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An autosomal-dominant progressive sensorineural hearing loss in six generations of a large family with 105 affected members was studied. The pattern of inheritance is autosomal dominant with an almost complete penetrance. The age of onset is between 5 and 15 years. Individuals with a normal audiogram at the age of 15 and over will not develop the d...
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Purpose:
The goal was to evaluate the potential effects of increasing hearing loss and advancing age on spectral envelope perception.
Method:
Spectral modulation detection was measured as a function of spectral modulation frequency from 0.5 to 8.0 cycles/octave. The spectral modulation task involved discrimination of a noise carrier (3 octaves w...
Citations
... In 1966, Huizing et al. [13,14] reported a five-generation Dutch family with 335 members and conducted a clinical follow-up for about 20 years [15][16][17]. This family had autosomal dominant deafness, with the hearing loss occurring mostly before the age of 15 years, and the minimum age of onset was 5 years. ...
Background
The most frequent clinical presentation of autosomal dominant nonsyndromic hearing loss (ADNSHL) is bilateral, symmetrical, postlingual progressive sensorineural hearing loss, which begins with impairment at high frequencies and eventually progresses to hearing loss at all frequencies. Autosomal dominant deafness-5 (DFNA5) is a subtype of ADNSHL caused by heterozygous variants in the gasdermin E (GSDME, also known as DFNA5) gene.
Methods
Deafness gene NGS panel analysis were performed on the proband of a six-generation Chinese family with hearing loss. The co-segregation analysis between the hearing loss and the novel variant was analyzed by Sanger sequencing and pure-tone audiometry. The minigene splicing assay was performed to evaluate the potential effect of the variant on messenger RNA splicing in vitro.
Results
The family exhibited autosomal dominant, progressive, postlingual, nonsyndromic sensorineural hearing loss, which was similar to that of the previously reported DFNA5 families. A novel heterozygous splice site variant in GSDME gene intron 8 was identified, which co-segregated with the hearing loss phenotype of the family. The variant caused skipping of exon 8 in the mutant transcript, leading to the direct linking of exons 7 and 9.
Conclusions
We identified a novel GSDME splice site variant c.1183 + 1 G > C in an extended Chinese family, which led to the skipping of exon 8. The results extended the pathogenic variants spectrum of the GSDME gene, provided further support for the 'gain-of-function' mechanism of DFNA5, and afforded a molecular interpretation for these patients with ADNSHL.
... In 1966, Huizing et al. [16,17] reported a ve-generation Dutch family with 335 members and conducted clinical follow-up for about 20 years [18][19][20]. This family had autosomal dominant deafness, with the hearing loss occurring mostly before the age of 15 years, and the minimum age of onset was 5 years. ...
Background
The major clinical manifestation of autosomal dominant nonsyndromic hearing loss (ADNSHL) is bilateral, symmetrical, postlingual progressive sensorineural hearing loss, which begins with impairment at high frequencies and eventually progresses to hearing loss at all frequencies. Autosomal dominant deafness-5 (DFNA5) is a subtype of ADNSHL caused by a heterozygous variant in the gasdermin E ( GSDME , also known as DFNA5) gene. Methods
Targeted genomic capture and sequencing were performed on the proband of a six-generation Chinese family with hearing loss. The co-segregation analysis between the hearing loss and the novel variant was analyzed by Sanger sequencing and pure-tone audiometry. The minigene splicing assay was performed to evaluate the potential effect of the variant on messenger RNA splicing in vitro . ResultsThe family exhibited autosomal dominant, progressive, postlingual, nonsyndromic sensorineural hearing loss, which was similar to the previously reported DFNA5 families. A novel heterozygous splice site variant in GSDME gene intron 8 was identified as “Likely pathogenic” according to the American College of Medical Genetics and Genomics (ACMG) guidelines, which co-segregated with the hearing loss phenotype of the family. The variant caused skipping of exon 8 in the mutant transcript, leading to the direct linking of exon 7 and 9.Conclusions
We identified a novel GSDME splice site variant c.1183+1 G>C in an extended Chinese family, which led to the skipping of exon 8, through targeted genomic capture and sequencing and co-segregation analysis. The results extended the pathogenic variant spectrum of the GSDME gene, provided further support for the “gain-of-function” mechanism of DFNA5, and afforded a molecular interpretation for these patients with ADNSHL.
... The first family in which the locus was identified was of Dutch origin and showed progressive symmetrical hearing loss that started at the high frequencies. 72,73,[192][193][194][195] Later, another Dutch family and a Chinese family were encountered. 75,77 The audiograms had so-called Z-shaped profiles. ...
To report hearing impairment and vestibular and ocular features in a Dutch DFNA11 family and to compare these results to reported data on three other DFNA11 families.
Family study.
Regression analysis was performed in relation to age to outline the development of hearing thresholds and speech recognition scores. Vestibular and ocular functions were examined.
First symptoms of hearing impairment started between the ages of 4 and 43 years. Most of the audiograms were symmetric and flat or downsloping. The annual threshold deterioration increased from 0.2 to 2.6 dB per year at 0.25 to 8 kHz in the longitudinal analyses and in the cross-sectional analysis from 0.3 to 0.9 dB per year. The speech recognition score was quite good, deteriorating by 0.9% per year from a 90% score at the age of 36 years onward. Remarkably, extensive ocular examination including corrected visual acuity and refraction measurements, slit-lamp examination, ophthalmoscopy, Goldmann perimetry, electroretinography and electro-oculography revealed signs of subclinical retinal dysfunction. None of the patients showed the classic triad of retinitis pigmentosa. Pure-tone thresholds, phoneme recognition scores, and vestibular responses of the mutation carriers were fairly similar to previously described DFNA11 families.
Even though the diverse mutations are located in different regions of the myosin VIIa gene, the cochleovestibular phenotype is fairly similar in all DFNA11 families. Surprisingly, only in this family was subclinical retinal dysfunction detected.
... Clinical studies and linkage analysis. The hearing loss in the Dutch family has been described [10][11][12][13][14][15] . Briefly, the hearing loss is nonsyndromic, progressive and starts at the high frequencies at age 5 to 15. ...
Nonsyndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 loci mapped on the human genome, however, only a limited number of genes implicated in hearing loss have been identified. We previously reported linkage to chromosome 7p15 for autosomal dominant hearing impairment segregating in an extended Dutch family (DFNA5). Here, we report a further refinement of the DFNA5 candidate region and the isolation of a gene from this region that is expressed in the cochlea. In intron 7 of this gene, we identified an insertion/deletion mutation that does not affect intron-exon boundaries, but deletes five G-triplets at the 3' end of the intron. The mutation co-segregated with deafness in the family and causes skipping of exon 8, resulting in premature termination of the open reading frame. As no physiological function could be assigned, the gene was designated DFNA5.
The surgical closure of congenital coronary artery fistulas (CAF) is associated with excellent immediate outcomes. Few studies have investigated the long-term prognosis in patients who have undergone surgery for the closure of CAF or differentiated among types of CAF or types of surgical procedures. In this study, we performed clinical examinations and computed tomography angiography (CTA) to characterize outcomes after CAF closure in pediatric patients. The medical records of 79 pediatric patients who underwent surgical closure of CAF were retrospectively reviewed. The median age of the patients included in the study at the time of surgery was 3.4 years (range 0.2 to 15.3 years). The patients had been followed up for 11 years (range 1 to 17 years) with electrocardiography, echocardiography, and coronary CTA. There were 67 medium-to-large CAF and 12 small CAF. Twenty-six (32.9%) CAF arose from the branch coronary artery (proximal type); the others arose from the parent coronary artery (distal type). The surgical procedure included endocardial closure in 16 cases, epicardial distal ligation in 51 cases, epicardial proximal and distal ligation in 12 cases. There was no instance of perioperative death among the cases included in the study. Twenty-eight patients were treated with antiplatelet medication postoperatively. No patient required re-operation during the follow-up period. Coronary thrombi were detected in 27 patients (34.2%). There was no instance of myocardial ischemia related to thrombosis. Among the patients with thrombosis, 26 had medium-to-large CAF (96.3%), and 23 had distal-type CAF (85.2%). Average age at surgery was higher among the patients with thrombosis than among the patients without thrombosis (7.4 years vs. 3.3 years, t = 5.509, P = 0.000). Among the patients with distal-type CAF, thrombosis was more common among the patients treated with ligation than treated with endocardial closure (41.5% vs. 16.7%, χ2 = 3.742,P = 0.043). There was no difference in risk for thrombosis between the patients who did vs. did not receive antiplatelet therapy (P = 0.436). The most common complication after CAF closure was thrombosis. Increased risk for thrombosis was associated with large fistulae, distal-type CAF, and older age at presentation. Antiplatelet treatment did not appear to decrease the risk of thrombosis. Among patients with distal-type CAF, risk for thrombosis was lower among patients treated with endocardial closure, compared with patients treated with epicardial ligation.
Nine non-related families with autosomal dominant hearing loss are presented. In each family, some of the individuals had pure tone audiograms (PTAs) with 3-6 kHz dips. The idea of stereotype patterns in familial dominant sensorineural hearing loss (SNHL) is fading and a high level of awareness of the variability of the pattern of hearing loss is therefore needed. To aid early identification, with the attendant benefits, we would therefore suggest that, even where the PTA suggests a noise-induced permanent threshold shift, acoustic or other trauma, an hereditary cause must be excluded.
This review focuses on the following progressive nonsyndromic autosomal dominant (DFNA) trait loci: DFNA1, DFNA2, DFNA4, DFNA5, DFNA6/14(/38), DFNA7, DFNA9, DFNA10, DFNA15, DFNA16, DFNA17, DFNA20/26 and DFNA21. It describes age-related pure tone thresholds and speech discrimination scores related to age and the level of hearing impairment. Vestibular findings, as far as previous described, are included as well.
Méthodes d'analyse d'audiogrammes en grand nombre The analysis of large numbers of audiograms raises the question if and how we can reduce the amount of data without discarding essential information. The present paper compares two ways of data reduction: principal-component analysis and curve fitting. The methods are tested on the audiograms of a large family suffering from a dominant hereditary, progressive hearing loss, beginning in the high frequencies. It is shown that principal-component analysis rejects information on the shape of the audiogram, as do all methods generally referred to as factor analysis. The information concerned is essential for our under-standig of the patient's ability to discriminate speech. Curve-fitting procedures are shown to be effective in data reduction. L'analyse de grands nombres d'audiogrammes pose la question de savoir si, et comment, on peut réduire la quantité de données sans rejeter de l'information importante. Cet article compare deux méthodes de réduction des données: l'analyse des composantes principales et l'ajustement de courbes. Ces méthodes sont éprouvées sur les audiogrammes d'une famille étendue souffrant de surdité progressive héréditaire à caractère dominant, commençant sur les aigus. Il apparaiˇt que l'analyse des composantes principales rejette l'information concernant la forme de la courbe audiométrique, ainsi que le font toutes les methodes reposant sur l'analyse factorielle. L'information ainsi affectée est celle qui est essentielle pour notre appréciation des possibilités du malade dans la compréhension de la parole. Les méthodes d'ajustement de courbes apparaissent efficaces dans la réduction des données.
The progressive nonsyndromic autosomal dominant (DFNA) traits considered here are those linked to the DFNA2, DFNA5, DFNA6/14(/38), DFNA9, DFNA10, DFNA15, DFNA20/26 and DFNA21 loci. This is a report on our use of the method of `Age Related Typical Audiograms' (ARTA). This method was developed especially to characterize progressive hearing impairment phenotypes. Pure tone threshold data are plotted in a familiar audiogram-like format covering, where possible, decade steps in age (decade audiograms). Such plots, if characteristic and specific enough, can be used as phenotype `fingerprints'. The threshold features array is an additional tool that can be used for statistical testing between fingerprints corresponding to different traits. The issue of genotype-phenotype correlation is dealt with in the case of some loci with multi-family presentation and sufficiently established genotypes.
