Abstract
Usher syndrome includes a group of genetically and clinically heterogeneous autosomal recessive diseases, such as retinitis pigmentosa (RP) and sensorineural hearing loss. Usher syndrome type I (USHI) is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to RP. The relationships between the Usher syndrome causing genes and the resultant phenotypes of Usher syndrome have not yet been fully elucidated. In the present study, we recruited a Chinese family with Usher syndrome and conducted paneled next-generation sequencing, Sanger sequencing, segregation analysis, and expression profile analysis. The functional effects of the identified cadherin-related 23 (CDH23) pathogenic variants were analyzed. The M101 pedigree consisted of a proband and seven family members, and the proband was a 39-year-old Chinese male who claimed that he first began to experience night blindness 11 years ago. We revealed novel, missense compound heterozygous variants c. 2572G > A (p.V858I) and c. 2891G > A (p.R964Q) in the CDH23 gene, which co-segregated with the disease phenotype causing Usher syndrome type ID (USH1D) in this Chinese pedigree. CDH23 mRNA was highly expressed in the retina, and this protein was highly conserved as revealed by the comparison of Homo sapiens CDH23 with those from nine other species. This is the first study to identify the novel, missense compound heterozygous variants c. 2572G > A (p.V858I) and c.2891G > A (p.R964Q) of CDH23, which might cause USH1D in the studied Chinese family, thereby extending CDH23 mutation spectra. Identifying CDH23 pathogenic variants should help in the detailed phenotypic characterization of USH1D.
Highlights
Usher syndrome is a group of genetically and clinically heterogeneous autosomal recessive diseases, such as progressive retinitis pigmentosa (RP) and sensorineural hearing loss (Boughman et al, 1983)
Compound heterozygous variants (c. 2572G > A) at exons 22 and (c. 2891G > A) 24 in the cadherin-related 23 (CDH23) gene (NM_001171930.1) with high confidence were identified in the proband, leading to the production of Isoleucine from Valine, and Glutamine from Arginine at amino acid positions 858 (V858I) and 964 (p.R964Q), respectively, in the CDH23 protein (NP_001165401) (Figure 1A, II: 2)
The mutations c. 2572G > A (p.V858I) and c. 2891G > A (p.R964Q) in the CDH23 gene were validated as compound heterozygous in the proband (Figure 1C; pedigree II: 1), with c. 2891G > A being inherited from his father (Supplementary Figure 1; pedigree I: 1) and c. 2572G > A being inherited from his mother (Supplementary Figure 1; pedigree I: 2), by Sanger sequencing
Summary
Usher syndrome is a group of genetically and clinically heterogeneous autosomal recessive diseases, such as progressive retinitis pigmentosa (RP) and sensorineural hearing loss (Boughman et al, 1983). USHI is an autosomal recessive heterogeneous disorder causing mutations in at least eight genes that produces a similar disease or phenotype. These genes are: MYO7A (OMIM: 276903) at 11q13.5 causing USH1B (USH1A is considered to be the same; OMIM: 276900), harmonin or USH1C (OMIM: 605242) at 11p15.1 causing USH1C (OMIM: 276904), CDH23 (OMIM: 605516) at 10q21-q22, causing USH1D (OMIM: 601067), PCDH15 (OMIM: 605514) at 10q21.1 causing USH1F (OMIM: 602083), SANS or USH1G (OMIM: 607696) at 17q24-25 causing USH1G (OMIM: 606943), and CIB2 (605564) at 15q24 causing USH1J (OMIM: 614869). The expression levels of CDH23 in different tissues were not fully described
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