Mutation spectra and founder effect of TMC1 in patients with non‐syndromic deafness in Xiamen area, China

Abstract

To analyze the spectrum and founder effect of TMC1 mutations in patients with non‐syndromic deafness in the Xiamen area. Sporadic pedigrees were detected by targeted next‐generation sequencing, and 110 unrelated patients from Xiamen Special Education School were analyzed through Sanger sequencing for the TMC1 gene. In total, 53 SNPs were designed to analyze the haplotypes of the TMC1 c.2050G>C mutation. The probands of three families were found to be homozygous for TMC1 c.2050G>C, and their parents were all heterozygous for the TMC1 c.2050G>C mutation. In 110 unrelated patients from Xiamen Special Education School, four were found to carry compound heterozygotes of TMC1 c.2050G>C, which were compound heterozygotes of c.804G>A, c.1127T>C, c.1165C>T, and c.1396_1398delAAC, respectively. Three types of TMC1 polymorphisms (c.45C>T, c.1713C>T, c.2208+49C>T) and two heterozygotes of novel variants (c.1764‐4C>A, c.2073G>A[p.K691K]) were found in the remaining 100 patients. In total, four novel variants were detected in this study. These mutations and variants were not detected in 100 normal samples. The haplotypes of the probands of families with TMC1 c.2050G>C were identical. There were unique hotspots and spectra of TMC1 mutations in the Xiamen deaf population. Haplotype analysis is useful to understand the founder effect of the hot spot mutation.

Novel homozygous variants in the TMC1 and CDH23 genes cause autosomal recessive nonsyndromic hearing loss

“…The TMC1 has 24 exons (Kawashima et al, 2015) and its encoded protein involves 760 amino acids with 6 transmembrane domains along with an intracellular N-terminal domain, three extracellular loops, two intracellular loops, and a short intracellular C-terminal domain (Jiang et al, 2018) (Figure 4a). The exact structure and function of TMC1 are uncertain but proposed structures show that the protein can potentially function as a transporter or a channel.…”

Next‐generation sequencing identifies rare pathogenic and novel candidate variants in a cohort of Chinese patients with syndromic or nonsyndromic hearing loss

“…Mutations in TMC1 can cause both autosomal dominant and recessive NSHL (Jiang et al, 2018; Kitajiri et al, 2007). We identified compound heterozygous mutations of c.625C>G (p.L209V) and c.2050G>C (p.D684H) in TMC1 in family HL13, which were segregated with HL in this family.…”

“…This suggests recessive inheritance of these two mutations. c.625C>G is a novel mutation, whereas c.2050G>C is a known mutation that is frequently detected in the deaf population in Xiamen, China (Jiang et al, 2018). Thus, c.2050G>C should be considered as a potential hotspot mutation in TMC1 in the deaf population from China.…”

Study of complex structural variations of X-linked deafness-2 based on single-molecule sequencing

“…An NGS panel of 109 human deafness genes, including all reported genes for NSHL and some relatively common genes for SHL (at the time when the panel was designed) (Supplementary Table S1) were selected [ 14 ]. This panel was designed using biotinylated oligonucleotide probes to capture all exons of 109 genes, and their splice sites with the flanking 50-bp intron sequences.…”