1. Guidelines for the Genetic Evaluation of Congenital Hearing Loss ( In Press, Genetics in Medicine) Michael Watson, PhD HRSA/MCHB contract 01-MCHB-25A to ACMG

2. A Multidisciplinary Expert Panel 1 b Walter Nance, MD, PhD - Med. Coll. Of VA, Chair b Kathleen Arnos, PhD - Gallaudet Univ. b John Carey, MD - Univ. of Utah Health Sciences b George Cunningham, MD - Calif. Dept. Health b Rena Falk, MD, - Cedars Sinai Med. Ctr. b Terese Finitzo, PhD - OZ Systems b Dynio Honrubia, MD - Harvard Med. Sch. b Bronya Keats, PhD - Louisiana State Univ. Sch. Of Med. b William Kimberling - Boys Town Nat’l. Med. Ctr. b Gail Lim, ARNP - Pediatrix Med Group b Cynthia Morton, PhD - Harvard Med. Sch.

3. A Multidisciplinary Expert Panel 2 b Arti Pandya, MD, MBA - Med. Coll of VA b Mary Kay Pelias, PhD, JD - Louisiana State Sch of Med b James Skordas, CCCA - Pediatrix Med Group b Richard Smith, MD - Univ of iowa Hosp. and Clinics b Michael Watson, PhD - American Coll of Med Genetics Ex-officio Members: Colleen Boyle, PhD - CD Marie Mann, MD - HRSA Colleen Boyle, PhD - CD Marie Mann, MD - HRSA Aileen Kenneson, PhD - CDC Jay Sheehan, MS - HRSA Aileen Kenneson, PhD - CDC Jay Sheehan, MS - HRSA Amy Donahue, PhD - NIDCD Brad Therrell, PhD, NNSGRC Amy Donahue, PhD - NIDCD Brad Therrell, PhD, NNSGRC Karl White, PhD - NCHAM Karl White, PhD - NCHAM Michele Lloyd-Puryear, MD, PhD - HRSA Michele Lloyd-Puryear, MD, PhD - HRSA

4. Hearing Loss Definition for this Purpose b Permanent b Bilateral or unilateral b sensory or conductive b >30 db loss in frequency important for speech recognition

5. Hearing Loss Etiologies b About 50% “environmental” Some genetic susceptibilitesSome genetic susceptibilites Some identified with genetic testsSome identified with genetic tests b About 50% genetic 30% syndromic - over 400 syndromes described30% syndromic - over 400 syndromes described over 75 NSHI-linked genes identifiedover 75 NSHI-linked genes identified over 30 syndrome-linked genes identifiedover 30 syndrome-linked genes identified

6. Deafness ~50% Environmental Genetic ~70% ~30% CMV meningitis rubella prematurity neonatal icterus ototoxicity other infections Syndromic Alport Norrie Pendred Usher Waardenburg Branchio-oto-renal Jervell and Lange-Nielsen Non-syndromic Autosomal dominant DFNA1 - DFNA3 Autosomal recessive DFNB1 - DFNB30 X-Linked DFN1 - DFN8 Mitochondrial 22% 77% ~1%

7. The Genetics Evaluation: Genetic Services Overview b What makes it hard syndromology in infantssyndromology in infants widely variable laboratory tests and expertisewidely variable laboratory tests and expertise very unstable knowledge basevery unstable knowledge base tests and result interpretation ranging from easy to complex and still evolvingtests and result interpretation ranging from easy to complex and still evolving –significant ethnic variability –common causes to private and very rare rapid translation of research into servicerapid translation of research into service b We specialize in communicating uncertainty

8. Genetic Evaluation: The Expertise Needed b Knowledge of genetics of hearing loss b Dysmorphology b Audiology b Otolaryngology b Genetic counseling b Communication with the deaf and hard of hearing b Considerable secondary expertise needed eye, heart, kidney, neurology etc.eye, heart, kidney, neurology etc.

9. Critical Evaluation Components b Family history (2-3 generation pedigree) b Ethnicity & country of origin b Inheritance pattern b Audiometric characteristics in family b Evidence of vestibular dysfunction b Syndrome vs. nonsyndromal

10. Is it a Syndrome? 1 Is it a Syndrome? 1 b Evaluate and inquire of family history for: visual anomaliesvisual anomalies facial/cervical dysmorphologyfacial/cervical dysmorphology endocrine abnormalitiesendocrine abnormalities cardiac signscardiac signs renal abnormalitiesrenal abnormalities skin and hairskin and hair

11. Is it a Syndrome? 2 Is it a Syndrome? 2 b The patient history of risk factors b Physical examination

12. The Genetic Testing and Triage Paradigm 1 b Based on the genetic evaluation If syndrome is suspectedIf syndrome is suspected – test if possible If nonsyndromic and isolated caseIf nonsyndromic and isolated case –check CMV and GJB2 (connexin 26) gene sequencing If syndromic and not isolatedIf syndromic and not isolated – check GJB2

13. The Genetic Testing and Triage Paradigm 2 b If nonsyndromic and suggestive of autosomal dominant check connexin 26 and otherscheck connexin 26 and others b If nonsyndromic and appears mitochondrial check connexin 26 and test mt genes associated with ototoxic responsecheck connexin 26 and test mt genes associated with ototoxic response b If nonsyndromic and both parents deaf likely connexin 26likely connexin 26

14. The Genetic Testing and Triage Paradigm 3 b Genetic counseling and education to ensure that parents and patients understand the findings and limitations Consider pre-test and post-test counselingConsider pre-test and post-test counseling Cultural sensitivityCultural sensitivity Provide information and supportProvide information and support b Habilitation options b Follow-up

15. Benefits of Genetic Evaluation b Knowledge of etiology allows appropriately targeted costly servicesappropriately targeted costly services allays parental guiltallays parental guilt Recurrence chance assessmentRecurrence chance assessment empowers personalized health maintenance strategyempowers personalized health maintenance strategy