P435: CEP78-associated cone-rod dystrophy and hearing loss unveiled through retinal dystrophy panel: Resolving uncertainty in a family with inconclusive WES

Dual sensory impairment (DSI), commonly referred to as combined hearing and vision loss, can stem from a diverse spectrum of conditions, each presenting unique clinical characteristics. When evaluated by clinicians lacking genetic expertise, patients are sometimes misclassified under a biased clinical disease entity, often the most recognized, such as Usher syndrome. However, our understanding of DSI has expanded significantly, broadening the scope of genetic differential diagnoses, including Alport syndrome, Stickler syndrome, and Alström syndrome. Here, we report a complex DSI case with a confirmed genetic diagnosis through retinal dystrophy panel sequencing. The patient, a 51-year-old female, was referred for a possible diagnosis of cone-rod dystrophy. Her history indicated progressive vision loss since the age of 13, primarily affecting central vision and significantly impairing reading vision. Additionally, she reported hearing loss from the age of 20. Ophthalmic examination revealed optic disc pallor, peripheral macular atrophy, and diffuse retinal atrophy in the periphery. Visual field testing demonstrated a characteristic central scotoma with some preserved peripheral vision. Electroretinogram findings exhibited bilaterally reduced rod- and cone-isolated responses, consistent with a clinical diagnosis of cone-rod dystrophy. Reviewing the family history revealed a healthy mother, a father with a history of mild hearing impairment, and a sister also experiencing early-onset vision and hearing loss. The sister's prior whole-exome sequencing done in 2015 uncovered heterozygous Variants of Uncertain Significance (VUS) in ABCA4 (c.1610, p.Arg537His), GUCY2D (c.860C>T, p.Pro287Leu) and MYH9 (c.32A>G, p.Tyr11Cys). Subsequent segregation analysis identified that our index patient carries the GUCT2D and MYH9 variants, while the mother carries the ABCA4 and GUCY2D variants. The father was unavailable for genetic testing. During the initial consultation, a "dual diagnosis" approach was considered. The familial hearing loss was attributed to possible pathogenicity of the VUS in the MYH9 gene inherited from the father, while the cone-rod dystrophy was potentially linked to the VUS in the GUCY2D gene, likely in an autosomal recessive pattern with a missing variant. To further explore possible unknown variants in the GUCY2D on the other allele, but also to allow for identification of new genes and variants, a retinal dystrophy panel sequencing was conducted. This revealed the patient is a compound heterozygote for a CEP78 pathogenic variant (c.1209-2A>C variant) and a likely pathogenic variant (c.856_857del, p.Leu286Glyfs*12), neither of which were documented in the proband's sister's 2015 whole-exome sequencing. Segregation analysis in our index patient’s son confirmed that these two CEP78 variants co-occur in trans. A clarification of her father’s hearing loss history was made, which supported a diagnosis of presbycusis. A genetic diagnosis of CEP78-associated cone-rod dystrophy and hearing loss syndrome was made. We present a fascinating case initially thought to have a dual molecular origin of autosomal dominant hearing loss from a VUS in MYH9 and retinal dystrophy from a VUS in GUCY2D, yet eventually found to have a single molecular diagnosis related to two pathogenic CEP78 variants detected in a retinal dystrophy panel. Neither of these CEP78 variants was reported in her affected sister’s WES report in 2015. A literature review on the CEP78 gene revealed that the first report on CEP78-associated cone-rod dystrophy and hearing loss was published in September 2016. This means the genotype-phenotype association for our case was merely established 6 years before our consultation and one year following the WES of the index patient’s sister. It is important to acknowledge that our understanding of genotype-phenotype associations is rapidly expanding. 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 techniques but also in the more comprehensive understanding of genotype-phenotype associations.

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