Virginia W. Norris

Does universal newborn hearing screening identify all children with GJB2 (Connexin 26) deafness? Penetrance of GJB2 deafness.

Objective: Deafness is the most common neurosensory defect at birth, and GJB2 (connexin 26) mutations are the most frequent genetic cause of hearing loss in many populations. The hearing loss caused by GJB2 mutations is usually congenital in onset and moderate to profound in degree. Considerable phenotypic variation has been noted however, including two anecdotal cases of apparent non penetrance at birth. The objective of this study is to document nine additional children with two pathogenic GJB2 mutations who had non penetrance of hearing loss at birth. Design: Subjects were identified through a national repository which includes deaf probands ascertained primarily from the United States through the Annual Survey of Deaf and Hard of Hearing Children and Youth conducted at the Research Institute at Gallaudet University. The hearing of each of these children had been screened at birth using standard audiologic techniques. Parents were interviewed and available medical records were reviewed. Testing for GJB2 mutations was performed by PCR and sequencing of the entire coding exon in all nine individuals. Results: Using parent interviews and medical records, we documented that all nine children passed newborn audiologic hearing screening. The age at which the hearing loss was subsequently identified in these nine children ranged from 12–60 mo. Of these nine children, 3 were compound heterozygotes and six were homozygous for the 35delG mutation in the GJB2 gene. Conclusion: These nine cases demonstrate that current newborn hearing screening does not identify all infants with two GJB2 mutations. These cases suggest that the frequency of non penetrance at birth is approximately 3.8% or higher. It is important to consider connexin deafness in any child with recessive nonsyndromic hearing loss as well as simplex cases with no history of other affected family members even when the newborn hearing screening results were within the normal range.

Identification of p.A684V Missense Mutation in the WFS1 Gene as a Frequent Cause of Autosomal Dominant Optic Atrophy and Hearing Impairment

Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy‐1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild‐type wolframin, strongly indicating that the mutation is disease‐causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.

Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene

Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype–phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 × 10−3 and 1 × 10−4. This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results.

A Comparative Analysis of the Genetic Epidemiology of Deafness in the United States in Two Sets of Pedigrees Collected More than a Century Apart

In 1898, E.A. Fay published an analysis of nearly 5000 marriages among deaf individuals in America collected during the 19(th) century. Each pedigree included three-generation data on marriage partners that included at least one deaf proband, who were ascertained by complete selection. We recently proposed that the intense phenotypic assortative mating among the deaf might have greatly accelerated the normally slow response to relaxed genetic selection against deafness that began in many Western countries with the introduction of sign language and the establishment of residential schools. Simulation studies suggest that this mechanism might have doubled the frequency of the commonest forms of recessive deafness (DFNB1) in this country during the past 200 years. To test this prediction, we collected pedigree data on 311 contemporary marriages among deaf individuals that were comparable to those collected by Fay. Segregation analysis of the resulting data revealed that the estimated proportion of noncomplementary matings that can produce only deaf children has increased by a factor of more than five in the past 100 years. Additional analysis within our sample of contemporary pedigrees showed that there was a statistically significant linear increase in the prevalence of pathologic GJB2 mutations when the data on 441 probands were partitioned into three 20-year birth cohorts (1920 through 1980). These data are consistent with the increase in the frequency of DFNB1 predicted by our previous simulation studies and provide convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness.

Etiology of unilateral hearing loss in a national hereditary deafness repository

PURPOSE The aim of this study was to characterize the genetic, audiologic, and epidemiologic characteristics of unilateral hearing loss (HL) in a national hereditary deafness repository. MATERIALS AND METHODS This is a prospective clinical study involving 34 subjects identified in a national hereditary deafness repository. Clinical data and family history of HL were obtained on enrollment. Candidate deafness genes were screened by single-stranded conformation polymorphism, and mutations were confirmed with sequencing. RESULTS Thirty-four subjects (19 males, 15 females) with unilateral HL were identified, ranging in age from 2 months to 36 years. The mean age at diagnosis was 7 years, and the left ear was affected in 62% of the cases. The racial distribution of our sample was 62% white, 23% African American, and 15% Hispanic. Imaging results were available in 47%, and most (69%) were considered normal. Nineteen percent had enlarged vestibular aqueducts, 2 had ipsilateral Mondini dysplasia, and 1 had a common cavity deformity. Twenty subjects (59%) had a family history of HL, with 26% specifically reporting familial unilateral HL. Mutational screening revealed sequence variants in the GJB2 (connexin 26), GJB3 (connexin 31), TECTA, and COCH genes. Two novel mutations were detected in COCH and TECTA. CONCLUSIONS Sequence variants in known deafness genes were detected in more than one-third of our study population, suggesting that gene/gene or gene/environmental interactions may indeed play a role in the etiology of some cases of unilateral deafness. Further prospective studies including congenital cytomegalovirus screening at birth and molecular screening of deafness genes in children with congenital unilateral HL will be required to establish the etiology of unilateral deafness with certainty.

Vestibular Dysfunction in DFNB1 deafness

Mutations of GJB2 and GJB6 (connexin‐26 and 30) at the DFNB1 locus are the most common cause of autosomal recessive, nonsyndromic deafness. Despite their widespread expression throughout the vestibular system, vestibular dysfunction has not been widely recognized as a commonly associated clinical feature. The observations of vertigo accompanying DFNB1 deafness in several large families prompted our hypothesis that vestibular dysfunction may be an integral, but often overlooked, component of DFNB1 deafness. Our aim was to define the prevalence of vestibular dysfunction in Cases of DFNB1 deafness and Controls with other forms of deafness. We developed and used a survey to assess symptoms of vestibular dysfunction, medical, and family history was distributed to Cases with deafness due to pathogenic GJB2 and/or GJB6 mutations and deaf Controls without DFNB1 deafness. Our results showed: Surveys were returned by 235/515 Cases (46%) with DFNB1 mutations and 121/321 Controls (38%) without these mutations. The mean age of Cases (41) was younger than Controls (51; P < 0.001). Vestibular dysfunction was reported by 127 (54%) of Cases and was present at significantly higher rates in Cases than in deaf Controls without DFNB1 deafness (P < 0.03). Most (63%) had to lie down in order for vertigo to subside, and 48% reported that vertigo interfered with activities of daily living. Vertigo was reported by significantly more Cases with truncating than non‐truncating mutations and was also associated with a family history of dizziness. We conclude that vestibular dysfunction appears to be more common in DFNB1 deafness than previously recognized and affects activities of daily living in many patients.

Fitness Among Individuals with Early Childhood Deafness: Studies in Alumni Families from Gallaudet University

The genetic fitness of an individual is influenced by their phenotype, genotype and family and social structure of the population in which they live. It is likely that the fitness of deaf individuals was quite low in the Western European population during the Middle Ages. The establishment of residential schools for deaf individuals nearly 400 years ago resulted in relaxed genetic selection against deaf individuals which contributed to the improved fitness of deaf individuals in recent times. As part of a study of deaf probands from Gallaudet University, we collected pedigree data, including the mating type and the number and hearing status of the children of 686 deaf adults and 602 of their hearing siblings. Most of these individuals had an onset of severe to profound hearing loss by early childhood. Marital rates of deaf adults were similar to their hearing siblings (0.83 vs. 0.85). Among married individuals, the fertility of deaf individuals is lower than their hearing siblings (2.06 vs. 2.26, p = 0.005). The fitness of deaf individuals was reduced (p = 0.002). Analysis of fertility rates after stratification by mating type reveals that matings between two deaf individuals produced more children (2.11) than matings of a deaf and hearing individual (1.85), suggesting that fertility among deaf individuals is influenced by multiple factors.

Provision of Genetic Services for Hearing Loss: Results from a National Survey and Comparison to Insights Obtained from Previous Focus Group Discussions

Hearing loss is a common sensory deficit and more than 50% of affected individuals have a genetic etiology. The discovery of 40 genes and more than 100 loci involved in hearing loss has made genetic testing for some of these genes widely available. Genetic services for deafness are also being sought more often due to the early identification of hearing loss through newborn screening services. The motivations for pursuing genetic testing, and how genetic services are provided to the client may differ among individuals. Additionally, information obtained through genetic testing can be perceived and used in different ways by parents of deaf children and deaf adults. This study aimed to follow up on focus group studies published earlier with a quantitative survey instrument and assess the preference of consumers for provision of genetic services. We conducted a national survey of hearing and deaf parents of children with hearing loss and of deaf adults. Data was compared and analyzed by hearing status of the participant, their community affiliation and the genetic testing status using nominal logistic regression. Consistent with our focus group results, the survey participants thought that a genetic counselor/geneticist would be the most appropriate professional to provide genetics services. Statistically significant differences were noted in the preferred choice of provider based on the genetic testing status. Parents preferred that genetic evaluation, including testing, occur either immediately at or a few months after the audiologic diagnosis of hearing loss. This data should help providers in clinical genetics keep patient preferences at the helm and provide culturally competent services.

The Changing Age of Individuals Seeking Presymptomatic Genetic Testing for Huntington Disease

Huntington disease (HD) is a progressive neurodegenerative disorder. Presymptomatic genetic testing allows at-risk individuals to clarify their risk status. Understanding the characteristics and motivations of individuals seeking HD presymptomatic genetic testing better equips genetic counselors and other healthcare professionals to provide comprehensive and personalized care. The aims of this study were to (1) determine whether the average age when individuals seek presymptomatic HD genetic testing has decreased over time, (2) assess motivations for seeking testing, (3) explore whether there is a relationship between age and motivations, and (4) explore genetic counselors’ perceptions of the shift in age. Data from the US HD testing centers (N = 4) were analyzed. A small but statistically significant decrease in age of individuals seeking presymptomatic testing was observed (p = 0.045). HD community members (N = 77) were surveyed regarding presymptomatic testing motivations. Younger individuals were more likely than older individuals to cite “To learn whether or not you would develop HD” and “To make choices about further education or a career” compared to older individuals (p < 0.05). Conversely, older individuals more frequently cited “To give children a better idea of their risk” (p < 0.002). Sixteen percent of genetic counselors surveyed (6/37) perceived a change in age of testing. All of these respondents had provided HD testing for ten or more years and anecdotally believed the age at testing has decreased over time. Study results help providers personalize counseling based on patient’s age and serve as a starting point for more research into the relationship between age at testing and motivations for testing.

Fitness Among Individuals with Early Childhood Deafness: Studies in Alumni Families from Gallaudet University: Fertility and Fitness

The genetic fitness of an individual is influenced by their phenotype, genotype and family and social structure of the population in which they live. It is likely that the fitness of deaf individuals was quite low in the Western European population during the Middle Ages. The establishment of residential schools for deaf individuals nearly 400 years ago resulted in relaxed genetic selection against deaf individuals which contributed to the improved fitness of deaf individuals in recent times. As part of a study of deaf probands from Gallaudet University, we collected pedigree data, including the mating type and the number and hearing status of the children of 686 deaf adults and 602 of their hearing siblings. Most of these individuals had an onset of severe to profound hearing loss by early childhood. Marital rates of deaf adults were similar to their hearing siblings (0.83 vs. 0.85). Among married individuals, the fertility of deaf individuals is lower than their hearing siblings (2.06 vs. 2.26, p = 0.005). The fitness of deaf individuals was reduced (p = 0.002). Analysis of fertility rates after stratification by mating type reveals that matings between two deaf individuals produced more children (2.11) than matings of a deaf and hearing individual (1.85), suggesting that fertility among deaf individuals is influenced by multiple factors.