# Optimizing Genetic Testing for Deafness for Clinical Diagnostics

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $508,845

## Abstract

Project Summary
 Hearing loss is the most common sensory deficit in humans. It is diagnosed in 1 in 500 newborns and
affects half of all octogenarians. Although causality is multifactorial, in developed countries a large fraction
of hearing loss is genetic and non-syndromic, i.e. not associated with other phenotypes.
 During the prior granting period, we implemented and integrated comprehensive genetic testing as a
cornerstone in the evaluation of the deaf and hard-of-hearing person. The American College of Medical
Genetics has recognized the merit of this approach, and in 2014 included comprehensive genetic testing
for the evaluation of deafness in their newest treatment guidelines. In the largest study to date to
corroborate this decision, we found an underlying genetic cause for hearing loss in 440 (39%) of 1119
sequentially accrued patients chosen without exclusion criteria. Pathogenic variants were present in 49
genes and included missense variants (49%), copy number changes (18%), indels (18%), nonsense
variants (8%), splice-site alterations (6%) and promoter variants (<1%), making comprehensive genetic
testing the single best test to order in the diagnosis of hearing loss after an audiogram.
 In this competitive renewal, we will build on these accomplishments by completing the following aims:
• Specific Aim 1: To optimize phenotype-genotype integration in the analysis of hereditary hearing loss
 by refining the use of hierarchical surface clustering and audioprofile surface analysis to determine
 which types of genetic hearing loss are associated with clinically meaningful sub-clusters
• Specific Aim 2: To validate and integrate physics-based protein modeling as a tool within the Deafness
 Variation Database to predict variant effect and the molecular and patient phenotype
• Specific Aim 3: To identify genetic modifiers of specific deafness-causing genes predicted by
 hierarchical surface clustering and validated by physics-based potential free-energy modeling
 The successful completion of this grant will improve the clinical care of persons with hearing loss by
enhancing phenome-genome integration and by making variant interpretation more robust. Knowledge
gained from this proposal will also lay the foundation for refined studies focused on the identification of
genetic modifiers – both positive and negative – associated with complex phenotypes such as noise-
induced and age-related hearing loss.

## Key facts

- **NIH application ID:** 10058828
- **Project number:** 5R01DC012049-10
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** TERRY A BRAUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,845
- **Award type:** 5
- **Project period:** 2011-09-21 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058828

## Citation

> US National Institutes of Health, RePORTER application 10058828, Optimizing Genetic Testing for Deafness for Clinical Diagnostics (5R01DC012049-10). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10058828. Licensed CC0.

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