Genomic study of a large family with complex neurological phenotype including hearing loss, imbalance and action tremor

To elucidate the pathophysiological and genetic mechanisms of hearing loss associated with the homoplasmic mitochondrial A1555G mutation in the absence of aminoglycoside exposure, we conducted audiological and genetic analyses on 67 maternally related members of a large Japanese family carrying this mutation. A consistent pattern was evident in the audiograms, with features of sensory presbycusis, cochlear origin at all levels of hearing loss, and a high degree of vulnerability of outer hair cells. That the degree of hearing loss was similar in affected subjects within the same sibling group but differed between sibling groups suggests the involvement of nuclear modifier genes. Total mitochondrial DNA sequences were completely identical among subjects with various levels of hearing loss, and lacked additional pathogenic mutations. For the diagnosis of sensorineural hearing loss, the mitochondrial A1555G mutation should be considered when these features are present even in the absence of aminoglycoside exposure.

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Polygenic Inheritance of Otosclerosis

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348947608500214 ◽

1976 ◽

Vol 85 (2) ◽

pp. 281-285 ◽

Cited By ~ 4

Author(s):

Judith C. Mendlowitz ◽

Kurt Hirschhorn

Keyword(s):

Hearing Loss ◽

General Population ◽

Mathematical Analysis ◽

Conductive Hearing Loss ◽

Extended Family ◽

Large Family ◽

Polygenic Inheritance ◽

Increased Risk ◽

The Family ◽

Conductive Hearing

A large family has been studied and its pedigree traced for six generations. Fifteen relatives are known to have had otosclerosis. Of these, the only six individuals who developed this disease before the age of twenty were offspring of second-cousin marriages. Other children in the extended family developed the disease later and may have had somewhat less severe symptoms. The original hypothesis that the severe, early onset cases occurred among those homozygous for a monogenic trait became improbable on mathematical analysis. We conclude that the inheritance of otosclerosis in this family is polygenic and probably multifactorial. Individuals marrying within the family have a greatly increased risk of giving birth to children who will develop otosclerosis early, and perhaps severely. Those who marry outside the family have a greatly decreased risk. They do, of course, have a higher risk than the general population of having children who will at some point experience a conductive hearing loss.

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NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss

Human Molecular Genetics ◽

10.1093/hmg/ddaa240 ◽

2020 ◽

Author(s):

Rodrigo Salazar da Silva ◽

Vitor Lima Goes Dantas ◽

Leandro Ucela Alves ◽

Ana Carla Batissoco ◽

Jeanne Oiticica ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Dominant ◽

Snp Array ◽

Large Family ◽

Sensory Function ◽

Causative Mutation ◽

Linkage Data ◽

Potential Candidate ◽

Mineral Density ◽

Progressive Hearing Loss

Abstract Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM_181659, c.2810C > G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3−/− did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3−/−, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3−/− and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment.

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The deafness, pre-auricular sinus, external ear anomaly and commissural lip pits syndrome – otological, vestibular and radiological findings

The Journal of Laryngology & Otology ◽

10.1017/s002221510012571x ◽

1994 ◽

Vol 108 (1) ◽

pp. 13-18 ◽

Cited By ~ 9

Author(s):

H. A. M. Marres ◽

C. W. R. J. Cremers ◽

P. L. M. Huygen ◽

F. B. M. Joosten

Keyword(s):

Hearing Loss ◽

Autosomal Dominant ◽

Round Window ◽

Large Family ◽

Ossicular Chain ◽

Branchial Arch ◽

Hearing Improvement ◽

Radiological Findings ◽

Conductive Hearing

Commissural lip pits, pinna dysplasia, pre-auricular sinus and hearing loss constitute a recently described autosomal dominant branchial arch syndrome. In a large family, eight out of the 74 members were also affected by conductive hearing loss. No inner ear abnormalities could be demonstrated on the CT scans. In three patients (four ears) out of four patients (six ears), exploratory tympanotomy revealed serious ossicular chain anomalies. In one ear, round window aplasia was also present. Long-term hearing improvement could only be achieved in one ear.

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AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance

Audiology and Neurotology ◽

10.1159/000474929 ◽

2017 ◽

Vol 22 (1) ◽

pp. 30-40 ◽

Cited By ~ 3

Author(s):

Ruth Lang-Roth ◽

Eva Fischer-Krall ◽

Cornelia Kornblum ◽

Gudrun Nürnberg ◽

Dieter Meschede ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Dominant ◽

Family Members ◽

Large Family ◽

Auditory Neuropathy ◽

Single Family ◽

Linkage Analyses ◽

A Genome ◽

Organ Systems ◽

Auditory Synaptopathy

Background: Auditory synaptopathy/neuropathy (AS/AN) is a heterogeneous disorder, which may be caused by environmental factors like postnatal hyperbilirubinemia or by genetic factors. The genetic forms are subdivided into syndromic and non-syndromic types, and show different inheritance patterns with a strong preponderance of autosomal-recessive forms. To date, only a single locus for non-syndromic autosomal-dominant AS/AN (AUNA1) has been reported in a single family, in which a non-coding DIAPH3 mutation was subsequently described as causative. Materials and Methods: Here, we report detailed clinical data on a large German AS/AN family with slowly progressive postlingual hearing loss. Affected family members developed their first symptoms in their second decade. Moderate hearing loss in the fourth decade then progressed to profound hearing impairment in older family members. Comprehensive audiological and neurological tests were performed in the affected family members. Genetic testing comprised linkage analyses with polymorphic markers and a genome-wide linkage analysis using the Affymetrix GeneChip® Human Mapping 250K. Results and Conclusion: We identified a large family with autosomal-dominant AS/AN. By means of linkage analyses, the AUNA1 locus was excluded, and putatively linked regions on chromosomal bands 12q24 and 13q34 were identified as likely carrying the second locus for autosomal-dominant AS/AN (AUNA2). AUNA2 is associated with a slowly progressive postlingual hearing loss without any evidence for additional symptoms in other organ systems.

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DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?

International Journal of Molecular Sciences ◽

10.3390/ijms21113951 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3951 ◽

Cited By ~ 1

Author(s):

Kevin T. Booth ◽

Hela Azaiez ◽

Richard J. H. Smith

Keyword(s):

Hearing Loss ◽

Founder Mutation ◽

East Asian ◽

Large Family ◽

Asian Population ◽

European Ancestry ◽

Unique Haplotype ◽

Variant Filtering ◽

Base Pair Deletion ◽

The Family

Deafness due to mutations in the DFNA5 gene is caused by the aberrant splicing of exon 8, which results in a constitutively active truncated protein. In a large family of European descent (MORL-ADF1) segregating autosomal dominant nonsyndromic hearing loss, we used the OtoSCOPE platform to identify the genetic cause of deafness. After variant filtering and prioritization, the only remaining variant that segregated with the hearing loss in the family was the previously described c.991-15_991-13delTTC mutation in DFNA5. This 3-base pair deletion in the polypyrimidine of intron 7 is a founder mutation in the East Asian population. Using ethnicity-informative markers and haplotype reconstruction within the DFNA5 gene, we confirmed family MORL-ADF1 is of European ancestry, and that the c.991-15_991-13delTTC mutation arose on a unique haplotype, as compared to that of East Asian families segregating this mutation. In-depth audiometric analysis showed no statistical difference between the audiometric profile of family MORL-ADF1 and the East Asian families. Our data suggest the polypyrimidine tract in intron 7 may be a hotspot for mutations.

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Functional Analysis of a Novel Connexin30 Mutation in a Large Family with Hearing Loss, Pesplanus, Ichthyosis, Cutaneous Nodules, and Keratoderma

Annals of Human Genetics ◽

10.1111/ahg.12141 ◽

2015 ◽

Vol 80 (1) ◽

pp. 11-19

Author(s):

Nishtha Pandey ◽

Dennis F. Xavier ◽

Arunima Chatterjee ◽

Ram-Shankar Mani ◽

Ravi Hiremagalore ◽

...

Keyword(s):

Functional Analysis ◽

Hearing Loss ◽

Large Family

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Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.38411 ◽

2017 ◽

Vol 173 (10) ◽

pp. 2826-2830 ◽

Cited By ~ 8

Author(s):

Akira Ganaha ◽

Tadashi Kaname ◽

Ayano Shinjou ◽

Yasutsugu Chinen ◽

Kumiko Yanagi ◽

...

Keyword(s):

Hearing Loss ◽

Large Family ◽

Related Disease

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An Age-Related Hearing Protection Locus on Chromosome 16 of BXD Strain Mice

Neural Plasticity ◽

10.1155/2020/8889264 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Qing Yin Zheng ◽

Lihong Kui ◽

Fuyi Xu ◽

Tihua Zheng ◽

Bo Li ◽

...

Keyword(s):

Hearing Loss ◽

Molecular Mechanisms ◽

Inbred Mouse ◽

Large Family ◽

Hearing Protection ◽

Chromosome 16 ◽

Age Related ◽

Protective Genes ◽

Cadherin 23 ◽

Age Related Hearing Loss

Inbred mouse models are widely used to study age-related hearing loss (AHL). Many genes associated with AHL have been mapped in a variety of strains. However, little is known about gene variants that have the converse function—protective genes that confer strong resistance to hearing loss. Previously, we reported that C57BL/6J (B6) and DBA/2J (D2) strains share a common hearing loss allele in Cdh23. The cadherin 23 (Cdh23) gene is a key contributor to early-onset hearing loss in humans. In this study, we tested hearing across a large family of 54 BXD strains generated from B6 to D2 crosses. Five of 54 strains maintain the normal threshold (20 dB SPL) even at 2 years old—an age at which both parental strains are essentially deaf. Further analyses revealed an age-related hearing protection (ahp) locus on chromosome 16 (Chr 16) at 57~76 Mb with a maximum LOD of 5.7. A small number of BXD strains at 2 years with good hearing correspond roughly to the percentage of humans who have good hearing at 90 years old. Further studies to define candidate genes in the ahp locus and related molecular mechanisms involved in age-related resilience or resistance to AHL are warranted.

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