OBJECTIVE: To detect pathogenic variant in a child featuring Usher syndrome type II. METHODS: Peripheral blood samples of the child and his parents were collected for the analysis of variants of hearing impairment-related genes. The findings were verified in 100 individuals with normal hearing. RESULTS: The child was found to harbor compound heterozygous variants of the USH2A gene, namely c.8224-1G>C in intron 41 and c.5678C>G(p.Ser1893X) in exon 28, which were inherited respectively from his mother and father. Based on the American College of Medical Genetics and Genomics standards and guidelines, both c.8224-1G>C and c.5678C>G(p.Ser1893X) variants of USH2A gene were predicted to be pathogenic(PVS1+PM2+PM3). CONCLUSION The compound heterozygous variants c.8224-1G>C and c.5678C>G of the USH2A gene probably underlay the disease in this child. Above finding has enriched the spectrum of USH2A gene variants.
Child ; Exons ; Extracellular Matrix Proteins/genetics* ; Family ; Humans ; Introns ; United States ; Usher Syndromes/genetics*

OBJECTIVE: To explore the genetic basis for a pedigree affected with congenital sensorineural deafness. METHODS: High-throughput sequencing was carried out to analyze the coding regions of 415 genes associated with hereditary deafness in the proband. Suspected variants were verified by PCR amplification and Sanger sequencing of her parents and sister. RESULTS: The proband was found to have carried a heterozygous c.5131G>A (p.Val1711Ile) variant of the CDH23 gene and a heterozygous c.2884C>T(p.Arg962Cys) variant of the PCDH15 gene, which were respectively inherited from her mother and father. Her sister (with normal hearing) was also heterozygous for the c.5131G>A (p.Val1711Ile) variant of the CDH23 gene but not the c.2884C>T (p.Arg962Cys) variant of the PCDH15 gene. Based on the guidelines of the American College of Medical Genetics and Genomics, both variants were predicted to be likely pathogenic (PS1+PM2+PP3+PP4). CONCLUSION The c.5131G>A (p.Val1711Ile) variant of the CDH23 gene and c.2884C>T (p.Arg962Cys) variant of the PCDH15 gene probably underlay the pathogenesis of Usher syndrome type 1D/F in this pedigree.
Female ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; Pedigree ; Usher Syndromes/genetics*

Objective: To investigate the variation of genes associated with Usher syndrome type 1(USH1)in 136 Chinese deafness families from Henan province. Methods: The data of 136 deafness families tested by next-generation sequencing(NGS) which identified in the center of genetics and prenatal diagnosis of the First Affiliated Hospital of Zhengzhou University from November 2016 to December 2019 were analysized and the variation frequency of six genes related to Usher syndrome type 1(MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2) were summarized. Results: Five deafness families were detected nine pathogenic or likely pathogenic variations in two genes, accounting for 3.7% of all families. Among them, four families were caused by MYO7A variations and one family was caused by CDH23 variation. Meanwhile, seven variations of two genes were reported for the first time. They were c.313delG, c.5257dupA, c.5435A>T, c.5636G>C, c.5722T>G of MYO7A, and c.155_166del, c.4802delA of CDH23. The patients' vision of family 2 and family 3 had no obvious abnormality at present, but according to genetic diagnosis and walking dealy, they were considered to be USH1. Conclusions: MYO7A is the most common caustive gene associated with USH1 in Henan deafness patients, the application of next-generation sequencing technology can make USH1 patients diagnosed earlier before the visual symptoms appear.
China/epidemiology* ; DNA Mutational Analysis ; Deafness/genetics* ; Humans ; Mutation ; Myosin VIIa ; Myosins/genetics* ; Pedigree ; Usher Syndromes/genetics*

OBJECTIVE: To analyze the clinical features and genetic variant in a patient with Usher syndrome. METHODS: Whole exome sequencing was carried out for the patient. Suspected variants were validated by Sanger sequencing of her parents and fetus. RESULTS: The proband was found to harbor compound heterozygous variants c.17_18insA (p.Tyr6Ter*) and c.4095_4096insA (p.Arg1366Lys fs*38) of the PCDH15 gene (NM_033056), which were respectively inherited from her father and mother. The same variants were not detected in 100 healthy controls. Based on the guidelines of the American Society of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+PM2+PP4). By prenatal diagnosis, her fetus was found to carry the c.4095_4096insA variant. After birth, the child has passed neonatal hearing screening test, and no abnormal auditory and visual function was found after the first year. CONCLUSION The compound heterozygous variants c.17_18insA (p.Tyr6Ter*) and c.4095_4096insA (p.Arg1366Lys fs*38) of the PCDH15 gene probably underlay the Usher syndrome is this proband.
Cadherin Related Proteins ; Cadherins/genetics* ; Child ; China ; Female ; Genetic Testing ; Humans ; Infant, Newborn ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Usher Syndromes/genetics*

Although the basic principles for the function of peripheral auditory system have been known for many years, the molecular mechanisms which affect deafness are not clear. In recent years, the study of hereditary deafness associated mouse models has revealed the molecular basis which is related with the formation and function of the hair bundle and the mechanosensory organelle of hair cell. This review focused on the role of protein network, which is formed by the proteins encoded by the Usher syndrome type 1 genes, in hair-bundle development and mechanotransducer channel gating. And the review also showed how the stereocilia rootlets contribute to the hair bundle's mechanical properties and how the hair bundle produces suppressive masking. Finally, the review revealed multiple roles of the tectorial membrane and extracellular matrix in the hair bundles stimulating in the cochlea.
Animals ; Cochlea ; physiopathology ; Disease Models, Animal ; Extracellular Matrix ; physiology ; Hair Cells, Auditory ; pathology ; Hearing Loss, Sensorineural ; genetics ; Humans ; Mechanotransduction, Cellular ; Mice ; Usher Syndromes ; genetics

OBJECTIVE: To detect potential variants in a family affected with Usher syndrome type I, and analyze its genotype-phenotype correlation. METHODS: Clinical data of the family was collected. Potential variants in the proband were detected by high-throughput sequencing. Suspected variants were verified by Sanger sequencing. RESULTS: The proband developed night blindness at 10 year old, in addition with bilateral cataract and retinal degeneration. Hearing loss occurred along with increase of age. High-throughput sequencing and Sanger sequencing revealed that she has carried compound heterozygous variants of the MYO7A gene, namely c.2694+2T>G and c.6028G>A. Her sister carried the same variants with similar clinical phenotypes. Her daughter was heterozygous for the c.6028G>A variant but was phenotypically normal. CONCLUSION The clinical features and genetic variants were delineated in this family with Usher syndrome type I. The results have enriched the phenotype and genotype data of the disease and provided a basis for genetic counseling.
Child ; Female ; Genetic Variation ; Genotype ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; Myosin VIIa ; genetics ; Night Blindness ; etiology ; Pedigree ; Phenotype ; Usher Syndromes ; genetics ; pathology

Objective:To analyze genetic factors and phenotype characteristics in pediatric population with slight-to-moderate sensorineural hearing loss. Methods:Children with slight-to-moderate sensorineural hearing loss of and their parents, enrolled from the Chinese Deafness Genome Project, were studied. Hearing levels were assessed using pure tone audiometry, behavioral audiometry, auditory steady state response（ASSR）, auditory brainstem response（ABR） thresholds, and deformed partial otoacoustic emission（DPOAE）. Classification of hearing loss is according to the 2022 American College of Medical Genetics and Genomics（ACMG） Clinical Practice Guidelines for Hearing Loss. Whole exome sequencing（WES） and deafness gene Panel testing were performed on peripheral venous blood from probands and validations were performed on their parents by Sanger sequencing. Results:All 134 patients had childhood onset, exhibiting bilateral symmetrical slight-to-moderate sensorineural hearing loss, as indicated by audiological examinations. Of the 134 patients, 29（21.6%） had a family history of hearing loss, and the rest were sporadic patients. Genetic causative genes were identified in 66（49.3%） patients. A total of 11 causative genes were detected, of which GJB2 was causative in 34 cases（51.5%）, STRC in 10 cases（15.1%）, MPZL2 gene in six cases（9.1%）, and USH2A in five cases（7.6%）.The most common gene detected in slight-to-moderate hearing loss was GJB2, with c. 109G>A homozygous mutation found in 16 cases（47.1%） and c. 109G>A compound heterozygous mutation in 9 cases（26.5%）. Conclusion:This study provides a crucial genetic theory reference for early screening and detection of mild to moderate hearing loss in children, highlighting the predominance of recessive inheritance and the significance of gene like GJB2, STRC, MPZL2, USH2A.
Humans ; Child ; Connexins/genetics* ; Connexin 26/genetics* ; Hearing Loss, Sensorineural/diagnosis* ; Mutation ; Usher Syndromes ; Hearing Loss, Bilateral ; Audiometry, Pure-Tone ; Intercellular Signaling Peptides and Proteins

OBJECTIVETo identify potential mutations in a Chinese family with Usher syndrome type II.

METHODSGenomic DNA was obtained from two affected and four unaffected members of the family and subjected to amplification of the entire coding sequence and splicing sites of USH2A gene. Mutation detection was conducted by direct sequencing of the PCR products. A total of 100 normal unrelated individuals were used as controls.

RESULTSThe patients were identified to be a compound heterozygote for two mutations: c.8272G>T (p.E2758X) in exon 42 from his mother and c.12376-12378ACT>TAA(p.T4126X) in exon 63 of the USH2A gene from his father. Both mutations were not found in either of the two unaffected family members or 100 unrelated controls, and had completely co-segregated with the disease phenotype in the family. Neither mutation has been reported in the HGMD database.

CONCLUSIONThe novel compound heterozygous mutations c.8272G>T and c.12376-12378ACT>TAA within the USH2A gene may be responsible for the disease. This result may provide new clues for molecular diagnosis of this disease.

Adult ; Amino Acid Sequence ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; China ; DNA Mutational Analysis ; Extracellular Matrix Proteins ; genetics ; Female ; Hearing ; Heterozygote ; Humans ; Male ; Molecular Sequence Data ; Mutation, Missense ; Pedigree ; Usher Syndromes ; genetics ; physiopathology

OBJECTIVETo investigate the disease-causing mutation in a Chinese family affected with Usher syndrome type II.

METHODSAll of the 11 members from the family underwent comprehensive ophthalmologic examination and hearing test, and their genomic DNA were isolated from venous leukocytes. PCR and direct sequencing of USH2A gene were performed for the proband. Wild type and mutant type minigene vectors containing exon 42, intron 42 and exon 43 of the USH2A gene were constructed and transfected into Hela cells by lipofectamine reagent. Reverse transcription (RT)-PCR was carried out to verify the splicing of the minigenes.

RESULTSPedigree analysis and clinical diagnosis indicated that the patients have suffered from autosomal recessive Usher syndrome type II. DNA sequencing has detected a homozygous c.8559-2A>G mutation of the USH2A gene in the proband, which has co-segregated with the disease in the family. The mutation has affected a conserved splice site in intron 42, which has led to inactivation of the splice site. Minigene experiment has confirmed the retaining of intron 42 in mature mRNA.

CONCLUSIONThe c.8559-2A>G mutation in the USH2A gene probably underlies the Usher syndrome type II in this family. The splice site mutation has resulted in abnormal splicing of USH2A pre-mRNA.

Adolescent ; Adult ; Aged ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; China ; Extracellular Matrix Proteins ; genetics ; metabolism ; Female ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Pedigree ; Usher Syndromes ; genetics ; metabolism ; Young Adult