SEMA4A – Retinitis Pigmentosa

SEMA4A encodes a 760-amino-acid transmembrane semaphorin crucial for photoreceptor survival. Autosomal recessive variants in SEMA4A have been implicated in progressive rod-cone dystrophy, clinically classified as Retinitis Pigmentosa.

1. Clinical Validity

Initial mutation screening of 135 unrelated RP patients identified two semaphorin-domain missense variants—c.1033G>C (p.Asp345His) and c.1049T>G (p.Phe350Cys)—present only in affected individuals and absent in 100 controls (PMID:16199541). No segregation or additional families were reported, yielding limited genetic support.

ClinGen Category: Limited

Rationale: 2 probands with rare semaphorin-domain variants in 135 RP cases, no segregation or recurrence (PMID:16199541).

2. Genetic Evidence

Inheritance: Autosomal recessive.

Segregation: no affected relatives reported (0).

Case series: 2 unrelated probands with missense variants in conserved semaphorin motifs.

Variant spectrum: missense only; no loss-of-function or splice.

Recurrent/founder: none described.

Phenotypic note: rod-cone dystrophy (HP:0000510).

3. Functional Evidence

Knock-in mouse models for D345H and F350C variants exhibit progressive retinal degeneration, abnormal SEMA4A localization, and impaired endosomal sorting. Structural modelling confirmed critical conformation at residue 350. AAV-mediated Sema4A gene transfer rescues photoreceptor loss in homozygous knock-in and knockout mice (PMID:23360997).

Tier: Moderate

Rationale: in vivo knock-in/knockout models replicate phenotype; rescue experiments demonstrate causality.

4. Conflicting Evidence

The R713Q variant (c.2138G>A (p.Arg713Gln)) fails to segregate with disease in three families and is insufficient to cause RP in heterozygous or homozygous state, disputing its pathogenicity (PMID:28805479).

5. Integration & Conclusion

Two unrelated autosomal recessive missense variants in SEMA4A show limited genetic support for RP, bolstered by robust functional data in murine models. Additional familial segregation and replication in independent cohorts are needed to elevate clinical validity.

Key Take-home: Rare semaphorin-domain missense variants in SEMA4A are plausible causes of autosomal recessive retinitis pigmentosa, representing targets for therapeutic gene transfer.

References

• Journal of medical genetics • 2006 • Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases. PMID:16199541
• Nature communications • 2013 • A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration. PMID:23360997
• Ophthalmic genetics • 2018 • On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness. PMID:28805479

Evidence Based Scoring (AI generated)