Exploring the diverse clinical and variant spectrum of CEP78‐associated syndrome: Novel pathogenic variants identified in a case series

Abstract

AbstractDual sensory impairment, commonly referred to as combined hearing and vision loss, can stem from a diverse spectrum of conditions, each presenting with its unique set of clinical characteristics. Our understanding of dual sensory impairment has expanded significantly in the past decade, broadening the scope of genetic differential diagnoses, including genes such as CEP250, ARSG, TUBB4B, CEP78, and ABHD12. A case series including three patients from two families with genetically diagnosed CEP78‐associated cone–rod dystrophy was identified. We collected and reviewed their clinical records, imaging data, and genetic testing results. In addition, a comprehensive literature review was conducted on the phenotype and the genetic testing modality employed in all published CEP78 cases through a PubMed search using the keyword “CEP78.” A retinal dystrophy panel detected a novel homozygous CEP78 pathogenic variant (c.1447C>T, p.Arg483*) in siblings—Cases 1 and 2—from Family 1. Both teenagers have a clinical diagnosis of cone–rod dystrophy with presumed normal hearing. Case 3 from Family 2, diagnosed with cone–rod dystrophy and early‐onset hearing loss, was found to carry a CEP78 pathogenic variant (c.1206‐2A>C) and a likely pathogenic variant (c.856_857del, p.Leu286Glyfs*12) also through panel‐based genetic testing. Intriguingly, neither of these variants was reported in an affected sibling's clinical whole‐exome sequencing (WES) report when performed in 2015. A review of CEP78‐related literature unveiled that the initial report linking CEP78 to cone–rod dystrophy and hearing loss was published in September 2016. Any pathogenic variant found in CEP78 before 2016 would have been categorized as a “clearly disruptive variant in a gene of uncertain significance (GUS)” and might not have been reported in the WES report. It is important to acknowledge that our understanding of genotype–phenotype associations is undergoing rapid expansion. It is also crucial to recognize that repeat genetic testing may represent a fundamentally different approach, given the technological advancements not only in the coverage of the sequencing but also in the more comprehensive understanding of genotype–phenotype associations. This case series also enriches the existing CEP78 literature by providing phenotypic details of the youngest case of CEP78‐associated retinopathy reported in the literature (Case 2), which expands our perspective on the natural history of disease in this disorder.