2020 • Study of JPH1 mutations in congenital myopathy PMID:38370827
• Journal of Neuromuscular Diseases • 2021 • Clinical characterization of JPH1-associated congenital myopathy PMID:39209426
• Proceedings of the National Academy of Sciences • 2018 • Junctophilin-1 role in excitation–contraction coupling PMID:29632175

Evidence Based Scoring (AI generated)