1. GENETICS OF DEAFNESS

2. CONGENITAL DEAFNESS
~ 1 in 900 children has congenital hearing impairment >20 dB in one or more frequencies
50 % inherited
50% environmental
Ototoxic drugs
Acustic trauma
Infections
70% Nonsyndromic
30% Syndromic
Usher
Alport
Pendred
Norrie
Waardenburg
Branchio-Oto-Renal
Jervell and Lange-Nielsen
~%77 AR
~%77 AR
~%22 AD
~%22 AD
~%1
X-linked
<%1 Mitochondrial
Known Genes 6

3. WHY IS IT IMPORTANT TO ELUCIDATE GENETIC DEFECTS UNDERLYING HEREDITARY DISORDERS?
Diagnosis
To answer the question on heredity of their disease or the
disease in the family
Adequate mutation based genetic counseling
Early diagnoses for family members
Insight in genes/proteins essential for development and function
of the inner ear
Handles for therapy

4. DAILY PRACTICE

5. AUDIOGRAMS

6. ARTA

7. Myosin VIIa
Asn458Ile

8. THE INNER EAR

9. LESSONS FROM DEAFNESS GENES
Kazmierczak et al 2007

10. IDENTIFICATION OF DISEASE GENES
Familystudies – good clinical characterization
Identification of the chromosomal location of the genetic defect
- Linkage analysis – homozygosity mapping
Identification of the mutated gene
- Which genes are in the linkage interval – genome browsers?
- Which of those genes are good candidates? - databases
* Expression pattern
* Function of the gene
* Animal models
* Selection of genes for mutation analysis
- Mutation analysis
- Interpretation of sequence variants
Alternative: Next Generation sequencing

11. TURKISH FAMILIES - CONSANGUINITY
Homozygous mutations
Homozygosity mapping – linkage analysis

12. mutation x  N M  N M  N M x  N M  N M M  M
HOMOZYGOSITY MAPPING

13. Single Nucleotide Polymorphisms - SNPs
Person A:
Person B:
…cctcctagggttgcaaagcctccttggctatg…
…cctcctagggttgcatagcctccttggctatg…
…cctcctagggttgcatagcctccttggctatg…
~ 500,000 SNPs G T A C

14. FAMILY TR57 Linkage interval: 11q13.2–q13.4,
~ 59 known genes , 18 hypothetical gene

15. DFNB63 LOCUS Fam TR57 26 known or predicted genes ~5.29 Mb DFNB63
15.5
Fam
FT1A-G
PKDF702
FT2
1.03 Mb
15.4
DFNA32
15.3
15.2
15.1
USH1C
14.3
14.2
D11S2371
D11S1337
D11S4179
D11S1291
D11S916
D11S1314
D11S4139
D11S4136
D11S4113
D11S987
14.1 13
26 known or predicted genes
DFNB51 12
11.2
11.12
11.11 11
12.1
~5.29 Mb
12.2
12.3
DFNB63
13.1
FGF3
13.2
13.3
DFNB63
13.4
13.5
MYO7A
14.1
14.2
14.3 21
22.1
22.2
22.3
23.1
DFNB24
23.2
23.3
TECTA
24.1
24.2
24.3 25
DFNB20

16. LRTOMT CHARACTERISATION
Genome browser build 36.1
LRTOMT1
LRTOMT2

17. EFFECT OF MUTATIONS Catechol-O-methyltransferase domein 3’ UTR
A215A
G163VfsX4 (c.358+4G>A)
3’ UTR
E110K
A29SfsX54 (c.358+4G>A)
W105R
R81Q
Catechol-O-methyltransferase domein

18. MOLECULAR MODELING

19. EFFECT OF MISSENSE MUTATIONS

20. LRTOMT IN THE MOUSE

21. INNER EAR

23. SUMMARY Applied bioinformatics is essential for several
steps in disease gene identification and analyses
The structure and function of the human genome
and genes is not completely characterized yet
LRTOMT is the causative gene for DFNB63. The
precise effect of the mutations on inner ear
function needs to be elucidated.