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Objective:To identify the causative gene in a family affected with Usher syndrome (USH) with retinitis pigmentosa sine pigmento (RPSP) and to analyze the genotype-phenotype correlation.Methods:A retrospective clinical study. A 9-year-old girl with RPSP type 1F USH diagnosed in the ophthalmology clinic of Henan Provincial People's Hospital in November 2019 and her parents were included in the study. The patient had bilateral night blindness for more than 4 years, she suffered from hearing loss 7 years, and is currently binaural sensorineural deafness. The best corrected visual acuity in both eyes was 0.5 +. There was showed no obvious pigmentation on the fundus. The visual acuity of the peripheral field of vision decreased. Optical coherence tomography showed that the outer layer of the peripheral retina became thinner and the ellipsoid band disappeared. On electroretinogram examination, the rod and cone system response was severely decreased. The clinical phenotype of the parents of the child were normal. The peripheral venous blood of the child and his parents were extracted, the whole genome DNA was extracted, the custom developed targeted capture kit (PS400) was used, and the next-generation sequencing technology was used to detect genetic mutations. The suspected pathogenic mutation sites were verified by Sanger; co-segregation was performed among family members. The pathogenicity of variants were evaluated according to the interpretation standards and guidelines of sequence variants. Bioinformatics techniques were used to assess the impact of variants on encoded proteins. Results:The results of genetic testing showed that the proband detected the PCDH15 gene c.4109dupA (p.K1370fs) (M1), c.17dupA (p.Y6_L7delinsX) (M2) compound heterozygous mutation sites, verified by Sanger sequencing, the mutations were in the family in a state of co-segregation. According to the evaluation of sequence variation interpretation standards and guidelines, M1 and M2 were pathogenic variants of the PCDH15 gene. M1 led to a complete change in the transmembrane structure of the encoded protein, and M2 caused the gene to only translate 6 amino acids, which predicted that the PCDH15 protein cannot be synthesized. According to the clinical phenotype, gene mutation pathogenicity and protein structure prediction, the final clinical diagnosis was PCDH15-related type 1F. Conclusions:PCDH15 genes c.4109dupA and c.17dupA are the pathogenic mutation sites of USH in this family. These compound heterozygous new mutations lead to the failure of normal synthesis of PCDH15 protein, which leads to ocular and ear manifestations.
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Objective@#The aim of this study was to investigate whether genetic variability in the protocadherin 15 (PCDH15) gene may correspond with increased susceptibility to noise-induced hearing loss (NIHL) in a Chinese population.@*Methods@#A nested case-control study was performed that followed a cohort of 7 445 noise-exposed workers in a steel factory of Henan province in China from January 1, 2006 to December 31, 2015. In this study, 394 cases who had an average hearing threshold of more than 40 dB (A) in high frequency were defined as the case group, and 721 controls who had an average hearing threshold of less than 35 dB (A) in high frequency and less than 25 dB (A) in speech frequency were defined as the control group. A questionnaire was completed by participants and a physical test was also conducted. SNP genotyping was performed using the SNPscanTM Kit. Multivariate unconditional logistic regression additive models were used to analyze the genotypes in different groups, and the association with NIHL. Unconditional logistic regression models were used to assess the associations between the genotypes and NIHL.@*Results@#The average age of study participants was (40.5±8.3) years and the median number of noise-exposed working years M (P25, P75) was 21.1 (9.1, 27.3). The range of noise exposed levels and the levels of cumulative noise exposure (CNE) were 80.1- 98.8 dB(A) and 86.6- 111.2 dB(A), respectively. Only the distribution of the genotypes (TT/CC/CT) of rs11004085 in the PCDH15 gene showed a significant difference between the case and control groups (P=0.049). In the case group, the distribution was 370 (93.9%), 24 (6.1%) and 0; in the control group, the distribution was 694 (96.3%), 23 (3.2%) and 1 (0.1% ). After smoking, drinking, hypertension, height and CNE adjustment, compared with the TT genotype individuals with the CC/CT genotype had a 1.90-fold increased risk of NIHL (95% CI: 1.06- 3.40). After stratified these data by the noise exposure level or CNE when the noise exposure level was>85 dB (A), compared with cases with the AA genotype of rs10825113, individuals with the GA/GG genotype had a 2.63-fold increased risk of NIHL (95% CI: 1.12- 6.14). When the CNE was ≤ 98 dB(A), compared with cases with the TT genotype of rs11004085, individuals with the CC/CT genotype had a 2.96-fold increased risk of NIHL (95% CI: 1.33- 6.56). However, these differences were not significant after Bonferroni correction had been applied.@*Conclusions@#The results confirmed that genetic variation within the PCDH15 gene may affect the susceptibility to NIHL.