1. Genetics of Hearing Loss
Danielle Mercer, Au.D., CG(ASCP)CM, CCC-A
August 25, 2017

2. Hearing Loss Statistics
3/1,000 newborns diagnosed with permanent hearing loss
>90% of deaf children are born to hearing parents.
~90% of young children’s knowledge is attributed to “incidental reception” of sounds around them.
One study showed 1/3 of kids with unilateral hearing loss had failed at least one grade.
Hearing loss prevalence in the United States:
Age 12+: 1 in 8
Age 65 to 74: 1 in 3
Age 75+: 1 in 2
3rd most common physical condition (after arthritis and heart disease)

3. Basic Types of Hearing Loss
Conductive hearing loss
Occurs when there is a problem conducting sound through the outer ear or the middle ear (or both)
Sensorineural hearing loss
Occurs when there is a problem in the inner ear (cochlea) or in transmission from the auditory nerve to the brain (or both)
Mixed hearing loss
Combination of both conductive and sensorineural hearing losses
Central hearing loss
AKA auditory processing disorders
Issue is in the brain, rather than the ear itself
Difficulty with speech understanding and/or inability to filter out competing sounds and noises
Explain there are four types of hearing losses and what the differences are.

4. Anatomy of the Ear Review basic anatomy of the ear.
Explain that there is an outer, middle and inner ear. Point out cochlea, middle ear bones, and eustachean tube.

5. Blank Audiogram
A graphic representation of the hearing loss is presented on an audiogram.
Describe the basics of how to read an an audiogram.

7. Normal to severe sloping hearing loss
Normal hearing
Normal to severe sloping hearing loss

8. Causes of Hearing Loss Genetics Perinatal infections
Exposure to ototoxic medications
Noise exposure
Aging
Auditory neuropathy
Middle ear fluid
Eardrum perforation
Occluding cerumen
Head injury
Genetics, perinatal infections and middle ear fluid are the most common causes of pediatric hearing loss

9. Hearing Loss 75% 25% 50% Genetic 50% Environmental 70% Nonsyndromic
More than 400 genes contribute to hearing loss.
˃75% Autosomal recessive
~20% Autosomal dominant
1-2% X-linked and Mitochondrial

10. DNA is packaged into chromosomes
DNA provides the genetic code.
The human genome contains ~20,000 genes in each cell.
These genes are packaged into 46 chromosomes (23 pairs).
Chromosomes 1-22 are autosomes. Chromosomes X and Y are sex chromosomes.
Females: XX
Males: XY

11. A chromosome is the organized form of DNA
p =short arm
q =long arm

12. Normal Karyotype: 46, XY

13. Patterns of Inheritance
Autosomal dominant
Gene on chromosome 1-22
One copy of gene is enough to cause trait
Autosomal recessive
Two copies of gene are needed to cause trait
X-linked
Gene on X chromosome
Males are more susceptible because they only have one X chromosome
Can be dominant or recessive
Mitochondrial
Gene in mitochondrial genome
Maternal inheritance

14. Autosomal Dominant

15. Autosomal Recessive
Talk about consanguinity

16. Autosomal Recessive

17. Autosomal Recessive ٠ ٠ ٠ ٠ ٠

18. X-Linked Recessive

19. X-Linked Recessive ٠ ٠ ٠

20. X-Linked Dominant

21. X-Chromosome Inactivation
In females, one X chromosome is inactivated in every cell of the body.
The inactivated X chromosome can be visualized as a Barr body.
Females with one copy of an X-linked recessive gene may be affected by this gene due to skewed X-inactivation.

22. Mitochondrial Mutations
Mitochondria: organelles responsible for energy production
Mitochondria have their own DNA.
Egg cells pass on mitochondria; sperm cells do not.

23. Mitochondrial

24. Risks of Affected Offspring Summarized
Autosomal dominant
50% affected (Dd)
50% unaffected (dd)
May arise in patients with no affected parent due to a new mutation.
♀ dd + ♂ Dd d d d D =
Dd OR dd

25. Risks of Affected Offspring Summarized
Autosomal recessive (unaffected parents)
25% affected (dd)
25% unaffected (DD)
50% unaffected carriers (Dd)
♀ Dd ♂ Dd D D d d =
DD OR Dd OR dd

26. Risks of Affected Offspring Summarized
Autosomal recessive (1 affected parent and 1 carrier parent)
50% affected (dd)
50% unaffected carriers (Dd)
♀ dd ♂ Dd D d d d =
Dd OR dd

27. Risks of Affected Offspring Summarized
X-linked recessive
Carrier mother
Males: 50% affected, 50% unaffected
Females: 50% unaffected, 50% unaffected carrier
♀ Dd ♂ D
Affected father
Males: 100% unaffected
Females: 100% unaffected carrier D d D =
DD OR Dd OR D OR d

28. Risks of Affected Offspring Summarized
Mitochondrial
Affected mother
100% of offspring affected
Affected father
None of offspring affected

29. Genetic hearing loss Highly heterogeneous More than
400 genes contribute to hearing loss (mostly syndromes)
100 genes associated with nonsyndromic hearing loss
1000 mutations
140 loci

30. Syndromic Hearing Loss
Hearing loss is associated with other clinical features.
Autosomal dominant
Waardenburg syndrome
Autosomal recessive
Pendred syndrome
Usher syndrome
X-linked
Alport syndrome

31. Waardenburg Syndrome Prevalence: 1 in 42,000 Physical features:
Sensorineural hearing loss
White forelock
Pale blue eyes or different colored eyes
Wide-spaced eyes
Expression is variable, including hearing loss
Usually autosomal dominant, but can be autosomal recessive.
Image from
A small number of cases are due to new mutations. Also note broad nasal bridge in photo; ~2% of congenitally deaf have Waardenburg syndrome

32. Pendred Syndrome Incidence: 1 in 13,000 Physical features
Sensorineural hearing loss
Thyroid goiter
Enlarged vestibular aqueduct
Mondini defect in 50% of patients
May have balance problems
Autosomal recessive inheritance
SNHL: often severe to profound; may be progressive

33. Usher syndrome Congenital deafness with progressive blindness
Accounts for about half of all concurrent deafblindness cases in adults
Rare, but is estimated to be 6 times more common in Louisiana Acadian population
Louisiana Acadian parishes shown in red

34. Louisiana Acadians
French descendants of Canadian Nova Scotia Acadians who migrated to Louisiana in the 1700’s
Reside in the southern part of Louisiana
Map of migration

35. Louisiana Acadians and genetic disorders
Founder population: A population that is founded by a small number of members from a larger population
Geographically and culturally isolated populations are at a higher risk of genetic disorders when compared to the general population
Autosomal recessive disorders are amplified in such populations
Examples of genetic disorders in this population
Usher Syndrome (combined deaf/blindness)
Non-syndromic deafness
Founder populations are ideal for gene discovery studies because they are genetically isolated. Members of these communities tend to mate with other community members, not realizing that they are genetically related thereby making the population more genetically homogenous. This leads to a higher incidence of genetic disorders that are typically rare in the general population

36. Founder Effect
Founder populations are those which have a common ancestry that began by a few members of the original population. Due to the small starting population size, the colony may have reduced genetic variation and a non-random sample of the genes from the original population. As a result, some diseases are found more frequently in these groups than in other populations, or they have distinct clinical or genetic features.

37. Usher Syndrome Incidence: 3 to 6 in 100,000
Increased incidence in Acadiana population in Louisiana and Ashkenazi Jewish
Type 1C is most common variant in Louisiana Acadian population
Physical features
Sensorineural hearing loss, often profound
Progressive vision loss
Possible balance problems
Autosomal recessive inheritance
About half of all concurrent deafness and blindness in adults is due to Usher syndrome. Talk about different types of Usher syndrome and importance of getting a diagnosis.

38. Usher Syndrome

39. Usher syndrome genes MYO7A USH2A USH3A USH1C ADGRV1 HARS CDH23 WHRN
Type I
Type II
Type III
MYO7A
USH2A
USH3A
USH1C
ADGRV1
HARS
CDH23
WHRN
PCD15
SANS
CIB2
See Yan and Liu, 2010; also loci USH1E, USH1J, USH1K. USH1A and USH2B discontinued.

40. Alport Syndrome Prevalence: 1 in 50,000 Physical features:
Progressive mild to severe high frequency sensorineural hearing loss
Renal disease
Vision loss, cataracts
Hypertension
Most cases X-linked dominant
More males affected
Males more severely affected than females
~85% of cases are X-linked dominant; 15% autosomal recessive, 1% autosomal dominant; usually shows up in late childhood or early adolescence

41. Down Syndrome AKA Trisomy 21 Most common trisomy, affecting
1 in 700 births
Full trisomies of other
chromosomes are usually
lethal
karyotype
blonde boy
girl gymnast

42. Down Syndrome Hearing deficits reported in 34 to 78% of patients
Hearing loss may be conductive, sensorineural, or mixed.
Small ear canals are common.
Otitis media is very common.

43. Genetic Nonsyndromic Hearing Loss
70% of genetic hearing loss cases are nonsyndromic
˃100 genes identified to date
75-80% autosomal recessive
20% autosomal dominant
1-2% X-linked and mitochondrial combined

44. GENERAL Characteristics of Nonsyndromic Hearing Loss
Autosomal recessive
Prelingual
Stable
Affects all frequencies
Autosomal dominant
Postlingual
Progressive
Affects a subset of frequencies

45. Connexin 26 (GJB2)
Connexin 26 is responsible for about 40% of all autosomal recessive nonsyndromic hearing loss cases.
Onset is usually prelingual.
Degree varies from mild to profound.
Can vary within same family
High frequencies may be more severely affected
˃200 different mutations have been identified.
35delG mutation accounts for ~70% of cases
Mutation disrupts potassium flow in the cochlea.

46. Mitochondrial Mutation and Ototoxicity
A1555G mutation in MT-RNR1 gene predisposes to ototoxicity.
gentamycin ‒ tobramycin
kanamycin ‒ amikacin
streptomycin
Hearing ranges from normal to profound sensorineural hearing loss.
Hearing loss can occur a few days to weeks after administration of the above antibiotics (even a single dose).
In the absence of ototoxic antibiotic exposure, ˃80% will have hearing loss by age 65 years.
Widely used in China for relatively minor infections due to low cost
Binds to bacterial ribosome and disrupts protein synthesis

47. Benefits of Genetic Testing
Recurrence risk estimates
Prognosis and preparing for the future
Diagnosis and treatment or prevention for other family members
Predictive information for cochlear implant success
Peace of mind in knowing the cause

48. Impact of a Positive Test Result
Negative psychological or social effects
Ethical concerns for children
May affect other family members
Feelings of guilt
Geneticist/genetic counselor will address these issues, but the audiologist should be aware of them May violate child’s right not to know 3. and may affect their reproductive decisions, which could lead to resentment

49. Limitations of Genetic Testing: Interpreting a Negative Result
A negative test result does NOT mean the cause is not genetic!
What was tested? This is what has been ruled out.
A genetic etiology may be missed by genetic testing if
the causative gene was not tested
the correct gene was tested, but not the correct mutation within the gene
the causative gene has not been linked to hearing loss

50. Our current project Goals Hypothesis
Recruit families from culturally and or geographically isolated populations with congenital/early-onset and hereditary deafness
Apply genetic testing with a focus on the identification of deafness-causing genes that are characteristic for these founder populations
Hypothesis
two specific founder populations, the Louisiana Acadians and Mexican Mayans, will harbor multiple novel hearing loss causing mutations that cumulatively contribute to the observed phenotypes.

51. Significance Identification of at-risk founder populations
Discovery of novel mutations and gene interactions
Better diagnostic tests for patients in these communities and general population
Better genotype/phenotype correlations
Better determination of patient prognosis
Targeted diagnostic tests, interventions, and services specific to these communities

52. Family 1 Pedigree

53. Family 1 Pedigree Autosomal recessive
Autosomal recessive form of inheritance

54. Usher Syndrome analysis
USH1c c.216 G.A mutation confirmed by targeted sequencing
Affected
Normal
Carrier GG GA AA
625 bp
Size of each band
Homozygous, heterozygous,
396 bp
229 bp

55. Autosomal dominant * *
Autosomal dominant mode of inheritance *

56. Variant Filtering
386 variants
Autosomal dominant (retinitis pigmentosa)
13 candidate genes
2 candidate genes found after manual review (PRPF3 and RHO)
Autosomal recessive (deafness and blindness)
1 gene (USH1C)

57. Summary of results for Family 1
Retinitis pigmentosa results
Usher Syndrome results
Gene: RHO
Protein: rhodopsin
Mutation: Phe45Leu
Autosomal dominant
Gene: PRPF3
Protein: spliceosome
Mutation: Thr445Met
Gene: USH1C
Protein: harmonin
Mutation: 216G>A
Autosomal recessive

58. Family 2 Pedigree
Mark tested individuals * * * *

59. Family 2 mutation analysis for USH1C c.216 G>A
Mutation analysis of proband’s cousin
Affected
Normal
Carrier
Normal
Carrier
Affected
VI-6 GG GA AA GG GA AA

60. 2 candidate genes found after manual review (USH1C and MYO7A)
Variant Filtering
802 variants
Autosomal recessive
50 candidate genes
2 candidate genes found after manual review (USH1C and MYO7A)

61. MYO7A Protein: Myosin VIIA Mutation Arg933His
Part of a group called “unconventional myosins”
Expressed in inner ear (stereocilia) and retina (retinal pigment epithelium)
Mutation Arg933His
Associated with Usher Syndrome Type 1B
Variant of unknown significance

62. Study Conclusions
Each of the Louisiana Acadian families showed at least two mutations in multiple genes responsible for deafness and/or blindness
Family 1: We found multiple genes with autosomal recessive and autosomal dominant modes of inheritance causing Usher Syndrome and retinitis pigmentosa leading to deafness and/or blindness
Family 2: Atypical presentations of Usher Syndrome of individuals with the classical Louisiana Acadian USH1C mutation are possibly due to mutations in other genes
All families analyzed so far exhibit multiple genetic mutations which are extremely rare in the general population

63. Acknowledgments Team members Mentor: Dr. Fern Tsien Lab personnel
Ayesha Umrigar
Mary Moore
Dr. Amanda Musso
Kashanda Foley
Team members
Alix D’Angelo (genetic counselor)
Dr. Annette Hurley (audiologist)
Dr. Chindo Hicks (bioinformatics)
Dr. Michael Norman (director of the Louisiana Deaf-Blind Project)
Dr. Michael Marble (pediatric geneticist)
Dr. John Doucet (Acadian genetics expert, Nicholls State University)
Dr. Don Mercante (biostatistics and epidemiology)
Camille Fournet (nurse)
Dr. Mona Bakeer (Clinical Laboratory Sciences)
Universidad Juarez Autonoma de Tabasco, Mexico; Department of Genetics
Dr. Raymundo Hernandez
Dr. Julia Lesher
Special thanks to the families and patient participants who make this research possible
Universidad Juarez Autonoma de Tabasco Department of Genetics
Dr. Raymundo Hernandez
Dr. Julia Lesher
Louisiana State University Health Sciences Center