Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations / 中华耳鼻咽喉头颈外科杂志

Objective: To analyze the phenotypic-genotypic characteristics of hereditary deafness caused by OTOA gene variations. Methods: Family histories, clinical phenotypes and gene variations of six pedigrees were analyzed, which were diagnosed with hearing loss caused by OTOA gene variations at the PLA General Hospital from September 2015 to January 2022. The sequence variations were verified by Sanger sequencing and the copy number variations were validated by multiplex ligation-dependent probe amplification (MLPA) in the family members. Results: The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies, and from moderate to severe in the high frequencies in the probands, which came from six sporadic pedigrees, among which a proband was diagnosed as congenital deafness and five were diagnosed as postlingual deafness. One proband carried homozygous variations and five probands carried compound heterozygous variations in OTOA gene. Nine pathogenic variations (six copy number variations, two deletion variations and one missense variation) and two variations with uncertain significance in OTOA were identified in total, including six copy number variations and five single nucleotide variants, and three of the five single nucleotide variants were firstly reported [c.1265G>T(p.Gly422Val),c.1534delG(p.Ala513Leufs*11) and c.3292C>T(p.Gln1098fs*)]. Conclusions: OTOA gene variations can lead to autosomal recessive nonsyndromic hearing loss. In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and postlingual, and that of a few presents as congenital. The pathogenic variations of OTOA gene are mainly copy number variations followed by deletion variations and missense variations.

Prenatal genetic test and clinical guidance for 213 hereditary deaf families / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To summarize the workflow, strategy and experience of prenatal genetic test for deafness based on the 6-year clinical practice.</p><p><b>METHODS</b>There were 213 families who received prenatal test from 2005 to 2011. Among the 213 families, 205 families had had one deaf child, including 204 couples with normal hearing and one couple of the deaf husband and normal wife, 8 families including 6 couples with normal hearing and 2 deaf couples, had no child before test. Genomic and mitochondrial DNA of each subject was extracted from whole blood. The etiology and recurrent risks in 212 families were confirmed by means of the genetic test of GJB2, SLC26A4 and mtDNA 12sRNA, but one family carried POU3F4 c.647G > A heterozygous mutation causing X-linked hereditary hearing impairment confirmed by pedigree study. The prenatal test was carried out during the pregnancy of all mothers from 11 to 30 weeks, and the following genetic information and counseling were supplied based on the results.</p><p><b>RESULTS</b>The recurrent risk was 25% in 209 families, including 204 families with one deaf child and 5 families without child, among which all couples were GJB2 or SLC26A4 mutation carriers and deaf children were caused by homozygous or compound GJB2/SLC26A4 mutations; The recurrent risk was 50% in 3 families, the father and his child in one family had compound SLC26A4 mutations and the mother with heterozygous SLC26A4 mutation, the wife had POU3F4 c.647G > A heterozygous mutation in another one family, and the husband with compound SLC26A4 mutations and the wife with mtDNA A1555G mutation and heterozygous SLC26A4 mutation simultaneously happened in the rest one family; The recurrent risk was 100% in one family of the deaf couple who were both found to carry homozygous or compound GJB2 mutations, and the deaf wife got pregnant by artificial insemination with the sperm from the local Human Sperm Bank. 226 times of prenatal test were applied in all 213 families that 11 families of them received prenatal test twice, and one family received three times. 46 times of prenatal testing showed that the fetuses carried parental mutations simultaneously or the same mutations with probands; while 180 times of prenatal test showed that the fetuses carried only one parental mutation or did not carry any mutation from parents. The following visit showed that all of these 180 families had given birth to babies who were all revealed to have normal hearing by new born hearing screening test.</p><p><b>CONCLUSIONS</b>Prenatal diagnosis for deafness assisted by genetic test can provide efficient information about offspring's hearing condition, and the normative workflow and precise strategy highly guarantee the safe and favorable implementation of prenatal diagnosis.</p>

Prenatal genetic counseling and instruction for deaf families by genetic test / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>Analyzed the molecular pathogenesis of probands by means of genetic test and assisted the local Family Planning Institute by providing prenatal genetic counseling and instruction for deaf families who eager to have more baby.</p><p><b>METHODS</b>Total of forty-three deaf families were recruited by two institutes for family planning from Guangzhou and Weifang. Forty-two families had one deaf child with normal hearing parents. One family was that parents and their child were all deaf. Genetic testing of GJB2, SLC26A4 and mitochondrial DNA (mtDNA) 12SrRNA were firstly performed in probands and their parents, following medical history, physical examination, auditory test and CT scan of temporal bone were completed. And then the genetic information and instruction were provided to each deaf family.</p><p><b>RESULTS</b>Fifteen of these 43 families had positive results of genetic test. In fifteen families, one family was confirmed that the parents and their child all carried homozygous GJB2 mutations and the recurrence risk was 100%. Twelve families were confirmed that the probands carried homozygous/compound GJB2 or SLC26A4 mutations while their parents were GJB2 or SLC26A4 carriers, and the recurrence risk was 25%. One family was confirmed that the proband, diagnosed with enlarged vestibular aqueduct syndrome (EVAS) by CT scan, carried heterozygous SLC26A4 mutation from the mother, and the recurrence risk was still 25% based on the hereditary pattern of EVAS although another SLC26A4 mutation from the father was not found. One family was confirmed that the proband carried a heterozygous GJB2 mutation from the mother and the possibility to be GJB2 carrier for offsprings was 50%. The rest 28 families were that all probands and their parents did not carry GJB2, SLC26A4 and mtDNA 12SrRNA pathological mutation.</p><p><b>CONCLUSIONS</b>Genetic testing can provide more accurate and useful prenatal genetic counseling and instruction to deaf families. Meanwhile, it is an ideal way to develop a cooperative relationship with the institute for family planning.</p>