Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT00341874 |
| Other study ID # |
999993016 |
| Secondary ID |
OH93-DC-016 |
| Status |
Enrolling by invitation |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 16, 2000 |
Study information
| Verified date |
November 1, 2023 |
| Source |
National Institutes of Health Clinical Center (CC) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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 approximately 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.
Description:
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 approximately 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.
