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Clinical characterisation of the CABP4-related retinal phenotype
Arif O Khan1, May Alrashed, Fowzan S Alkuraya
1Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia. arif.khan@mssm.edu
Background:
Calcium binding protein 4 (CABP4), specifically located in photoreceptor synaptic terminals, has been associated with congenital stationary night blindness based on this clinical diagnosis being made for three individuals from two Swiss families with CABP4 mutations; however, the few reported cases limit phenotype-genotype correlation. We expand the number of reported patients with CABP4 mutations and clinically characterise the CABP4-related phenotype.
Methods:
A retrospective case series of 11 individuals (age 2â 26 years; four consanguineous families) with early-onset retinal dysfunction found to harbour CABP4 mutations after a strategy of homozygosity analysis and/or candidate gene testing.
Results:
The 11 patients from four families harboured the same homozygous CABP4 mutation (c.81_82insA; p.Pro28Thrfs*4) and shared a common haplotype. All patients had congenital nystagmus, stable low vision, photophobia and a normal or near-normal fundus appearance. None complained of night blindness when specifically questioned. Eight had hyperopic cycloplegic refractions (≥+ 1.00 dioptre). Electroretinography showed an electronegative waveform response to scotopic bright flash, near-normal to subnormal rod function, and delayed and/or decreased cone responses or was non-recordable. Although these and previously reported families with homozygous mutations were labelled with different clinical diagnoses, all had similar clinical features.
Conclusion:
These typical clinical features, which do not include a symptom of night blindness, suggest CABP4 mutations. The phenotype is best uniformly termed congenital cone-rod synaptic disorder. In Saudi Arabia a founder homozygous c.81_82insA CABP4 mutation is a recurrent cause.
Insights
Mutations in Calcium Binding Protein 4 (CABP4) cause a congenital cone-rod synaptic disorder, characterized by nystagmus and vision loss, not night blindness. This finding refines diagnosis for retinal dysfunction.
Area of Science:
- Ophthalmology
- Genetics
- Neuroscience
Background:
- Calcium Binding Protein 4 (CABP4) is located in photoreceptor synaptic terminals.
- Previous studies linked CABP4 mutations to congenital stationary night blindness, but limited cases hindered phenotype-genotype correlation.
- This study expands the cohort of patients with CABP4 mutations to better define the associated phenotype.
Purpose of the Study:
- To clinically characterize the phenotype associated with CABP4 mutations.
- To establish a more accurate diagnostic term for the observed retinal dysfunction.
Main Methods:
- A retrospective case series included 11 individuals (ages 2-26) from four families with early-onset retinal dysfunction.
- Genetic analysis involved homozygosity testing and candidate gene screening to identify CABP4 mutations.
- Clinical characterization included ophthalmic examinations, refractive error assessment, and electroretinography.
Main Results:
- All 11 patients shared a homozygous CABP4 mutation (c.81_82insA; p.Pro28Thrfs*4) and common haplotype.
- Clinical features included congenital nystagmus, stable low vision, photophobia, and normal fundus appearance; night blindness was absent.
- Electroretinography revealed electronegative waveforms, impaired rod and cone function, consistent across patients despite varied prior diagnoses.
Conclusions:
- The consistent clinical features, notably the absence of night blindness, strongly suggest CABP4 mutations.
- The phenotype is best described as congenital cone-rod synaptic disorder.
- A founder mutation (c.81_82insA) in CABP4 is a recurrent cause of this disorder in Saudi Arabia.