Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: SRPK3

Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the panel as Green (no evidence for monogenic association).

Created: 4 Aug 2025, 1:08 p.m. | Last Modified: 4 Aug 2025, 1:08 p.m.

Panel Version: 5.12

Comment on list classification: There is no evidence that monogenic variants in this gene cause myopathy. Digenic inheritance is not currently accommodated in tiering. The TTN gene is already included on this panel as Green meaning cases could still be picked up if a TTN variant is present. As this is digenic, this gene has been made Red and tagged 'digenic'.

Created: 19 Jun 2025, 12:57 p.m. | Last Modified: 19 Jun 2025, 12:57 p.m.

Panel Version: 5.8

Based on the Srpk3-null mouse phenotype, which resembles human centronuclear myopathy (PMID:16140986), Töpf et al. 2024 (PMID: 38429495) analysed exome datasets from patients with neuromuscular disease for deleterious variants in the SRPK3 gene. They identified 35 affected individuals from 25 families. Main phenotype is most cases comprised early-onset myopathy and muscle weakness.

Two families displayed dilated cardiomyopathy, associated with a dominantly inherited heterozygous truncating variant in TTN. Authors noted that the myopathic phenotype in these families only manifested when SRPK3 and TTN variants were found in combination, indicating digenic inheritance. The cooccurrence of SRPK3 and TTN variants was then assessed in the remaining cohort, and replicated in all index cases.

Segregation analysis was done in 20 families, showing that in most cases SRPK3 variants were inherited from an unaffected mother and were present in all affected male siblings, with exception of 7 families where variants did not cosegregate with the disease in 9 unaffected male carriers.

Similar results were found by Sharkova et al. 2025 (PMID: 39667923) who report two sibs with prenatal onset muscular dystrophy and digenic variants in the SRPK3 and TTN gene. Myopathy was not present in individuals who carried the SRPK3 but not the TTN variant.

No reports of intellectual impairment or neurological involvement similar to other reports (PMID: 36993381; 39073169) was found across the 26 myopathic families.

Created: 19 Jun 2025, 12:56 p.m. | Last Modified: 19 Jun 2025, 12:56 p.m.

Panel Version: 5.7

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

• 16140986
• 38429495
• 39667923

Green List (high evidence)

multiple cases with: "that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene."
Sources: Literature

Created: 24 Aug 2024, 1:26 p.m.

Mode of inheritance
Other

Publications

• 38429495