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, CGCJohn C. Carey, MD, MPHUniversity of UtahDivision of Medical GeneticsDepartment of Pediatrics
2 Congenital Hearing Loss Birth Prevalence:1 in in 500 birthsincludes mild to profound, unilateral and bilateral CHL
3 Congenital Hearing Loss Rate per 1,000 of Permanent Congenital Hearing Lossin Published Reports of UNHS ProgramsLocation of Program Cohort Size Prevalence per 103New Jersey, ,New York, ,Colorado, ,Texas, ,Hawaii, ,Estimate = / 1000
4 Modified from www.ACMG.net Genetic ~50%Environmental ~50%aminoglycosidesinfections (bacterial or viral)traumaSyndromic ~30%Branchiootorenal (BOR)CHARGE SyndromeNonsyndromic ~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 Dominant54 Loci MappedDFNB - Autosomal RecessiveDFNB1 = GJB251 Loci MappedDFN - X-Linked7 Loci MappedSyndromic Hearing Loss Genes30 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 formingintracellular channels =Gap Junction protein A / BAllows recirculationof ions (K+)Nature Genetics, February 2001.
8 >80 mutations identified Connexin 26 / GJB2>80 mutations identified35 del G (formerly del 30)Carrier freq ≈ 3.5% Caucasians167 del TCarrier freq ≈ 4% Ashkenazi Jewish235 del CSeen in Asian populations*M34TCarrier freq ≈ 2-3% CaucasiansHypothesized as recessive allele← GJB2Chromosome 13Kenneson et al., Genet Med, 2002
9 Study Development Universal Newborn Hearing Screening + Advances in Genetics of Hearing Loss=Prospective study of etiology ofcongenital hearing lossUtah, Hawaii, Rhode Island, and the Centers for Disease Control and Prevention
10 Study ObjectivesTo determine the etiology of congenital hearing loss based on children identified through a statewide newborn hearing screening (EHDI) programTo evaluate all children with permanent hearing loss, unilateral or bilateral, of any degree, from a genetic perspectiveTo 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 HypothesisThe 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 participateSend letter inviting participation in studyGenetic Evaluation: Determination of syndrome, pedigree analysisNo evidence of syndromeAcquired cause (e.g. CMV)Syndromic(e.g. Waardenburg, CHARGE, etc.)Offer GJB2, mitochondrial testing
14 Nonsyndromic hearing loss Autosomal dominant or Autosomal recessive inheritanceSporadicX-linked or maternal inheritanceOffer GJB2 and mitochondrial testingPOSITIVENEGATIVELVASummarize and classify caseGJB2 hetRefer for ophthalmology, EKG (?), etc., through PCPGJB6 testingOffer additional genetic counseling and family member referralsPendred studies
15 Results 93 Probands 19 syndromic cases 1 cases acquired hearing loss (primarily Caucasian / N. European, Hispanic)20 cases from RI73 cases from UT19 syndromic cases1 cases acquired hearing lossCMV induced73 cases non-syndromic
18 of 53 Bilateral Non-syndromic SNHL: DNA Testing Resultsof 53 Bilateral Non-syndromic SNHL:GJB2 Results (12)35 del G / 35 del G homozygote (3)L 90 P / 35 del G cmpd heterozygote35 del G / 358 del GAG cmpd heterozygote35 del G heterozygote (3)L 90 P heterozygoteS 193 N heterozygoteM 34 T heterozygote (2)
19 DNA Testing Results GJB6 Results Mitochondrial DNA Results no mutations found (RI, n = 20)Mitochondrial DNA Resultsno mutations found
20 Summary 93 probands 73 nonsyndromic 65 sensorineural hearing loss 53 bilateral, sensorineural hearing loss12 / 53 (23%) have GJB2 variant5 / 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 microtia11 familial ptsTOTAL = (of 73 probands)Rhode Island:3 patients with prematurity and aminoglycoside exp2 familial ptsOthers with jaundice, aminoglycoside exposure, and non-isolated microtiaTOTAL > 5(of 20 probands)
23 ConclusionsFrequency of GJB2 mutations in this population is consistent with reported estimatesIdentification of the etiology of hearing loss allows for accurate genetic counseling in terms of recurrence risk, natural history, and anticipatory guidance.
24 ConclusionsIncorporation 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 clinicswebsiteparent brochureSpanish literatureDNA Testing (Utah and Hawaii)Connexin 30 testingPendrin testing
26 Contributors - Hawaii Patricia Heu, MD Principal Investigator Sylvia Au, MS, CGCState Genetics CoordinatorGenetic CounselorsAllison Taylor, MSLianne Hasagawa, MSKirsty McWalter, MS
28 Contributors - Utah University of Utah Janice C. Palumbos, MS, CGC Bronte Clifford, BSRong Mao, PhDUtah State UniversityKarl White, PhDUtah Dept. of HealthRichard Harward, MS
29 Contributors Centers for Disease Control and Prevention John Eichwald, MAAileen Kenneson, PhDKrista 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."