Identification of a novel CABP4 frameshift variant and a secondary USH2A missense variant in congenital cone-rod...

Congenital cone-rod synaptic disease (CRSD) belongs to a group of genetically and clinically heterogeneous retinal disorders. Pathogenic variants in the CABP4 gene coding for the calcium-binding protein four can lead to this condition. Several disease-causing variants lead to this condition. In support of this, our current study aimed to genetically characterize a consanguineous Lebanese family with two young siblings who show CRSD.

Whole-exome sequencing identified a novel frameshift insertion in both affected siblings; c.363dup, p.(Lys122Glufs *21) in CABP4. The elder sibling carried a secondary homozygous missense variant; c.12575 G > A, p.(Arg4192His) in USH2A that is known to be associated with retinitis pigmentosa. CABP4 variant co-segregated with the phenotype in all the available family members. The ACMG guidelines classified CABP4 and USH2A variants as likely pathogenic and pathogenic, respectively. The secondary USH2A missense variant may lead to a more pronounced phenotype, necessitating an effective follow-up for better patient management.

The current findings highlight the involvement of CABP4 pathogenic variants in CRSD.