1. A Multistate Study of Etiology in Infants Identified through Universal Newborn Hearing Screening
Karin M. Dent, MS, CGC
John C. Carey, MD, MPH
University of Utah
Division of Medical Genetics
Department of Pediatrics

2. Congenital Hearing Loss
Birth Prevalence:
1 in in 500 births
includes mild to profound, unilateral and bilateral CHL

3. Congenital Hearing Loss
Rate per 1,000 of Permanent Congenital Hearing Loss
in Published Reports of UNHS Programs
Location of Program Cohort Size Prevalence per 103
New Jersey, ,
New York, ,
Colorado, ,
Texas, ,
Hawaii, ,
Estimate = / 1000

4. Modified from www.ACMG.net
Genetic ~50%
Environmental ~50%
aminoglycosides
infections (bacterial or viral)
trauma
Syndromic ~30%
Branchiootorenal (BOR)
CHARGE Syndrome
Nonsyndromic ~70%
Autosomal Dominant 20%
Autosomal Recessive 80%
X-linked ~1%
Mitochondrial <1%
Modified from

5. Genetics of Hearing Loss
Nonsyndromic Human Hearing Loss Genes*
DFNA - Autosomal Dominant
54 Loci Mapped
DFNB - Autosomal Recessive
DFNB1 = GJB2
51 Loci Mapped
DFN - X-Linked
7 Loci Mapped
Syndromic Hearing Loss Genes
30 single genes known
*50% have been identified Hereditary Hearing Loss web page:

6. Genetic Causes of Hearing Loss: Contribution of Cx26
Syndromic ~30%
Nonsyndromic ~70%
Mt <1%
Dominant 20%
X-linked ~1%
Recessive 80%
DFNB1 = GJB2 (Connexin 26)
50% of DFNB - mutations of GJB2 or Connexin 26
~15% of congenital hearing loss – Cx26 mutations

7. GJB2 / Connexin 26 gene Mechanism Expressed in the cochlea
Membrane protein forming
intracellular channels =
Gap Junction protein A / B
Allows recirculation
of ions (K+)
Nature Genetics, February 2001.

8. >80 mutations identified
Connexin 26 / GJB2
>80 mutations identified
35 del G (formerly del 30)
Carrier freq ≈ 3.5% Caucasians
167 del T
Carrier freq ≈ 4% Ashkenazi Jewish
235 del C
Seen in Asian populations
*M34T
Carrier freq ≈ 2-3% Caucasians
Hypothesized as recessive allele
← GJB2
Chromosome 13
Kenneson et al., Genet Med, 2002

9. Study Development Universal Newborn Hearing Screening +
Advances in Genetics of Hearing Loss =
Prospective study of etiology of
congenital hearing loss
Utah, Hawaii, Rhode Island, and the Centers for Disease Control and Prevention

10. Study Objectives
To determine the etiology of congenital hearing loss based on children identified through a statewide newborn hearing screening (EHDI) program
To evaluate all children with permanent hearing loss, unilateral or bilateral, of any degree, from a genetic perspective
To determine the frequency of GJB2 and mitochondrial mutations in this population

11. Study Objectives cont…
To establish a model infrastructure linking genetic services to statewide newborn hearing screening

12. Hypothesis
The majority of infants identified through the newborn hearing screening program will have hearing loss due to various genetic causes including known syndromes and mutations in the GJB2 gene.

13. STUDY DESIGN and FLOW Identified Case Fails screens, enters database
Decline to participate
Send letter inviting participation in study
Genetic Evaluation: Determination of syndrome, pedigree analysis
No evidence of syndrome
Acquired cause (e.g. CMV)
Syndromic
(e.g. Waardenburg, CHARGE, etc.)
Offer GJB2, mitochondrial testing

14. Nonsyndromic hearing loss
Autosomal dominant or Autosomal recessive inheritance
Sporadic
X-linked or maternal inheritance
Offer GJB2 and mitochondrial testing
POSITIVE
NEGATIVE
LVA
Summarize and classify case
GJB2 het
Refer for ophthalmology, EKG (?), etc., through PCP
GJB6 testing
Offer additional genetic counseling and family member referrals
Pendred studies

15. Results 93 Probands 19 syndromic cases 1 cases acquired hearing loss
(primarily Caucasian / N. European, Hispanic)
20 cases from RI
73 cases from UT
19 syndromic cases
1 cases acquired hearing loss
CMV induced
73 cases non-syndromic

16. Results cont… Syndromic cases (19) - Williams syndrome
- Wolf-Hirschhorn (4p-)
- CHARGE syndrome
- 18q deletion syndrome
- Kabuki syndrome
- 22q deletion syndrome
- 10p trisomy syndrome
- Wildervank
- Trisomy 21
- Waardenburg x 2
- Oculoauriculovertebral
- VATER
- Branchiootorenal (BOR)
- Pendred
- MCA x 4

17. Results cont… Nonsyndromic Cases (73) 8 cases Conductive
isolated microtia, meatal atresia
65 cases Sensorineural
53 Bilateral
12 Unilateral
52 Sporadic
1 adopted
13 Familial

18. of 53 Bilateral Non-syndromic SNHL:
DNA Testing Results
of 53 Bilateral Non-syndromic SNHL:
GJB2 Results (12)
35 del G / 35 del G homozygote (3)
L 90 P / 35 del G cmpd heterozygote
35 del G / 358 del GAG cmpd heterozygote
35 del G heterozygote (3)
L 90 P heterozygote
S 193 N heterozygote
M 34 T heterozygote (2)

19. DNA Testing Results GJB6 Results Mitochondrial DNA Results
no mutations found (RI, n = 20)
Mitochondrial DNA Results
no mutations found

20. Summary 93 probands 73 nonsyndromic 65 sensorineural hearing loss
53 bilateral, sensorineural hearing loss
12 / 53 (23%) have GJB2 variant
5 / 53 (9.4%) 35 del G homozygotes or compound heterozygotes

21. Risk Factors for Hearing Loss
Prematurity (<37 wks gestation),
jaundice,
aminoglycoside exposure,
external ear defects,
family history of hearing loss

22. Risk Factors Utah: TOTAL = 24 (of 73 probands) Rhode Island:
4 patients with prematurity
(1 of 4 w/ aminoglycoside X)
1 pt aminoglycoside exp (full term pgcy)
8 pts microtia
11 familial pts
TOTAL = (of 73 probands)
Rhode Island:
3 patients with prematurity and aminoglycoside exp
2 familial pts
Others with jaundice, aminoglycoside exposure, and non-isolated microtia
TOTAL > 5
(of 20 probands)

23. Conclusions
Frequency of GJB2 mutations in this population is consistent with reported estimates
Identification of the etiology of hearing loss allows for accurate genetic counseling in terms of recurrence risk, natural history, and anticipatory guidance.

24. Conclusions
Incorporation of genetic services into newborn screening programs for hearing loss is beneficial for families.
Majority of newborns identified through universal screening had no clinical risk factors for hearing loss.

25. Future Directions Ascertainment (All) DNA Testing (Utah and Hawaii)
pt evaluations in outreach clinics
website
parent brochure
Spanish literature
DNA Testing (Utah and Hawaii)
Connexin 30 testing
Pendrin testing

26. Contributors - Hawaii Patricia Heu, MD Principal Investigator
Sylvia Au, MS, CGC
State Genetics Coordinator
Genetic Counselors
Allison Taylor, MS
Lianne Hasagawa, MS
Kirsty McWalter, MS

27. Contributors – Rhode Island
Jeffrey Milunsky, MD
Boston University
Dianne Abuelo, MD
Rhode Island Hospital
Kristilyn Zonno, MS
Betty Vohr, MD
Women & Infant’s Hospital
Julie Jodoin, MEd, MA
Jyllian Anterni, BS

28. Contributors - Utah University of Utah Janice C. Palumbos, MS, CGC
Bronte Clifford, BS
Rong Mao, PhD
Utah State University
Karl White, PhD
Utah Dept. of Health
Richard Harward, MS

29. Contributors Centers for Disease Control and Prevention
John Eichwald, MA
Aileen Kenneson, PhD
Krista Biernath, MD
"The information provided in this presentation was supported by Cooperative Agreement Number from the Centers for Disease Control and Prevention (CDC). The contents are solely the responsibility of the authors and do not necessarily represent the official views of CDC."