What is the likely diagnosis and recommended genetic work‑up for multiple siblings with autosomal‑recessive retinitis pigmentosa, intellectual disability, aggressive behavior, normal brain MRI and no other systemic findings?

Likely Diagnosis: SCAPER-Related Syndrome

The clinical presentation of autosomal recessive retinitis pigmentosa with intellectual disability, behavioral disturbance (aggression), and normal brain MRI in multiple siblings is most consistent with SCAPER-related syndrome, and genetic testing should begin with whole exome sequencing or targeted SCAPER gene analysis. 1

Clinical Features Supporting SCAPER Mutations

The constellation you describe matches precisely what has been documented with SCAPER mutations:

• Retinitis pigmentosa with typical funduscopic findings including bone spicule pigmentation, attenuated retinal vessels, and waxy optic disc pallor 1
• Mild to moderate intellectual disability affecting multiple siblings in an autosomal recessive pattern 1
• Behavioral disturbances specifically including attention-deficit/hyperactivity disorder and aggression 1
• Normal brain MRI despite neurodevelopmental involvement, as SCAPER affects cellular function rather than gross brain structure 1
• No other systemic abnormalities, distinguishing this from other syndromic forms of retinitis pigmentosa 1

Recommended Genetic Work-Up

First-Tier Testing

Whole exome sequencing (WES) is the most efficient initial approach for this presentation, as it will capture SCAPER mutations and other rare autosomal recessive causes simultaneously 2

• SCAPER mutations are identified through biallelic pathogenic variants (homozygous or compound heterozygous) 1
• WES has a diagnostic yield of 15-25% for neurodevelopmental disorders when chromosomal microarray is negative 2
• Given the consanguinity implied by autosomal recessive inheritance in multiple siblings, homozygous mutations are likely 1

Alternative Targeted Approach

If WES is not immediately accessible, targeted SCAPER gene sequencing should be performed:

• Sequence all coding exons of SCAPER looking for deletions, insertions, or nonsense mutations 1
• The mutations documented include frameshift deletions and insertions causing premature protein truncation 1
• Confirm biallelic inheritance by testing both parents as obligate carriers 1

Complementary Testing

Chromosomal microarray analysis (CMA) should be performed if not already done, though the yield is lower given the normal MRI and lack of dysmorphic features 2:

• CMA identifies clinically relevant copy number variants in approximately 40% of children with autism spectrum features, but lower in isolated RP with intellectual disability 2, 3
• This helps exclude microdeletion/microduplication syndromes 2

Other Differential Diagnoses to Consider

While SCAPER is most likely, the genetic work-up should also capture:

Less Likely but Possible Causes

• RP1 mutations can cause autosomal recessive RP, but intellectual disability and behavioral problems are not typical features 4
• MFRP mutations cause posterior microphthalmos with RP and foveoschisis, but these patients have microphthalmos on examination which you would have noted 5
• Fragile X syndrome should be excluded given intellectual disability and behavioral issues, though RP is not a feature; testing yield is approximately 0.5% in unselected cohorts with neurodevelopmental disorders 2

Critical Diagnostic Pitfalls

Do not pursue extensive metabolic or mitochondrial work-up initially unless additional features emerge:

• The normal brain MRI argues strongly against most metabolic disorders that would cause this triad 2
• SCAPER is ubiquitously expressed in retina and brain from early embryonic development, explaining the isolated retinal and neurodevelopmental phenotype without structural brain abnormalities 1

Ensure complete ophthalmologic documentation including:

• Electroretinography (ERG) showing rod-cone dystrophy pattern 1
• Optical coherence tomography (OCT) to document retinal layer involvement 1
• This confirms true retinitis pigmentosa rather than other pigmentary retinopathies 5, 6

Genetic Counseling Implications

The recurrence risk for future siblings is 25% with each pregnancy if both parents are confirmed carriers of SCAPER mutations 2, 1:

• Both parents should undergo carrier testing once a mutation is identified 1
• Prenatal diagnosis and preimplantation genetic diagnosis become options for future pregnancies 2
• Extended family screening may identify other carriers, particularly in consanguineous families 1