Non-Syndrome Hereditary Hearing Impairment - Gene Mapping: India/Pakistan Protocol
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|ClinicalTrials.gov Identifier: NCT00341874|
Recruitment Status : Recruiting
First Posted : June 21, 2006
Last Update Posted : June 20, 2018
|First Submitted Date||June 19, 2006|
|First Posted Date||June 21, 2006|
|Last Update Posted Date||June 20, 2018|
|Study Start Date||September 8, 1992|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures
||New genes and loci associated with hearing loss will be identified and new strategies to prevent and preserve hearing will be developed [ Time Frame: 07/01/2020 ]|
|Original Primary Outcome Measures||Not Provided|
|Change History||Complete list of historical versions of study NCT00341874 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures||Not Provided|
|Original Secondary Outcome Measures||Not Provided|
|Current Other Outcome Measures||Not Provided|
|Original Other Outcome Measures||Not Provided|
|Brief Title||Non-Syndrome Hereditary Hearing Impairment - Gene Mapping: India/Pakistan Protocol|
|Official Title||Non-Syndromic Hereditary Hearing Impairment - Gene Mapping: India/Pakistan Protocol|
The incidence of hearing impairment in India and Pakistan is higher than in the United States. This can be attributed to several factors, including infection and high rate of inbreeding which may result in homozygosity for a rare recessive mutation. The average family size is larger in India and Pakistan when compared to the United States. In addition, there are more than 1 billion people in India while the population size of Pakistan is approximately 148 million. The ability to detect linkage is greatly enhanced in an extended inbred family. It is estimated that as many as 45% - 60% of marriages in Pakistan are between close relatives (the vast majority of marriages are to first cousins). While the percentage of consanguineous marriages are not as high in India as compared to Pakistan, the population size of India is much larger.
Hearing impairment is the result of abnormal ear development, abnormal ear function or both and yet little is known about the molecular mechanisms involved in the development and homeostasis of the inner ear. Although the genes for several recessive deafness loci have been identified, there are still many families segregating deafness that cannot be ascribed to one of the currently known genes. The purpose of this study is to continue to identify genes that cause nonsyndromic hereditary hearing impairment by enrolling families segregating deafness.
Objective: One objective of this study is to genetically map and identify mutated genes for human hereditary hearing loss. A second objective is to study the function of these genes in the auditory system using mouse models. Human hereditary hearing impairment is the result of abnormal ear development, abnormal ear function or both. Although the genes for numerous deafness loci have been mapped and identified, there are still many families segregating deafness as a monogenic trait but a mutant allele can t be ascribed to one of the currently reported deafness genes . In order to map and identify novel mutated genes associated with hearing loss in humans, we will continue to ascertain large families segregating syndromic and nonsyndromic deafness as a monogenic trait.
Study population: This study will ascertain subjects from consanguineous Pakistani families segregating hearing loss consisting of both nonsyndromic and syndromic forms of deafness of genetic etiology. Since a majority of Pakistani marriages are between first cousins, this tends to bring together the same recessive mutations for hearing loss with multiple affected individuals within single family lines, which is an advantage for this genetic study. A few years ago we stopped ascertaining families in India. We continue to ascertain both affected and unaffected Pakistani family members from age 2 years and up. Adults provide informed consent both for themselves and their children who agree to participate in this study. We will ascertain both genders and all Pakistani races and ethnicities.
Design: Subjects will be screened and consented by our collaborating Associate Investigator in Pakistan. After consenting, the subjects will undergo a history and physical, audiological assessment and testing, vestibular assessment and testing, and blood and urine analysis tests, along with a blood sample or buccal swab sample that will be used for genomic DNA extraction. Probands at the time of ascertainment are initially assumed to have a form of nonsyndromic deafness. Additional tests may be performed depending on the history or physical of the individual or after the deafness gene is identified. Data from functional studies in animal models may also point to other concomitant clinical features along with hearing loss. These additional tests may include: photographs or videotapes of a subject s body and face; eye and vision examinations for those with suspected or known eyesight problems related to their genetic hearing loss mutations, and EKGs and/or Echocardiograms for those with suspected or known heart problems related to their genetic hearing loss mutations. Urine and blood analyses may be requested for those individuals with genetic nephritic issues or infertility. For example, when a deaf female individual in a family is subsequently discovered to have Perrault syndrome, a recessive disorder characterized by hearing loss (usually the initial manifestation) and ovarian dysgenesis/primary amenorrhea, additional evaluations would then be conducted for a definitive diagnosis of Perrault syndrome. Such an evaluation would include a pelvic ultrasound scan and measurements of serum estrogen and gonadotropins. Similarly, in some of these families, hearing impaired males may be asked about their fertility since the possibility of male infertility in families segregating Perrault syndrome remains an open question. For genetic analyses, genomic DNA extracted from a blood sample or a buccal swab from affected and unaffected members of families segregating hereditary hearing loss will be genetically screened with polymorphic markers (STRs or SNPs) for linkage to the known deafness loci. The hearing phenotype of children (>2 years old), adolescent and adult subjects will be assigned on the basis of performance from audiological examinations. Genomic DNA from families where deafness is found to be unlinked to the known deafness loci will then be used in genome wide screens with ~ 950,000 SNP markers distributed across the entire human genome to identify novel deafness loci. Alternatively, DNA samples from affected and unaffected individuals will undergo whole exome sequencing (WES) or whole genome sequencing (WGS) with a focus on potentially pathogenic variants located only in chromosomal regions of markers genetically linked to deafness. Subsequently, novel deafness genes will be positionally identified and their functions studied.
Outcome measures: Novel deafness loci and genes associated with hearing loss will be identified and will provide new insight into mechanisms required for sound transduction in humans . Data from this study is likely to be the basis of commercially available tests for early diagnosis and timely genetic counseling for at risk couples as well as the development of strategies to preserve hearing and prevent hearing loss.
|Study Design||Observational Model: Family-Based
Time Perspective: Other
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Not Provided|
|Study Population||Not Provided|
|Study Groups/Cohorts||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Study Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
|Ages||2 Years to 99 Years (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers||Yes|
|Listed Location Countries||Pakistan|
|Removed Location Countries||India, United States|
|Other Study ID Numbers||999993016
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Institute on Deafness and Other Communication Disorders (NIDCD) )|
|Study Sponsor||National Institute on Deafness and Other Communication Disorders (NIDCD)|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||April 9, 2018|