Case-Control Genotyping of the c.788C>T Variant of Transforming Growth Factor-Beta 1 Gene in Otosclerosis in the South Indian Population.

BACKGROUND: Otosclerosis is a common conductive hearing loss resulting from abnormal bone metabolism. The c.788C>T variant in the transforming growth factor-beta 1 gene is associated with otosclerosis in all studied populations, except the Indian population. In this study, we predicted the functional effects of reported variants in transforming growth factor-beta 1 and analyzed the c.788C>T variant in a case-control cohort from India and in the genomes present in public databases. METHODS: Clinically confirmed otosclerosis cases (n=120) and controls (n=120) were recruited and genotyped by polymerase chain reactionrestriction fragment length polymorphism and DNA sequencing. In addition, Ensembl 1000 Genome, Ensembl NHLBI Exome, GnomAD, and Genome Asia 100K human genome databases were analyzed for allele frequency. RESULTS: Among the 3 variants studied, a significant functional effect was observed only for the c.788C>T variant. This variant was found in 1 case but absent in all others and controls. Odds ratio, 95% CI, and P-value under the dominant model were 1.00, 0.0197-50.8116, and 1.00, respectively. Analysis of genomic databases showed a frequency of 0-11.21% and 0-1.25% for the c.788C>T variant and the individuals homozygous for this variant, respectively. CONCLUSION: We did not find any genetic association between the c.788C>T variant and otosclerosis in the South Indian population; however, it was not monomorphic as had previously been reported from the Odisha population of Eastern India. Moreover, contrary to an earlier report that the c.788C>T variant was never found in a homozygous condition, homozygous individuals were found in the European, Asian, Latin American, and Ashkenazi Jews populations.

Pedigree Analysis and Audiological Investigations of Otosclerosis: An Extended Family Based Study.

BACKGROUND AND OBJECTIVES: To analyse the audiometric profile and the pedigree of a large family with otosclerosis to understand the inheritance pattern and its implication in clinical management of the disease. Subjects and. METHODS: Pedigree analysis was performed on the basis of family history and audiometric tests. Pure tone audiometry, tympanometry, and acoustic reflexes were evaluated for the family members. Audiometric analysis was also carried out for the individuals who have already underwent corrective surgery at the time of study. RESULTS: Out of 112 family members, 17 were affected individuals, and 11 of them were surgically confirmed. Hearing loss (HL) started unilaterally and progressed to bilateral form. Otosclerosis was presented in early 20's in the first and second generations but it was delayed to mid-late 30's in the fourth generation. An affected female was diagnosed with otosclerosis during her pregnancy. Though the disease was familial, a mother of four affected offspring in this family did not develop otosclerosis until she died at the age of 84. CONCLUSIONS: The five-generation family, which was analysed in the present study, exhibited autosomal dominant inheritance of otosclerosis with reduced penetrance. Bilateral HL and pregnancy-aggravated otosclerosis were observed in this family. It was found for the first time that the age of onset of the disease delayed in the successive generations. The current study indicated the importance of detailed pedigree analysis for better clinical management of otosclerosis.