Transcript Multistate Study of Etiology in Newborn Hearing Screening

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
Congenital Hearing Loss

Birth Prevalence:
–1 in 300 - 1 in 500 births
–includes mild to profound,
unilateral and bilateral CHL
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Congenital Hearing Loss
Rate per 1,000 of Permanent Congenital Hearing Loss
in Published Reports of UNHS Programs
Prevalence per 103
Location of Program
Cohort Size
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%

Genetic ~50%


Syndromic ~30%


Branchiootorenal (BOR)
CHARGE Syndrome
aminoglycosides
infections (bacterial or viral)
trauma
Nonsyndromic ~70%
Mitochondrial <1%
Autosomal Dominant 20%
X-linked ~1%
Autosomal Recessive 80%
Modified from www.ACMG.net
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: www.uia.ac.be/dnalab/hhh
Genetic Causes of Hearing Loss:
Contribution of Cx26
Genetic
~50%
Syndromic
~30%
Nonsyndromic
~70%
Mt <1%
Dominant
20%
Recessive
80%

X-linked
~1%
DFNB1 = GJB2 (Connexin 26)
– 50% of DFNB - mutations of GJB2 or Connexin 26

~15% of congenital hearing loss – Cx26 mutations
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% Caucasians

← GJB2
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
Chromosome 13
Kenneson 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
Identified Case
Fails screens, enters database
Decline to
participate
Send letter inviting
participation in study
Genetic Evaluation:
Determination of syndrome,
pedigree analysis
Acquired cause
(e.g. CMV)
No evidence
of syndrome
Syndromic
(e.g. Waardenburg,
CHARGE, etc.)
Offer GJB2,
mitochondrial testing
Nonsyndromic hearing loss
Autosomal dominant or
Autosomal recessive
inheritance
X-linked or maternal
inheritance
Sporadic
Offer GJB2 and
mitochondrial testing
POSITIVE
NEGATIVE
LVA
GJB2 het
GJB6
testing
Summarize and
classify case
Offer additional genetic
counseling and family member
referrals
Refer for ophthalmology,
EKG (?), etc., through PCP
Pendred
studies
Results

93 Probands
(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
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
Results cont…

Nonsyndromic Cases (73)
– 8 cases Conductive

isolated microtia, meatal atresia
– 65 cases Sensorineural
53 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 Results
 no
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:

Rhode Island:
4 patients with prematurity
(1 of 4 w/ aminoglycoside X)


1 pt aminoglycoside exp

8 pts microtia


11 familial pts


TOTAL = 24
(full term pgcy)
(of 73 probands)

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, MD
Principal Investigator

Sylvia Au, MS, CGC
State Genetics Coordinator
Genetic Counselors



Allison Taylor, MS
Lianne Hasagawa, MS
Kirsty McWalter, MS
Contributors – Rhode Island

Betty Vohr, MD
Women & Infant’s Hospital

Julie Jodoin, MEd, MA
Women & Infant’s Hospital

Jyllian Anterni, BS
Women & Infant’s Hospital

Jeffrey Milunsky, MD
Boston University

Dianne Abuelo, MD
Rhode Island Hospital

Kristilyn Zonno, MS
Rhode 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."