Transcript Guidelines for the Genetic Evaluation of Congenital

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
A Multidisciplinary Expert Panel
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Walter Nance, MD, PhD - Med. Coll. Of VA, Chair
Kathleen Arnos, PhD - Gallaudet Univ.
John Carey, MD - Univ. of Utah Health Sciences
George Cunningham, MD - Calif. Dept. Health
Rena Falk, MD, - Cedars Sinai Med. Ctr.
Terese Finitzo, PhD - OZ Systems
Dynio Honrubia, MD - Harvard Med. Sch.
Bronya Keats, PhD - Louisiana State Univ. Sch. Of Med.
William Kimberling - Boys Town Nat’l. Med. Ctr.
Gail Lim, ARNP - Pediatrix Med Group
Cynthia Morton, PhD - Harvard Med. Sch.
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A Multidisciplinary Expert Panel
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Arti Pandya, MD, MBA - Med. Coll of VA
 Mary Kay Pelias, PhD, JD - Louisiana State Sch of Med
 James Skordas, CCCA - Pediatrix Med Group
 Richard Smith, MD - Univ of iowa Hosp. and Clinics
 Michael Watson, PhD - American Coll of Med Genetics
Ex-officio Members:
Colleen Boyle, PhD - CD
Marie Mann, MD - HRSA
Aileen Kenneson, PhD - CDC
Jay Sheehan, MS - HRSA
Amy Donahue, PhD - NIDCD
Brad Therrell, PhD, NNSGRC
Karl White, PhD - NCHAM
Michele Lloyd-Puryear, MD, PhD - HRSA
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Hearing Loss
Definition for this Purpose
 Permanent
 Bilateral or unilateral
 sensory or conductive
 >30 db loss in frequency important for
speech recognition
Hearing Loss Etiologies
 About 50% “environmental”
• Some genetic susceptibilites
• Some identified with genetic tests
 About 50% genetic
• 30% syndromic - over 400 syndromes
described
• over 75 NSHI-linked genes identified
• over 30 syndrome-linked genes identified
Environmental
CMV
meningitis
rubella prematurity
neonatal icterus
ototoxicity
other infections
Syndromic
~50%
Deafness
Alport
Norrie
Pendred
Usher
Waardenburg
Branchio-oto-renal
Jervell and Lange-Nielsen
~30%
~50%
Non-syndromic
Genetic
22%
77%
~70%
~1%
~1%
Autosomal dominant
DFNA1 - DFNA3
Autosomal recessive
DFNB1 - DFNB30
X-Linked
DFN1 - DFN8
Mitochondrial
The Genetics Evaluation:
Genetic Services Overview
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What makes it hard
• syndromology in infants
• widely variable laboratory tests and expertise
• very unstable knowledge base
• tests 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 service
 We specialize in communicating uncertainty
Genetic Evaluation:
The Expertise Needed
Knowledge of genetics of hearing loss
 Dysmorphology
 Audiology
 Otolaryngology
 Genetic counseling
 Communication with the deaf and hard of hearing
 Considerable secondary expertise needed
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• eye, heart, kidney, neurology etc.
Critical Evaluation Components
 Family history (2-3 generation pedigree)
 Ethnicity & country of origin
 Inheritance pattern
 Audiometric characteristics in family
 Evidence of vestibular dysfunction
 Syndrome vs. nonsyndromal
Is it a Syndrome?
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 Evaluate and inquire of family history for:
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visual anomalies
facial/cervical dysmorphology
endocrine abnormalities
cardiac signs
renal abnormalities
skin and hair
Is it a Syndrome?
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 The patient history of risk factors
 Physical examination
The Genetic Testing and
Triage Paradigm1
 Based on the genetic evaluation
• If syndrome is suspected
– test if possible
• If nonsyndromic and isolated case
– check CMV and GJB2 (connexin 26) gene
sequencing
• If syndromic and not isolated
– check GJB2
The Genetic Testing and
Triage Paradigm2
 If nonsyndromic and suggestive of
autosomal dominant
• check connexin 26 and others
 If nonsyndromic and appears
mitochondrial
• check connexin 26 and test mt genes
associated with ototoxic response
 If nonsyndromic and both parents deaf
• likely connexin 26
The Genetic Testing and
Triage Paradigm3
 Genetic counseling and education to
ensure that parents and patients
understand the findings and limitations
• Consider pre-test and post-test counseling
• Cultural sensitivity
• Provide information and support
 Habilitation options
 Follow-up
Benefits of Genetic Evaluation
 Knowledge of etiology allows
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appropriately targeted costly services
allays parental guilt
Recurrence chance assessment
empowers personalized health maintenance
strategy