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. 2020 Apr 30:11:422.
doi: 10.3389/fgene.2020.00422. eCollection 2020.

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the CDH23 Gene Causing Usher Syndrome Type ID in a Chinese Patient

Lianmei Zhang  1   2 , Jingliang Cheng  2 , Qi Zhou  3 , Md Asaduzzaman Khan  2 , Jiewen Fu  2 , Chengxia Duan  3 , Suan Sun  1 , Hongbin Lv  3 , Junjiang Fu  2
Affiliations

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the CDH23 Gene Causing Usher Syndrome Type ID in a Chinese Patient

Lianmei Zhang et al. Front Genet. .

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.

Keywords: CDH23 gene; Usher syndrome type ID; genotype/phenotype correlation; missense mutation; targeted next-generation sequencing.

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Figures

FIGURE 1
FIGURE 1
(A) M101 pedigree with Usher syndrome type ID. Normal individuals are shown as clear circles (females) or squares (male). The filled square indicates the proband (II: 2, arrow) with the compound heterozygous mutation of the CDH23 gene: NM_001171930.1:exon22:c.2572G > A:p.V858I (M1); exon24: c. 2891G > A: p.R964Q(M2). “+,” wild-type allele. (B) Representative retinal phenotypes of proband II: 2. Top panel. Representatively FP in patient II: 2 of the right eye. Middle and bottom panel. Representatively FFA in patient II: 2 of both right and left eyes, respectively. (C) Pyrogram profiles for variant verification by Sanger sequencing, indicating the sequenced results in II: 2 (missense c. 2572G > A mutant type) (top panel), II: 2 (missense c.2891G > A mutant type) (bottom panel). The arrows show the mutation position NM_001171930.1: c.2572G > A or c. 2891G > A in the CDH23 gene, respectively.
FIGURE 2
FIGURE 2
The CDH23 comparison and conserved mutant positions. (A) The conservation analysis of CDH23 in indicated species. (B) The conserved mutant position of p.V858 (highlighted in green). (C) The conserved mutant position of p.R964 (highlighted in green). Variants p.V858I and p.R964Q of CDH23 are indicated in Figures 3B,C, respectively.
FIGURE 3
FIGURE 3
The mRNA expression in human CDH23 and mouse Cdh23 tissues. (A) The CDH23 mRNA expression in human tissues from RNA-seq data. (B) The Cdh23 mRNA levels in the indicated tissues. (C) The Cdh23 mRNA levels in the indicated development times in retinal tissue in mice. d, days; w, weeks; m, month(s); nc, no DNA template; muscle, skeletal muscle. Whole embryo eyeballs at 12.5 days (12 d) and 20.5 days (20 d) before birth, in panel (C), respectively.
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