1 / 28

Personalized Medicine of Deafness

Personalized Medicine of Deafness. Marci M. Lesperance, MD, FACS, FAAP Professor and Division Chief, Pediatric Otolaryngology. CANC. deafness. CV disease. diabetes. Head/neck. breast. adrenal. colon. Types of deafness. • Conductive • Sensorineural • Auditory neuropathy

skyla
Download Presentation

Personalized Medicine of Deafness

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Personalized Medicine of Deafness Marci M. Lesperance, MD, FACS, FAAP Professor and Division Chief, Pediatric Otolaryngology

  2. CANC deafness CV disease diabetes Head/neck breast adrenal colon

  3. Types of deafness • Conductive • Sensorineural • Auditory neuropathy • Syndromic vs. nonsyndromic

  4. Hearing Loss • Most common sensory disorder, affects 28 million Americans • Over 500 syndromes such as Usher (deafness and retinitis pigmentosa causing blindness) • 50% develop presbycusis (age-related HL) by age 80 • 2 in 1000 children are born with educationally significant hearing loss; 5 in 1000 by adolescence • Association studies of presbycusis show increased risk with smoking, high BMI, noise exposure; moderate alcohol consumption is protective • SNHL can be rehabilitated but not cured

  5. The inner ear • Inaccessible, within the temporal bone • Tiny quantities of proteins • Genetics • Animal models • Proteomics • Histopathology Richardson et al, Ann Rev Physiol 2011

  6. Positional cloning/ positional candidate approach to discovering novel genes Human Genome Working Draft GENE1 GENE2 GENE3 …… GENE200

  7. Dror and Avraham, Neuron 2010

  8. 2010 2012 DFNA43 DFNA6/14 DFNA2 DFNB9 DFNB66 DFNA38 DFNB44 DFNB47 DFNA13 DFNA5 DFNB25 DFNA37 DFNB49 DFNB6 DFNB55 DFNB53 DFNB39 DFNB32 DFNB42 DFNB60 DFNA22 DFNB4 DFNB58 DFNA7 DFNA27 DFNB37 DFNA18 DFNB14 DFNB27 DFNA1 DFNA49 DFNA24 DFNB31 DFNB15 DFNB17 DFNA15 DFNA16 DFNB36 DFNA21 DFNA28 DFNB26 DFNA44 DFNA34 DFNB13 DFNA42 DFNB59 DFNB38 DFNA39 DFNB45 DFNA50 DFNA10 DFNA42 DFNA52 DFNB51 DFNB62 DFNA32 DFNB18 DFNA31 DFNB30 DFNB63 DFNB7/11 DFNB1 DFNA48 DFNA9 DFNA40 DFNB23 DFNB2 DFNA47 DFNA3 DFNB5 DFNA25 DFNB16 DFNA19 DFNA11 DFNA51 DFNB22 AUNA1 DFNA41 DFNA23 DFNB12 DFNA8/12 DFNA36 DFNA30 DFNB35 DFNB50 DFNB57 DFNB21 DFNB48 DFNB31 DFNA53 DFNB24 DFNB33 DFNB20 DFN6 DFN4 DFNB68 DFNB19 DFNA57 DFN3 DFNB3 DFNB15 DFNA17 DFN2 DFNA4 DFNB8/10 DFNB65 DFNB28 DFNY DFNA20/26 DFNB29 DFNB40 Courtesy Heidi Rehm, PhD

  9. Connexin 26 (GJB2), DFNB1 • Mutations account for 15-50% of recessive non-syndromic SNHL in US population • Testing widely available ($300-$500) • One mutation (35delG) accounts for 75-80% of all mutations in Caucasians • 35delG homozygotes typically have congenital profound SNHL, but modifiers likely exist • 3.01% carrier rate of 35delG in Iowa population (Green et al. 1999)

  10. Patterns of sensorineural hearing loss Low frequency SNHL WFS1 mutations Also DIAPH1, FGFR3 Mid frequency “cookie-bite” TECTA (alpha tectorin) mutations High frequency or flat audiogram: many genes

  11. Genetic testing for nonsyndromic auditory neuropathy • OTOF (otoferlin) • 48 coding exons and splice sites; recessive • $1500 through Partners- does not accept 3rd party payment • Pejvakin – reported in two families from Iran • DIAPH3 (Schoen et al. 2010, PNAS) • Autosomal dominant auditory neuropathy; currently no lab offering clinical testing

  12. BCN view of the world • Does a definitive dx remain uncertain even after H&P exam and conventional diagnostic studies? • Does the patient display clinical features related to the inherited mutation in question? • What justifies the patient’s increased risk? i.e. family history, ethnic background • Is this disease treatable or preventable? • Will the result of the test directly influence the tx being delivered to the patient? • Requires informed consent and genetic counseling

  13. Deafness gene platforms • OtoChip™- 19 assorted genes for deafness including Usher, mitochondrial, $3800 • Otogenetics: 80+ genes, $488/sample • OtoSCOPE: 60+ genes, $2000/sample • Missing most “syndromic” genes such as: • FGF3 : deafness, microtia, and microdontia (DFNB63) • BSND: Bartter syndrome, DFNB73 (mild renal dysfunction) • FGFR3: Muenke craniosynostosis; CATSHL (camptodactyly and tall stature with HL)

  14. Whole exome sequencing • All coding exons and intron-exon junctions • At least 2 samples/family to reduce number of variants for follow-up • Cross referencing to linkage region(s) • Trending toward whole genome sequencing (at some lower coverage) • Unknown exons expressed specifically in the ear • Splice mutations, distant enhancers/promoters • Better sensitivity for deletions/duplications

  15. Annotation • dB SNP filter • Includes deafness mutations such as 35delG • Allow minor allele frequency <5% • Exome variant server (U Washington) filter • Up to 10,000 alleles • Subjects not necessarily screened for deafness; some reported deafness mutations seen • Splice mutations may be called as non-synonomous or synonomous variants • Deafness mutations may occur in noncoding sequence (5’UTR mutation in DIAPH3)

  16. Interpretation • Pooling samples reduces costs but may sacrifice coverage of particular linkage region • Failure to confirm on Sanger sequencing • Easier to detect homozygous mutations causing recessive disease • Dominant requires analysis of every variant and confirmation of segregation in the family

  17. Most common non-genetic cause: Human cytomegalovirus infection • HCMV affects 1.1/1000 live births • 5% symptomatic; 30-65% incidence of SNHL • 95% are asymptomatic; 8-15% incidence SNHL • Must detect in first 3 weeks of life; universal screening of blood or saliva; newborn blood spots have low sensitivity (JAMA 2010) • Antibody testing may be able to exclude HCMV as an etiology

  18. The future is here! • Identifying a genetic etiology helps with prognosis and recurrence risk • Economies of scale will bring the price down • Developing a clinical algorithm and drawing genotype-phenotype correlations

  19. Interval Genomic Viewer plots • 3 SNPs in ZNF575 • Average 10x • chr19:44039571 • chr19:44039572 • chr19:44039574 • Alignment error • PCR duplication artifact • Note poor coverage of 3rd sample Jishu Xu

  20. 1 SNP in KCNN4 • chr19:44271753 • A19:4T (23x) • A34:6T (40x) • AA 14:0 (14x) • PCR duplication artifact

  21. Utility of chromosomal microarray analysis (CMA) for evaluation of deafness • GJB2 null alleles due to distant deletions • ~100kb deletion of STRC (DFNB16) • CHD7 (CHARGE syndrome) • TWIST (Saethre-Chotzen syndrome) • Recessive disorders with 0-1 mutations (e.g., SLC26A4 gene ) 555kb deletion of chromosome 16p13.3

  22. Non-syndromic Sensorineural Hearing Loss: Summary • Recessive is usually congenital and profound; GJB2 (also pseudodominant) • Dominant is usually delayed onset and progressive • Low frequency WFS1 • Mid frequency “cookie-bite” TECTA (alpha-tectorin) • Auditory neuropathy: OTOF, DIAPH3 • Otherwise, no predominant genes; some in single families or yet unidentified • Next generation sequencing technologies

  23. Genotype cohorts provide some prognostic information Snoeckx et al. GJB2 mutations and hearing loss: a multicenter study, Am J Hum Genet, 2005.

  24. OtoChipTM • 19 genes, 70,000 bases; $3800, 8 week TAT • Nonsyndromic SNHL:CDH23, DFNB31 (WHRN), GJB6, MYO6, MYO7A, OTOF, PCDH15, SLC26A4 (PDS), TMC1, TMIE, TMPRSS3, USH1C • Mitochondrial tRNAser(UCN) and 6 in 12S rRNA • OTOF, SLC26A4 • Usher syndrome :CDH23, CLRN1, DFNB31, GPR98 (exons 8, 20, 31-41 & 89), MYO7A, PCDH15, USH1C, USH1G, USH2A • Not included : WFS1, TECTA, KCNQ4

  25. OtoSCOPE (Shearer et al. 2010) • 50 nonsyndromic deafness genes, including mitochondrial and miRNA, and 4 Usher genes • Identified genetic etiology in 5/6 unknowns • p.A366T/p. N1098S in CDH23 (DFNB12, USH1D) • ~100kb deletion in STRC/p.Q1353X • p.D288DfsX17 in MYO6 (DFNA22) • p.E1965X in MYH14 (DFNA4) • p.L281Sin KCNQ4 (DFNA2) • Found 4 variants in one dominant case, none segregating with deafness- etiology unknown

  26. AudioGene http://audiogene.eng.uiowa.edu • Input the audiometric thresholds and AudioGene will predict the most likely genes for dominant SNHL • Not available for all genes • Can’t analyze more than one audiogram at a time • Can view audioprofiles for selected genes • Often, noise exposure alters the classic pattern KCNQ4

  27. High frequency SNHL • KCNQ4 mutation • Noise exposure • Presbycusis • Or many other genes!

  28. 1 SNP in SARS2 • chr19:39408746

More Related