Presentation on theme: "A Multistate Study of Etiology in Infants Identified through Universal Newborn Hearing Screening Karin M. Dent, MS, CGC John C. Carey, MD, MPH University."— Presentation transcript:
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 in 500 births – –includes mild to profound, unilateral and bilateral CHL serm.fr/cric/audition/engli sh/start2.htm
Congenital Hearing Loss Rate per 1,000 of Permanent Congenital Hearing Loss in Published Reports of UNHS Programs Location of ProgramCohort Size Prevalence per 10 3 New Jersey, , New York, , Colorado, , Texas, , Hawaii, , Estimate = 2- 4 / 1000
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:
Genetic Causes of Hearing Loss: Contribution of Cx26 DFNB1 = GJB2 (Connexin 26) –50% of DFNB - mutations of GJB2 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% 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
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 inheritance Sporadic 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 cases –1 cases acquired hearing loss CMV induced –73 cases non-syndromic
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: 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, 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 & Infants Hospital Julie Jodoin, MEd, MA Women & Infants Hospital Jyllian Anterni, BS Women & Infants 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 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."