What Should Audiologists Know about Genetics. Jackie L. Clark, PhD UT Dallas; U Witwatersrand

Transcription

1 What Should Audiologists Know about Genetics Jackie L. Clark, PhD UT Dallas; U Witwatersrand Some Material and Slides from Annual Summer Genetics Workshop at Gallaudet University; Washington, D.C. Disclaimer All statements in this presentation are solely made by myself and not on behalf of the American Academy of Audiology 1

2 8 year old male Lump at base of neck Moderate mixed hearing loss - bilaterally Konigsmark Classification of Hearing Loss No associated abnormality External ear abnormality Eye disorder Musculoskeletal Integumentary System (hair, skin & nails that protect body from outside world ) Renal System Nervous System 2

3 Deaf Offspring of Deaf Parents (150 per 1000 births) Deaf Offspring of Hearing Parents (0.85 per 1000 births) Environmental 1% 32% Cx 40% Other Genetic 44% PDS 15% Other Environmental 8% CMV 25% Cx 30% Other Genetic 25% PDS 10% mt A1555G 1% 3

4 Homologous pair { Adenine = A Thymine = T Guanine = G Cytosine = C Human Genome Program, U.S. Department of Energy, Genomics and Its Impact on Medicine and Society: A 2001 Primer,

5 Genes 5

6 6

7 Cell division distributing identical genetic material from one generation to the next Occurs in humans, animals, plants, fungi Result is 4 gametes with ½ the chromosomes of the original cell Occurs in all organisms Result is 2 daughter cells Same number chromosomes as original cell 7

8 Structural Alterations of Chromosomes Inversions break of one arm and flipped Deletions of section or 1-chromosome Duplications gain an extraneous chromosome Translocations Reciprocal translocations Robertsonian translocations Segment breaks from the chromosome Reverses its orientation and reattaches in the original position Inversion More commonly seen in Chromosome 9, more often results in reproductive problems 8

9 National Cancer Institute: Understanding Gene Testing press2.nci.nih.gov/sciencebehind/genetesting/genetesting00.htm DELETIONS This is Charlotte when she was six years old. Charlotte has Cri du Chat syndrome (5p-) i.e. 5 th chromosome at upper arm has deletion 9

10 Duplication Down Syndrome Trisomy pattern of Chromosome 21 Small Concha Hourglass Stenosis of EAC Early Retraction of posterior-inferior portion of TM Reciprocal Translocation Occurs between 2- nonhomologous chromosomes Does not cause any genetic information to be lost or duplicated 10

11 Transmission Genetics Important Terminology Genotype genetic make-up (i.e.: specific genetic constitution of an organism; the allele combinations in an individual that cause a particular trait or disorder) Phenotype physical properties (i.e.: observable properties of an organism; the expression of genes in traits or symptoms) SPEAKING OF PHENOTYPES Heterogeneity Phenocopy Pleiotropy 11

12 Heterogeneity Many genes one phenotype deafness blood clotting disorders blindness Phenocopy An environmentally caused trait that appears to be inherited, either because the trait resembles a Mendelian disorder s symptoms OR because it mimics inheritance by occurring in certain relatives. thalidomide phenocopy of phocomelia hair loss from chemotherapy genetic disorder alopecia phenocopy of 12

13 One gene e.g. Marfan syndrome Pleiotropy many effects on phenotype (i.e. physical properties) tall, thin, long fingers heart problems- weakened aorta dislocated lenses Classification of Genetic Deafness By Phenotype Syndromic Forms ( ~300) 20-30% (complex interlinked set of disorders e.g. BOR) Non-Syndromic Forms ( ~115) 70-80% (hearing loss occurs without other associated disorders e.g. Connexin) By Mode of Transmission Autosomal Recessive 80% Autosomal Dominant % X-linked 1-2% Y-linked. <1% Mitochondrial % 13

14 14 Morton & Nance NEJM 354: ,2006 CX31 KCNQ4 A9 A37 A7 A34 B6 B15 A18 OTOF B9 A16 B25 A6,14 A27 A39 B26 A24 Diaphanous A1, COL11A2 A13 EYA4 A10 DFNA5 PDS B4 B14,B17 B13 A28 A36 B7,B11 POU4F3 A15 B23 A19 CDH3/B12 A32/B18 MYO7A TECTA B20 A25 CX26/Cx30 A2/B1 COCH/A9 A23 B16 A30 MYO15/B3 A20/A26 B19 A4 TMPRSS3 B8/10 CLDN14 B29 B29 MYH9 A17 POU3F4 NSDF genes mapped/identified

15 Dominant Genes Penetrance The percentage of individuals who possess a dominant gene and express it. A trait is incompletely penetrant when not every individual who has the genotype displays the phenotype. Variable Expressivity A genotype producing a phenotype that varies among individuals. Another example of penetrance Deaf Hard of Hearing Male Female 15

16 Pedigree Construction KEY Classification of Genetic Deafness By Mode of Transmission Autosomal Recessive 80% Autosomal Dominant % X-linked 1-2% Y-linked. <1% Mitochondrial % 16

17 Characteristics of AD Traits only one copy of gene to produce phenotype chance of recurrence is ½ vertical family pattern Persons with the trait have a parent with the trait, unless they represent a new mutation If line broken; stays broken male:female = 1:1 Male to male transmission can occur Dominant Inheritance Male Female 17

18 Male Female Deaf Waardenburg Syndrome Autosomal dominant or recessive, depending on clinical subtype (WS1-4) Sensorineural hearing loss (variable) Pigmentation abnormalities Dystopia canthorum (widely spaced inner canthi) in some subtypes Variable penetrance 18

19 Sellars, S, Beighton, P. (1983). The Waardenburg syndrome in deaf children in southern Africa. South African Medical Journal. 63: Gorlin, R.J, Toriello, H.V., Cohen, M.M. Hereditary Hearing Loss and Its Syndromes. New York: Oxford University Press, Treacher Collins Syndrome Inheritance: autosomal dominant Clinical features: Malar hypoplasia Malformed auricles Conductive hearing loss Ear tags Downward slanting palpebral fissures Mandibular hypoplasia Macrostomia Gene: TCOF1 (5q32-q33.1) Photographs from KL Jones, 4th Edition Smith s Recognizable Patterns of Human Malformations 19

20 Autosomal Recessive Inheritance Consanguinity Obligate Carriers Autosomal Recessive (AR) Characteristics of AR traits Double dose of gene required Chance of recurrence ¼ Carrier (heterozygous) parents Horizontal family pattern Male : Female 1:1 20

21 Autosomal Recessive Inheritance I II III IV Male Female Autosomal Recessive Inheritance I II III IV Male Female 21

22 Pendred syndrome (PS) Autosomal recessive Accounts for 1-10% of Genetic Deafness Thyroid goiter (enlargement) incompletely penetrant Variable sensorineural hearing loss (can have rapid progression); occasional mixed HL Enlarged vestibular aqueducts (EVA) +/- Mondini cochlea Defective thyroxin organification 22

23 PS: An endolymph disorder? Everett et al., Hum. Mol. Genet. 10: , 2001 Fluctuating and Progressive 23

24 Connexin 26 Deafness (DFNB) Family of gap junction proteins (GJB) 30-40% of profound deafness in the US 50-80% of recessive pre-lingual deafness Incidence varies among populations Variable phenotype Single mutation (35delG) in 60-70% Member of family of gap junction proteins Usher Syndrome Autosomal recessive > 3 clinical sub-types (HL, RP, Vestibular dysfunction) Type I: V, RP early, HLcongenital (age of walking often delayed as late as 2 yrs) Type II: RP late, HL moderate Type III: RP late, HL progressive, V 10 Loci Mapped/Cloned Commonest cause of deaf/blindness Late Stages: Tactile communication USH1: Stereocilia Disorder 24

25 Pcdh15 av-jfb (USH1F model) mutant wild-type Hampton et al., Hearing Research, 2003 X-Linked Recessive Inheritance Males >> females No father to son transmission All the daughters of a male with the trait will be carriers Carrier females- 50% chance to have sons with the trait, 50% chance to have carrier daughters Trait may be transmitted through a series of carrier females 25

26 Consanguinity in an X-linked recessive pedigree resulting in a homozygous affected female Who are the obligate carriers in this family? 26

27 Pedigree Construction KEY 27

28 Lisa has been married for 10 years and is currently 10 weeks pregnant. She has had trouble keeping her pregnancies. Two previous pregnancies resulted in miscarriages at 10 weeks gestation. Lisa is 36 years old and is in good health. She Is married to John, age 35, also in good health. Lisa has two younger brothers, Michael, age 27 and Rick, age 25. Both are in good health. Lisa s father, Jerome, age 62 is deaf. He was born deaf, just like some other members of his family. Lisa s paternal grandmother has two deaf brothers. Also, Jerome s sister Meg has a deaf son. Meg was surprised when her son was born deaf because her husband is hearing. Both of Lisa s paternal grandparents are also hearing. Lisa s mother, Mary is in good health at age 57. Mary has an identical twin sister, Linda. Lisa s maternal grandparents are deceased. Both died in their 80 s of natural causes. Lisa s paternal grandparents are of English and Irish extraction. Her maternal grandparents are Swedish. John, Lisa s husband, has a brother, Sam age 29 who has a condition called Treacher-Collins syndrome. He has a conductive hearing loss and some changes in the structure of his face associated with the syndrome. John s sister, Brenda is age 25 and in good health. She had a son who died at birth because part of his brain was missing. John doesn t have any more information about this problem. Brenda also has a daughter who is 2 years of age and in good health. John s parents are in good health. Their ethnic background is Jewish. 28

29 KEY Deaf Swedish Irish / English Treacher Collins syn. part of brain missing Jewish d. 80 s d. 80 s natural natural causes causes A & W A & W Linda Mary a. 57 A & W Jerome a. 62 Meg Sam a. 29 Brenda a. 25 John Lisa a. 35 a. 36 A&W A&W d. birth 2 A & W 10 wks. 10 wks. 10wks. P Head Shapes (Craniosynostosis) Bossing 29

30 Unusual Facial Landmarks Hypoplasia Alae Nasai (under development) Nasal Columella Epicanthal Fold 1. Normal eye 2. Normal structure in infants (maybe temporary) 3. True epicanthal fold 30

31 Heterochromia Coloboma Genetic link Occurs ~2nd month ga Hole in structure of eye (at iris, retina, choroid, or optic disc) May cause blurred vision 31

32 Sclera grey, purple coloring of whites of eyes Synophrys eye brows growing together Micrognathia Microglossia 32

33 Choana: (Plural: choanae) The passageway from the back of one side of the nose to the throat. There are two choanae, one on either side of the nose. The choanae must be open to permit breathing through the nose. Diagnosis and Treatment of Hearing Impairment in Children; Pappas (1998) 33

34 Tags & Pits 8 year old male Lump at base of neck Moderate mixed hearing loss - bilaterally Pendred Syndrome 34