First missense mutation in CEP78 in a family with cone-rod dystrophy, sensorineural hearing loss, obesity and subfertility

Abstract

Purpose : Bi-allelic truncating mutations in CEP78 were recently found to cause a recognizable phenotype characterized by cone-rod dystrophy (CRD) with sensorineural hearing loss. Here, we aimed to identify the causal mutation in a family presenting with CRD and sensorineural hearing loss, and to explore ciliary phenotypic features in homozygous affected individuals and heterozygous carriers.

Methods : Whole exome sequencing was performed in 2 affected siblings using the SureSelectXT V6 kit (Agilent), followed by sequencing on a NextSeq 500 instrument (Illumina). Segregation analysis in 5 additional family members was done using Sanger sequencing. Skin biopsies and nasal brush samples were obtained from both affected individuals and their parents to study ciliary structure and length.

Results : We identified the following novel missense mutation in CEP78 in a homozygous state in both affected individuals: c.449T>C, p.(Leu150Ser). This mutation was found to segregate with disease in 7 individuals. The affected nucleotide and amino acid are highly conserved, and the change is predicted to be damaging by several in silico prediction programs (SIFT, MutationTaster, PolyPhen2). Detailed phenotyping revealed the presence of additional features reminiscent to a ciliopathy such as recurrent airway infections in the affected individuals and heterozygous carriers, obesity in both parents and both affected individuals, and subfertility in one affected male. Functional studies are currently ongoing on fibroblasts, nasal epithelial cells and semen samples to investigate if this CEP78 mutation affects ciliary structure, and if this is associated with the recurrent airway infections and subfertility observed.

Conclusions : In conclusion, we identified the first missense mutation in CEP78 causing CRD and sensorineural hearing loss, a recently identified syndrome distinct from Usher syndrome. The affected individuals as well as heterozygous carriers studied here displayed additional features, suggesting a potential involvement of CEP78 in more complex ciliopathies than previously anticipated.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.