?New? autosomal-dominant infantile sensorineural non-progressive high-frequency hearing loss: Report on a Brazilian family.

Zanchetta, Sthella; Ohara, Kouzaburo; Rodrigues, Patricia T.; Carvalho, Ester Luisa Leite; Richieri-Costa, Antônio

doi:10.1002/1096-8628(20001106)95:1<13::aid-ajmg4>3.0.co;2-t

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…A surdez de herança autossômica recessiva é responsável por cerca 80% dos casos de PA não-sindrômica (VAM CAMP; SMITH, 03/2017; ZANCHETTA et al, 2000).…”

Section: Surdez De Herança Autossômica Recessivaunclassified

Estudos genético-moleculares em surdez não sindrômica e sindrômica

Silva¹

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2017" Genetic etiology may represent up to 60% of deafness cases, it is one of the most genetically heterogeneous diseases and may exhibit all Mendelian inheritance patterns and mitochondrial inheritance as well. Studies of families with many individuals affected by hearing loss allowed the mapping of more than 110 locus, candidates for containing deafness genes. However, many of these genes have only a few families associated described so far and a significant portion of them has yet to be identified. Gene identification and characterization is an important tool that provides several benefits, such as a more accurate genetic counseling for families, better understanding of genotype-phenotype correlations as well as discovery of biological pathways crucial for hearing. The general objective of this dissertation was to identify novel genes and mutations related to non-syndromic deafness in Brazilian families. We investigated the cause of post-lingual nonsyndromic hearing loss in three familial cases. In the first family case, with autosomal dominant inheritance, a genomic scanning through SNP-array was performed and a statistical analysis of the data was done with the Alohomora program. The data of the parametric (Lod Score) and non-parametric (Z-mean) analyzes were compared to obtain the candidate chromosomal regions. In the candidate chromosomal regions, segregation analysis of the microsatellite haplotypes was shown to be compatible with linkage to the deafness in the family. Then, exome sequencing of the proband was completed, analysis of the variants, contained within the candidate chromosomal regions identified by linkage, was performed as well as the segregation analysis. A candidate variant that segregates with the deafness in this family was identified in a gene that was not previously associated with deafness, but that interacts with a known deafness gene. In familial case 2, definition of the genetic cause was accomplished and its autosomal recessive inheritance pattern confirmed through the detection of two pathogenic mutations in the TMPRSS3 gene in compound heterozygosis, both previously described. Thus, we corroborate data from the literature that point out the importance of this gene in the less common cases of both post-lingual hearing loss and autosomal recessive inheritance. In case 3, with autosomal dominant inheritance, exome sequencing of the proband revealed two novel heterozygous variants that were predicted to be pathogenic by bioinformatics tools: p.R42C (GJB3) and p.S906 * (MYO6). The proband and her normal hearing mother presented the variant in the GJB3 gene, that is located in the same amino acid position of variant that causes the skin disease Eritrokeratodermia variabilis. Neither subjects had this skin disease. Thus, the GJB3 variant was considered to be of uncertain significance. Segregation with deafness of the novel nonsense MYO6 mutation was confirmed in the family. This mutation is in the neck domain of myosin VI, after the motor domain. These findings give further support for...

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“…A surdez de herança autossômica recessiva é responsável por cerca 80% dos casos de PA não-sindrômica (VAM CAMP; SMITH, 03/2017; ZANCHETTA et al, 2000).…”

Section: Surdez De Herança Autossômica Recessivaunclassified

Estudos genético-moleculares em surdez não sindrômica e sindrômica

Silva¹

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“…No entanto, estudos funcionais com camundongos demonstraram que a reciclagem de íons potássio não é o principal fator responsável pela perda de audição, sugerindo que outros mecanismos podem levar à perda auditiva (Chen et al, 2014;Zhu et al, 2015 (Hilgert et al, 2009). Ao contrário da surdez de herança autossômica recessiva, na qual cerca de metade dos casos ocorre devido a mutações nos genes GJB2 e GJB6, variantes causativas de perdas auditivas de herança autossômica dominante ocorrem em uma variedade de genes, de modo que não há predominância de mutações em um único gene (Zanchetta et al, 2000;Shearer et al, 2017). A perda auditiva de herança autossômica dominante já teve 67 lócus mapeados e 47 genes identificados (http://www.hereditaryhearingloss.org).…”

Section: Genética Das Perdas Auditivasunclassified

Identificação de variantes patogênicas em famílias com perda auditiva de herança autossômica dominante.

Bueno¹

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Hearing loss is one of the most frequent sensorial disorders in humans. When inherited, hearing loss can be autosomal dominant or recessive, X-linked or mitochondrial. Sixty-seven loci have already been mapped and 47 genes were identified as associated with autosomal dominant hearing loss, which is responsible for about 20-30% of hereditary cases. This study aimed to investigate the frequency and the origin of the c.2090T>G p.Leu697Trp mutation in MYO3A gene, identified in the Laboratory of Human Genetics-(LGH) IBUSP as related to nonsyndromic autosomal dominant hearing loss, in Brazilian families with autosomal dominant hearing loss. This study also aimed to identify the genes and corresponding mutations that explain nonsyndromic autosomal dominant hearing loss in two large families also under investigation in LGH-IBUSP. In relation to studies regarding the c.2090T>G p.Leu697Trp mutation in MYO3A gene, the screening of this mutation in a collection of 101 probands from families with autosomal dominant hearing loss revealed the presence of the mutation in four families, in addition to the two families originally ascertained in the laboratory. We concluded that this mutation explained about 3% of autosomal dominant deafness cases investigated, and it plays an important role in causing autosomal dominant hearing loss among Brazilian families, which justifies its investigation in similar pedigrees concerning the phenotype and the mechanism of genetic transmission. Additional analysis, as identity by descent (IBD), performed by the Laboratory team, revealed a kinship coefficient equivalent to second cousins between the affected individuals of the five families, which indicates close relationship between them and a probable common origin for the mutation. The age of the mutation (age of the most recent common ancestor) was estimated near 27,4 generations, which is equivalent to about 675 years (CI: 350-1325). Local ancestry study approaches revealed that the region in which the mutation is located has European Ancestry. Though it is not possible to estimate whether the mutation arose in Europe or in Brazil in an individual of European origin, the identification of the same alteration in an individual with hearing loss in Netherlands, reported in the LOVD database,

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A Chromosome 17 Locus Engenders Frequency-Specific Non-Progressive Hearing Loss that Contributes to Age-Related Hearing Loss in Mice

Peguero

Tempel

2015

JARO

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The 129S6/SvEvTac (129S6) inbred mouse is known for its resistance to noise-induced hearing loss (NIHL). However, less is understood of its unique age-related hearing loss (AHL) phenotype and its potential relationship with the resistance to NIHL. Here, we studied the physiological characteristics of hearing loss in 129S6 and asked if noise resistance (NR) and AHL are genetically linked to the same chromosomal region. We used auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to examine hearing sensitivity between 1 and 13 months of age of recombinant-inbred (congenic) mice with an NR phenotype. We identified a region of proximal chromosome (Chr) 17 (D17Mit143-D17Mit100) that contributes to a sensory, non-progressive hearing loss (NPHL) affecting exclusively the high-frequencies (>24 kHz) and maps to the nr1 locus on Chr 17. ABR experiments showed that 129S6 and CBA/CaJ F1 (CBACa) hybrid mice exhibit normal hearing, indicating that the hearing loss in 129S6 mice is inherited recessively. An allelic complementation test between the 129S6 and 101/H (101H) strains did not rescue hearing loss, suggesting genetic allelism between the nphl and phl1 loci of these strains, respectively. The hybrids had a milder hearing loss than either parental strain, which indicate a possible interaction with other genes in the mouse background or a digenic interaction between different genes that reside in the same genomic region. Our study defines a locus for nphl on Chr 17 affecting frequencies greater than 24 kHz.

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?New? autosomal-dominant infantile sensorineural non-progressive high-frequency hearing loss: Report on a Brazilian family.

Cited by 3 publications

References 15 publications

Estudos genético-moleculares em surdez não sindrômica e sindrômica

Estudos genético-moleculares em surdez não sindrômica e sindrômica

Identificação de variantes patogênicas em famílias com perda auditiva de herança autossômica dominante.

A Chromosome 17 Locus Engenders Frequency-Specific Non-Progressive Hearing Loss that Contributes to Age-Related Hearing Loss in Mice

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