Julie A Muskett1, Parna Chattaraj1, John F Heneghan2, Fabian R Reimold2, Boris E Shmukler2, Carmen C Brewer1, Kelly A King1, Christopher K Zalewski1, Thomas H Shawker3, John A Butman3, Margaret A Kenna4,5, Wade W Chien6, Seth L Alper2, Andrew J Griffith1. 1. Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland. 2. Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 3. Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland. 4. Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts. 5. Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, Massachusetts. 6. Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, U.S.A.
Abstract
OBJECTIVES/HYPOTHESIS: Hearing loss and enlarged vestibular aqueduct (EVA) can be inherited as an autosomal recessive trait caused by mutant alleles of the SLC26A4 gene. In some other families, EVA does not segregate in a typical autosomal recessive pattern. The goal of this study was to characterize the SLC26A4 genotypes and phenotypes of extended families with atypical segregation of EVA. STUDY DESIGN: Prospective study of cohort of families ascertained between 1998 and 2014 at the National Institutes of Health Clinical Center. METHODS: Study subjects were members of eight families segregating EVA in at least two members who were not related as siblings. Evaluations included pure-tone audiometry, temporal bone imaging, SLC26A4 nucleotide sequence analysis, SLC26A4-linked marker genotype and haplotype analysis, and pedigree analysis. RESULTS: One family had members with EVA caused by different etiologies, and two families had pseudodominant inheritance of recessive mutations of SLC26A4. In five families, the etiology remained unknown and could include inheritance of mutant alleles at another genetic locus, nongenetic influences, or a combination of these factors. CONCLUSIONS: Familial EVA can demonstrate a variety of atypical segregation patterns. Pseudodominant inheritance of SLC26A4 mutations or recessive alleles of other hearing loss genes may be more likely to occur in families in which deaf individuals have intermarried. The etiologic basis of atypical segregation of EVA without detectable SLC26A4 mutations remains unknown. Future studies of these families may reveal novel genes for EVA. LEVEL OF EVIDENCE: NA Laryngoscope, 126:E240-E247, 2016.
OBJECTIVES/HYPOTHESIS: Hearing loss and enlarged vestibular aqueduct (EVA) can be inherited as an autosomal recessive trait caused by mutant alleles of the SLC26A4 gene. In some other families, EVA does not segregate in a typical autosomal recessive pattern. The goal of this study was to characterize the SLC26A4 genotypes and phenotypes of extended families with atypical segregation of EVA. STUDY DESIGN: Prospective study of cohort of families ascertained between 1998 and 2014 at the National Institutes of Health Clinical Center. METHODS: Study subjects were members of eight families segregating EVA in at least two members who were not related as siblings. Evaluations included pure-tone audiometry, temporal bone imaging, SLC26A4 nucleotide sequence analysis, SLC26A4-linked marker genotype and haplotype analysis, and pedigree analysis. RESULTS: One family had members with EVA caused by different etiologies, and two families had pseudodominant inheritance of recessive mutations of SLC26A4. In five families, the etiology remained unknown and could include inheritance of mutant alleles at another genetic locus, nongenetic influences, or a combination of these factors. CONCLUSIONS: Familial EVA can demonstrate a variety of atypical segregation patterns. Pseudodominant inheritance of SLC26A4 mutations or recessive alleles of other hearing loss genes may be more likely to occur in families in which deaf individuals have intermarried. The etiologic basis of atypical segregation of EVA without detectable SLC26A4 mutations remains unknown. Future studies of these families may reveal novel genes for EVA. LEVEL OF EVIDENCE: NA Laryngoscope, 126:E240-E247, 2016.
Authors: Shannon P Pryor; Gail J Demmler; Anne C Madeo; Yandan Yang; Chris K Zalewski; Carmen C Brewer; John A Butman; Karen B Fowler; Andrew J Griffith Journal: Arch Otolaryngol Head Neck Surg Date: 2005-05
Authors: H-J Park; S Shaukat; X-Z Liu; S H Hahn; S Naz; M Ghosh; H-N Kim; S-K Moon; S Abe; K Tukamoto; S Riazuddin; M Kabra; R Erdenetungalag; J Radnaabazar; S Khan; A Pandya; S-I Usami; W E Nance; E R Wilcox; S Riazuddin; A J Griffith Journal: J Med Genet Date: 2003-04 Impact factor: 6.318
Authors: L A Everett; B Glaser; J C Beck; J R Idol; A Buchs; M Heyman; F Adawi; E Hazani; E Nassir; A D Baxevanis; V C Sheffield; E D Green Journal: Nat Genet Date: 1997-12 Impact factor: 38.330
Authors: P Kopp; O K Arseven; L Sabacan; T Kotlar; J Dupuis; H Cavaliere; C L Santos; J L Jameson; G Medeiros-Neto Journal: J Clin Endocrinol Metab Date: 1999-01 Impact factor: 5.958
Authors: Kathleen S Arnos; Katherine O Welch; Mustafa Tekin; Virginia W Norris; Susan H Blanton; Arti Pandya; Walter E Nance Journal: Am J Hum Genet Date: 2008-07-24 Impact factor: 11.025
Authors: Atteeq U Rehman; Regie Lyn P Santos-Cortez; Meghan C Drummond; Mohsin Shahzad; Kwanghyuk Lee; Robert J Morell; Muhammad Ansar; Abid Jan; Xin Wang; Abdul Aziz; Saima Riazuddin; Joshua D Smith; Gao T Wang; Zubair M Ahmed; Khitab Gul; A Eliot Shearer; Richard J H Smith; Jay Shendure; Michael J Bamshad; Deborah A Nickerson; John Hinnant; Shaheen N Khan; Rachel A Fisher; Wasim Ahmad; Karen H Friderici; Sheikh Riazuddin; Thomas B Friedman; Ellen S Wilch; Suzanne M Leal Journal: Eur J Hum Genet Date: 2014-12-10 Impact factor: 4.246
Authors: Jane Rose; Julie A Muskett; Kelly A King; Christopher K Zalewski; Parna Chattaraj; John A Butman; Margaret A Kenna; Wade W Chien; Carmen C Brewer; Andrew J Griffith Journal: Laryngoscope Date: 2016-11-15 Impact factor: 3.325
Authors: Parna Chattaraj; Tina Munjal; Keiji Honda; Nanna D Rendtorff; Jessica S Ratay; Julie A Muskett; Davide S Risso; Isabelle Roux; E Michael Gertz; Alejandro A Schäffer; Thomas B Friedman; Robert J Morell; Lisbeth Tranebjærg; Andrew J Griffith Journal: J Med Genet Date: 2017-08-05 Impact factor: 6.318
Authors: Janet R Chao; Parna Chattaraj; Tina Munjal; Keiji Honda; Kelly A King; Christopher K Zalewski; Wade W Chien; Carmen C Brewer; Andrew J Griffith Journal: BMC Med Genet Date: 2019-07-02 Impact factor: 2.103