CABP4

Inheritance Pattern: AR

Disease ID:MONDO:0012490

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012490

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0020300

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012490

Submitter: ClinGen

Variants in the *CABP4* gene were first reported in relation to cases of night blindness with autosomal recessive inheritance in the year 2006 (Zeitz et al., PMID: 16960802). The spectrum of disease has subsequently expanded to include affected patients described with congenital cone-rod synaptic disorder (PMID: 19074807), Leber congenital amaurosis (PMID: 20157620), incomplete congenital stationary night blindness similar to Åland eye disease (PMID: 28002560), photoreceptor-bipolar cell transmission disorder (PMID: 29525873), or congenital stationary synaptic dysfunction (PMID: 28559085). These affected patients exhibit reduced visual acuity, often with onset in early childhood, that may remain stable for some time following diagnosis. Additional features can include nystagmus, photophobia, strabismus, color vision defects, night blindness, and/or electroretinogram responses showing an electronegative waveform or reduced amplitudes from cones and/or rods. A recent publication has also shown co-segregation of a *CABP4* variant with affected status in a family with autosomal dominant inheritance of nocturnal frontal lobe epilepsy (PMID: 29108277). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the cases with a recessive mode of inheritance shared a biallelic loss-of-function mechanism, with overlapping phenotypes that were consistent with a single spectrum of disease. On the other hand, the autosomal dominant family was distinguished by the epilepsy phenotype that had not previously been noted among heterozygous carriers from the autosomal recessive pedigrees. Therefore, cases caused by inherited *CABP4* variants have been split into two separate disease entities, with the present curation focusing on autosomal recessive cases referred to as *CABP4*-related retinopathy. Eight suspected disease-causing variants were scored as part of this curation (three nonsense, two frameshift, two missense, and one disrupting a canonical splice site), which have been collectively reported in seven probands in six publications (PMID: 16960802 PMID: 19074807 PMID: 20157620 PMID: 28002560 PMID: 29525873 PMID: 28559085 ). All probands were homozygous or compound heterozygous for their respective variants, and none were reported to have consanguineous parents. One family had evidence of the variant segregating with affected status, but did not have a sufficient number of affected members to contribute to the scoring (PMID: 20157620). The mechanism of pathogenicity appears to be biallelic loss-of-function, characterized in some cases by frameshift, nonsense, or canonical splice site variants predicted to result in nonsense-mediated decay. This gene-disease association is also supported by experimental evidence that *CABP4* exhibits its highest expression levels in retina tissue (PMID: 30239781). *CABP4* encodes a calcium-binding protein that localizes to the presynaptic region and interacts with the Cav1.4 channel (encoded by the *CACNA1F* gene) to modulate its voltage activation (PMID: 15452577). A mouse model harboring a homozygous deletion of exons 1 and 2 recapitulates one of the features of the human patients by exhibiting reduced light-adapted and dark-adapted ERG responses, as well as reduced current responses from rod outer segments and reduced voltage-clamp flash measurements from rod bipolar cells (PMID: 15452577). Underlying these functional defects are histological abnormalities including thinning of the outer plexiform layer, fewer photoreceptor terminals in the outer plexiform layer, flat rod spherules and cone pedicles, and abnormal localization of presynaptic cytomatrix markers (PMID: 15452577). In summary, *CABP4* is definitively associated with *CABP4*-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina GCEP on September 3rd, 2026 (SOP Version 12).