…Promoting communication from birth E arly H earing D etection and I ntervention

Sensorineural Function of the Cochlea “With over a million essential moving parts, the auditory receptor organ, or cochlea, is the most complex mechanical apparatus in the human body.” (Hudspeth 1985)

50% Genetic50% Environmental 24% CMV intrauterine infection Other infections Rubella Bacterial Meningitis Toxoplasmosis NICU-related hypoxia Rh incompatibility ototoxic medications low birth weight 30% Syndromic (>400) 70% nonsyndromic (usually sensorineural) 22% autosomal dominant (29 loci) 77% autosomal recessive (30 loci) 1% X-linked (8 loci) <1% mitochondrial (2 loci) Causes of Prelingual Hearing Loss

Recent Genetic Research Designs: Include people diagnosed with hearing loss in childhood Exclude children with syndromes Exclude children with known risk factors

50% Genetic50% Environmental 24% CMV intrauterine infection Other infections Rubella Bacterial Meningitis Toxoplasmosis NICU-related hypoxia Rh incompatibility ototoxic medications low birth weight 30% Syndromic (>400) 70% nonsyndromic (usually sensorineural) 22% autosomal dominant (29 loci) 77% autosomal recessive (30 loci) 1% X-linked (8 loci) <1% mitochondrial (2 loci) Prelingual Hearing Loss

Nonsyndromic Hearing Loss Unknown:DFNA5 K+ channel:KCNQ4 Connexins:GJB2 (Connexin 26) GJB3 GJB6 Cytoskeleton:MYO7A MYO15 DIAPH1 OTOF Extracellular Matrix:TECTA COCH Transcription Factors:POU3F4 POU4F3 Mitochondrial:12S rRNA tRNA Ser

Nonsyndromic Hearing Loss Single genes (connexin 26) Gene + environment (mitochondrial + ototoxic medications) Gene + gene (mitochondrial plus other) Other gene-environment interactions?

50% Genetic50% Environmental 24% CMV intrauterine infection Other infections Rubella Bacterial Meningitis Toxoplasmosis NICU-related hypoxia Rh incompatibility ototoxic medications low birth weight 30% Syndromic (>400) 70% nonsyndromic (usually sensorineural) 22% autosomal dominant (29 loci) 77% autosomal recessive (30 loci) 1% X-linked (8 loci) <1% mitochondrial (2 loci) Causes of Prelingual Hearing Loss

Syndromic Hearing Loss Alport Charcot-Marie-Tooth Goldenhar Jervell and Lange-Nielsen Mitochondrial disorders Neurofibromatosis Norrie Disease Pendred Treacher Collins Stickler Usher Waardenburg Vohwinkle

In utero infection CMV, Herpes, HIV, Rubella, Syphilis In utero exposure to ototoxic drugs Aminoglycosides, Alcohol, Cocaine Intrauterine growth restriction Premature birth Low birthweight Neonatal bacterial meningitis Hyperbilirubinemia Mechanical ventilation Head trauma Recurrent or persistent otitis media Treatment with aminoglycoside antibiotics Family History, Genetics Risk Factors for Hearing Loss

Causes of Hearing Loss Do other genetic and/or environmental factors modify expression of hearing loss in syndromes? Gene-environment interactions?

Cases: Infants with a permanent hearing loss identified through the universal newborn hearing screen; Children who passed the screen at birth but are diagnosed with hearing loss before the age of 3 Level 2 Research – Etiology of Hearing Loss in Infants and Young Children

Methods: collect information on known factors and family history clinical evaluation DNA analysis of GJB2 (Connexin 26), A1555G and A7445G (mitochondrial genes) Level 2 Research – Etiology of Hearing Loss in Infants and Young Children

Level 2 Research – Etiology of Hearing Loss in Infants and Young Children GAHIRIUT Estimated Eligible Participants Per Year Estimated Total Participants Over 3 years Estimated Total Participants = 448 Based on estimated 80% participation

Analyses: Description of factors associated with hearing loss in infants and young children Association of specific genes with hearing loss in infants and young children Level 2 Research – Etiology of Hearing Loss in Infants and Young Children

Analyses: Interaction between genes and environment that cause hearing loss Gene-gene interactions that cause hearing loss Level 2 Research – Etiology of Hearing Loss in Infants and Young Children

…Promoting communication from birth E arly H earing D etection and I ntervention