Case report: Compound heterozygous nonsense PCDH15 variant and a novel deep‐intronic variant in a Chinese child with profound hearing loss

Abstract

Background Usher syndrome is a condition characterized by partial or total hearing loss and progressive pigmentary retinopathy. Usher syndrome type 1F is caused by biallelic loss‐of‐function variants in Protocadherin 15 (PCDH15), which encodes the PCDH15 protein that plays an important role in the morphogenesis and cohesion of stereocilium bundles and retinal photoreceptor cell maintenance and function. Methods We report a child with bilateral nonsyndromic sensorineural hearing loss who received an inconclusive diagnosis based on clinical gene panel testing, which identified a paternal heterozygous nonsense variant (NM_033056.4: c.733C>T, p.R245*) in PCDH15. This variant has been described as a founder variant in the Ashkenazi Jewish population. Results A novel deep‐intronic variant (NM_033056.4: c.705+3767_705+3768del) inherited from the patient's mother was identified by trio‐based whole‐genome sequencing (WGS). A minigene splicing assay revealed that c.705+3767_705+3768del results in aberrant retention of 50 or 68 bp of intron 7. Conclusion Our genetic test results provided precise genetic counseling and prenatal diagnosis for this family, and our findings highlight the power of WGS for detecting deep‐intronic variants in patients with undiagnosed rare diseases. Additionally, this case expands the variant spectrum of the PCDH15 gene and our results support the extremely low carrier frequency of c.733C>T in the Chinese population.

A novel compound heterozygous PCDH15 variants may be associated with arRP in a Chinese pedigree

“…The cosegregation analysis demonstrated the novel variants shows a strict genotype-phenotype correlation in the pedigree of the RP family such that the mutation was present in a compound heterozygote state in proband; parents and offspring were single heterozygote carriers for the mutation and thus remained clinically unaffected. Our ndings supported an autosomal recessive inheritance pattern of the disease, as speculated in our family-based analysis, which further con rms several previous studies involving PCDH15 mutations in arRP [13,19,20]. Finally, our 3D modeling results showed an overall destabilization of the protein upon mutation leading to PCDH15 disfunction, which result in abnormal protein localization in the phototransduction cascade and retinoid cycle.…”

Review and research gap identification in genetics causes of syndromic and nonsyndromic hearing loss in Saudi Arabia

“…A homozygous variant (c.60_61del) was reported for hearing loss in an East Asian female who showed prepubertal onset of photoreceptor degeneration (Chen et al, 2022). A complex Usher syndrome Chinese family was also identified, wherein a compound heterozygous variant was detected in the PCDH15 gene (Yang et al, 2023). The exonic heterozygous nonsense variant c.733C > T (p.Arg245*) was inherited from the paternal, and a deep intronic variant (c.705+3767_705+3768del) was inherited from the mother.…”