A Multistate Study of Etiology in Infants Identified

through Universal Newborn Hearing

Screening

Karin M. Dent, MS, CGCJohn C. Carey, MD, MPHUniversity of UtahDivision of Medical GeneticsDepartment of Pediatrics

Congenital Hearing Loss

Birth Prevalence:

–1 in 300 - 1 in 500 births

– includes mild to profound, unilateral and bilateral CHL

http://www.iurc.montp.inserm.fr/cric/audition/english/start2.htm

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, 1997 15,749 3.30

New York, 2000 27, 938 1.96

Colorado, 1998 41,976 2.56

Texas, 1998 54,228 2.15

Hawaii, 1997 9,605 4.15

Estimate = 2- 4 / 1000

I ≈ 1/500

Environmental ~50%

aminoglycosides infections (bacterial or viral) trauma

Genetic ~50%

Syndromic ~30%

Branchiootorenal (BOR) CHARGE Syndrome

Nonsyndromic ~70%

Autosomal Dominant 20%

Autosomal Recessive 80%

X-linked ~1%

Mitochondrial <1%

Modified from www.ACMG.net

Genetics of Hearing Loss

Nonsyndromic Human Hearing Loss Genes*Nonsyndromic Human Hearing Loss Genes*

DFNA - Autosomal Dominant– 54 Loci Mapped 54 Loci Mapped

DFNB - Autosomal Recessive– DFNB1 = DFNB1 = GJB2GJB2– 51 Loci Mapped 51 Loci Mapped

DFN - X-Linked– 7 Loci Mapped7 Loci Mapped

Syndromic Hearing Loss Genes 30 single genes known

*50% have been identified Hereditary Hearing Loss web page: www.uia.ac.be/dnalab/hhhwww.uia.ac.be/dnalab/hhh

Genetic Causes of Hearing Loss:

Contribution of Cx26

DFNB1 = GJB2 (Connexin 26)

– 50% of DFNB - mutations of 50% of DFNB - mutations of GJB2GJB2 or Connexin 26 or Connexin 26

~15% of congenital hearing loss – Cx26 mutations

Genetic ~50%

Syndromic ~30%

Nonsyndromic ~70%

Dominant 20%

Recessive 80%

X-linked ~1%

Mt <1%

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.

Connexin 26 / GJB2

>80 mutations identified

35 del G (formerly del 30)– Carrier freq ≈ 3.5% CaucasiansCarrier freq ≈ 3.5% Caucasians

167 del T– Carrier freq ≈ 4% Ashkenazi JewishCarrier freq ≈ 4% Ashkenazi Jewish

235 del C– Seen in Asian populationsSeen in Asian populations

*M34T– Carrier freq ≈ 2-3% CaucasiansCarrier freq ≈ 2-3% Caucasians– Hypothesized as recessive alleleHypothesized as recessive allele

← GJB2

Chromosome 13Kenneson et al., Genet Med, 2002

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

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

Study Objectives cont…

To establish a model infrastructure linking genetic services to statewide newborn hearing screening

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.

STUDY DESIGN and FLOW

Decline to participate

No evidence of syndrome

Identified Case Fails screens, enters database

Send letter inviting participation in study

Genetic Evaluation: Determination of syndrome,

pedigree analysis

Acquired cause (e.g. CMV) Syndromic

(e.g. Waardenburg, CHARGE, etc.)

Offer GJB2, mitochondrial testing

Nonsyndromic hearing loss

Autosomal dominant or Autosomal recessive

inheritanceSporadic

X-linked or maternal inheritance

Offer GJB2 and mitochondrial testing

POSITIVE NEGATIVE

Summarize and classify case Refer for ophthalmology,

EKG (?), etc., through PCP

Offer additional genetic counseling and family member

referrals

GJB2 het

GJB6 testing

LVA

Pendred studies

Results

93 Probands (primarily Caucasian / N. European, Hispanic)

20 cases from RI 73 cases from UT

– 19 syndromic cases19 syndromic cases

– 1 cases acquired hearing loss1 cases acquired hearing loss CMV induced

– 73 cases non-syndromic73 cases non-syndromic

Results cont…

Syndromic cases (19)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

Results cont…

Nonsyndromic Cases (73)

– 8 cases Conductive8 cases Conductive isolated microtia, meatal atresia

– 65 cases Sensorineural65 cases Sensorineural53 Bilateral

12 Unilateral

13 Familial

52 Sporadic• 1 adopted

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)

DNA Testing Results

GJB6 Results no mutations found (RI, n = 20)

Mitochondrial DNA Resultsno mutations found

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

Risk Factors for Hearing Loss

Prematurity (<37 wks gestation), jaundice, aminoglycoside exposure, external ear defects, family history of hearing loss

Risk Factors

Utah:

4 patients with prematurity

(1 of 4 w/ aminoglycoside X)

1 pt aminoglycoside exp (full term pgcy)

8 pts microtia

11 familial pts

TOTAL = 24 (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)

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.

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.

Future Directions

Ascertainment (All)– pt evaluations in outreach clinics– website– parent brochure– Spanish literature

DNA Testing (Utah and Hawaii)– Connexin 30 testing– Pendrin testing

Contributors - Hawaii

Patricia Heu, MDPrincipal Investigator

Sylvia Au, MS, CGCState Genetics Coordinator

Genetic Counselors

Allison Taylor, MS Lianne Hasagawa, MS Kirsty McWalter, MS

Contributors – Rhode Island

Betty Vohr, MDWomen & Infant’s Hospital

Julie Jodoin, MEd, MAWomen & Infant’s Hospital

Jyllian Anterni, BSWomen & Infant’s Hospital

Jeffrey Milunsky, MD

Boston University

Dianne Abuelo, MDRhode Island Hospital

Kristilyn Zonno, MSRhode Island Hospital

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

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 01048 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."