Presentation is loading. Please wait.

Presentation is loading. Please wait.

Karin M. Dent, MS, CGC John C. Carey, MD, MPH University of Utah

Similar presentations

Presentation on theme: "Karin M. Dent, MS, CGC John C. Carey, MD, MPH University of Utah"— Presentation transcript:

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
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."

Download ppt "Karin M. Dent, MS, CGC John C. Carey, MD, MPH University of Utah"

Similar presentations

Ads by Google