What is the most likely diagnosis and appropriate genetic testing for a 23‑year‑old male with autosomal‑recessive retinitis pigmentosa, mild‑to‑moderate intellectual disability, aggressive behavior, normal brain MRI, no other systemic anomalies, and similarly affected siblings?

SCAPER-Associated Syndromic Retinitis Pigmentosa

The most likely diagnosis is SCAPER-associated autosomal recessive syndromic retinitis pigmentosa with intellectual disability, and the appropriate genetic testing is whole exome sequencing or a comprehensive retinal dystrophy gene panel that includes SCAPER. 1

Clinical Rationale

This presentation is highly characteristic of SCAPER mutations, which cause a specific syndrome combining:

• Autosomal recessive retinitis pigmentosa affecting multiple siblings 1
• Mild to moderate intellectual disability 1, 2
• Behavioral disturbances including attention-deficit/hyperactivity disorder and aggression 1
• Normal brain MRI (no structural brain abnormalities) 1
• Absence of other systemic anomalies 1

The constellation of features in this 23-year-old male with affected siblings fits precisely with the syndromic form of SCAPER-related disease, where biallelic mutations cause both retinal degeneration and neurodevelopmental manifestations. 1, 2

Recommended Genetic Testing Approach

First-tier testing should be chromosomal microarray (CMA) to rule out copy number variants, as this has the highest diagnostic yield (7.8-10.6%) in unexplained intellectual disability and should be performed before single-gene testing. 3, 4

Second-tier testing should be whole exome sequencing (WES) or a comprehensive retinal dystrophy panel (300+ genes) that includes SCAPER, as this approach identifies mutations in 30-80% of retinitis pigmentosa cases depending on technology used. 1, 5 WES is particularly valuable because:

• It can identify mutations in known RP genes that may present with atypical features 5
• It allows detection of novel variants in SCAPER and other syndromic RP genes 1, 2
• It provides comprehensive coverage when the phenotype suggests a genetic syndrome 4

Parental testing should follow proband testing to confirm biallelic inheritance pattern and provide accurate genetic counseling for family planning. 1, 6

SCAPER Gene and Phenotype

SCAPER (S-phase Cyclin A-Associated Protein residing in the Endoplasmic Reticulum) mutations cause a recognizable syndrome:

• Ocular findings: Typical retinitis pigmentosa with waxy optic disc pallor, attenuated retinal vessels, bone spicule pigmentation, and progressive night blindness 7, 1
• Neurodevelopmental features: Mild to moderate intellectual disability with attention-deficit/hyperactivity disorder and behavioral problems including aggression 1, 2
• Inheritance: Autosomal recessive with biallelic mutations (compound heterozygous or homozygous) 1, 2
• Expression pattern: SCAPER is expressed in retina (photoreceptor layers, retinal pigment epithelium) and brain from early embryonic development 1

Important Clinical Nuances

Phenotypic variability exists: While most SCAPER cases present with both retinal and neurodevelopmental features, rare cases of isolated retinitis pigmentosa without intellectual disability have been reported, suggesting variable expressivity. 8 However, given this patient has both features with affected siblings, syndromic SCAPER disease is most likely.

The normal brain MRI is expected and does not exclude SCAPER mutations, as the intellectual disability results from functional rather than structural brain abnormalities. 1

Behavioral manifestations are part of the syndrome, not secondary psychiatric conditions, and include attention-deficit/hyperactivity disorder and aggression as core features. 1, 2

Critical Pitfalls to Avoid

Do not rely solely on clinical diagnosis without molecular confirmation, as genetic testing is essential for accurate genetic counseling, recurrence risk assessment (25% for future siblings), and potential eligibility for emerging gene-specific therapies. 6, 1

Do not assume all retinitis pigmentosa with intellectual disability has the same cause, as multiple genetic syndromes can present similarly (including Bardet-Biedl syndrome, Usher syndrome type 1, and other ciliopathies), making molecular diagnosis critical for prognosis and management. 5

Do not overlook family segregation analysis, as confirming that both parents are heterozygous carriers strengthens the diagnosis and provides definitive recurrence risk counseling. 1, 6