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A Multistate Study of Etiology in Infants Identified through Universal 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

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A Multistate Study of Etiology in Infants Identified through Universal Newborn Hearing Screening

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  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 300 - 1 in 500 births • includes mild to profound, unilateral and bilateral CHL http://www.iurc.montp.inserm.fr/cric/audition/english/start2.htm

  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, 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

  4. Environmental ~50% • aminoglycosides • infections (bacterial or viral) • trauma Genetic ~50% • Syndromic ~30% • Branchiootorenal (BOR) • CHARGE Syndrome Nonsyndromic ~70% Mitochondrial <1% AutosomalDominant 20% X-linked ~1% Autosomal Recessive 80% I ≈ 1/500 Modified from www.ACMG.net

  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: www.uia.ac.be/dnalab/hhh

  6. 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% Mt <1% Dominant 20% X-linked ~1% Recessive 80%

  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. ←GJB2 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 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 (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. 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 • 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%) 35delG 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. 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) Risk Factors

  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) • 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. 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 – Rhode Island

  28. 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 - Utah

  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 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."

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