single gene slide
DESCRIPTION
medicalscience geneticsTRANSCRIPT
![Page 1: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/1.jpg)
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Classification of Genetic Diseases
• Single gene mendelian medical disorders• Chromosomal disorders• Multifactorial inheritance• Mitochondria inheritance• Somatic mutation
![Page 3: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/3.jpg)
Single gene mendelian medical disorders
OMIM http://www.ncbi.nlm.nih.gov/omim
• Autosomal dominant 3,802 reports• Autosomal recessive 3,771 reports• X-linked 1,848 reports• Y-linked 266 reports
• Over-all about 0.5-1% of live birth
![Page 4: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/4.jpg)
Genetic terminology
• Genotype vs Phenotype• Allele vs Locus (Loci)
B B
A a A and B are loci.A or a is an allele of locus A.Locus A is heterozygous but locus B is homozygous.
![Page 5: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/5.jpg)
Achondroplasia
![Page 6: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/6.jpg)
P
What is the risk of his child?
The achondroplasia patient 15 years from now
![Page 7: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/7.jpg)
P
What is the risk of his child?
How to know the risk
![Page 8: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/8.jpg)
Your role
• Understand mode of inheritance
• Risk calculation• Counseling
![Page 9: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/9.jpg)
Mode of Inheritances
- Classification of genetic diseases
-Understand how genotypes are inherited.
-Understand how genotypes lead to phenotypes.
Risk calculation
![Page 10: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/10.jpg)
How to know classification of genetic diseases of the patient?
(How to know inheritance of this patient?)
![Page 11: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/11.jpg)
P
What is the risk of his child?
The achondroplasia patient 15 years from now
![Page 12: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/12.jpg)
![Page 13: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/13.jpg)
Punnett’s Square
![Page 14: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/14.jpg)
P
What is the risk of his child?
The achondroplasia patient 15 years from now
50%
![Page 15: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/15.jpg)
Please self describe characteristic of classical autosomal dominant pedigree
![Page 16: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/16.jpg)
Why is his parent normal?
The achondroplasia patient pedigree
PWhat is the risk of this child?
![Page 17: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/17.jpg)
Why is his parent normal?
The achondroplasia patient pedigree
New Mutation
P
![Page 18: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/18.jpg)
Fitness vs Denovo Mutation
Familial Hypercholesterolemia
Severe Osteogenesis Imperfecta
Who was most likely new mutation?
![Page 19: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/19.jpg)
Mosaicism
![Page 20: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/20.jpg)
Gonadal Mosaicism
Recurrence risk of AD new mutation family is not zero.
![Page 21: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/21.jpg)
Genetic concept:Advanced parental age
MATERNAL
Chromosomal disorders
(nondisjunction)
PATERNAL
Single gene defects:Autosomal dominant
(point mutation)
![Page 22: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/22.jpg)
P
What is the risk of his child?
Why is his parent normal?
The achondroplasia patient 15 years from now
![Page 23: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/23.jpg)
Retinoblastoma
![Page 24: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/24.jpg)
P
P
P
1 2
1 2
1 2 3 4
1 2 3
I
II
III
IV
How II2 is ill?
How III1 is not ill?
Risk of III4, IV2, IV3?
Example of Retinoblastoma pedigree
![Page 25: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/25.jpg)
P
P
P
1 2
1 2
1 2 3 4
1 2 3
I
II
III
IV
How II2 is ill?AD inheritance
Example of Retinoblastoma pedigree
![Page 26: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/26.jpg)
P
P
P
1 2
1 2
1 2 3 4
1 2 3
I
II
III
IV
How II2 is ill?AD inheritanceHow III1 is not ill?Non-penetrance20%
Example of Retinoblastoma pedigree
![Page 27: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/27.jpg)
P
P
P
1 2
1 2
1 2 3 4
1 2 3
I
II
III
IV
How II2 is ill?AD inheritanceHow III1 is not ill?Non-penetrance20%Risk of III4 = 40%
Example of Retinoblastoma pedigree
![Page 28: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/28.jpg)
P
P
P
1 2
1 2
1 2 3 4
1 2 3
I
II
III
IV
How II2 is ill?AD inheritanceHow III1 is not ill?Non-penetrance20%Risk of III4 = 40%IV2 = 40%
Example of Retinoblastoma pedigree
![Page 29: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/29.jpg)
P
P
P
1 2
1 2
1 2 3 4
1 2 3
I
II
III
IV
How II2 is ill?AD inheritanceHow III1 is not ill?Non-penetrance20%Risk of III4 = 40%IV2 = 40%IV3 = 1/15
Example of Retinoblastoma pedigree
![Page 30: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/30.jpg)
?
II1 is 3 yr old.II2 is 1 yr old. Diagnosis?
I
II
1 2
![Page 31: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/31.jpg)
?
Two year later.II2 is 3 yr old. Diagnosis?
I
II
1 2
![Page 32: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/32.jpg)
?
II2 is retinoblastoma.Why?
I
II
1 2
I
II
1 2
Three year later
![Page 33: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/33.jpg)
?
Why?Variation in expression (age of onset)
I
II
1 2
I
II
1 2
II1 was ill at 3 yrs butII2 is ill at 4 yrs.
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Neurofibromatosis IExample of Variation in Expression:Severity of Phenotype
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AD Inheritance- Exceptions
• New mutation• Reduced penetrance• Variable expressivity• Germline mosaicism
![Page 36: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/36.jpg)
Examples of AD Disorders• Skeletal dysplasia
– Achondroplasia– Osteogenesis imperfecta
• Connective tissue disorders– Marfan syndrome– Ehlers Danlos syndrome
• Craniosynostosis– Crouzon syndrome– Apert syndrome
• Neurocutaneous syndrome – Neurofibromatosis– Tuberous sclerosis
• Adult-onset genetic disorders– Familial hypercholesterolemia– Huntington disease– AD polycystic kidney disease
Please do self study to understand these diseases’phenotypes. No need to remember all detail at this point.
![Page 37: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/37.jpg)
Achondroplasia
![Page 38: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/38.jpg)
Osteogenesis imperfecta
![Page 39: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/39.jpg)
Marfan syndrome
![Page 40: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/40.jpg)
• tall stature• Ectopia lentis• Dilated arotic root
![Page 41: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/41.jpg)
Ehlers-Danlos syndrome
![Page 42: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/42.jpg)
Crouzon syndrome
![Page 43: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/43.jpg)
Apert syndrome
![Page 44: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/44.jpg)
Neurofibromatosis type I
![Page 45: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/45.jpg)
Tuberous sclerosis
Angiofibroma
Ashleaf
Shagreen
![Page 46: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/46.jpg)
Summarized AD pedigree
![Page 47: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/47.jpg)
Example of AutosomalRecessive in Thailand
Alpha Thalassemia Hydropfetalis Beta Thalassemia
![Page 48: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/48.jpg)
Autosomal recessive medical disorders in general are rare.1:20,000 to 1:100,000
Nevertheless, some are more common in particular populations.
Cystic fibrosis 1:2,000 to 1:4,000 in Caucasian.
Phenylketonuria 1:10,000 in Caucasian.
Sickle cell anemia 1:500 in African.
Thalassemia (alpha & beta) 1:100 in South-East Asia &Mediterranean
Why?
![Page 49: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/49.jpg)
Autosomal recessive medical disorders in general are rare.1:20,000 to 1:100,000
Nevertheless, some are more common in particular populations.
Why?
-Selective advantage (of carrier)-Common ancestor-Mating within small population because of racial, geographic and ethnic differences.-Genetic drift
![Page 50: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/50.jpg)
A high frequency of a specific gene mutation in a population founded by a small ancestral
group
Generations later
Founder Effect
Original population
Marked population decrease,
migration, or isolation
![Page 51: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/51.jpg)
![Page 52: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/52.jpg)
Autosomal Recessive Inheritance
![Page 53: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/53.jpg)
![Page 54: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/54.jpg)
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Absolute risk of birth defect between couple
First degree relative 30-50%Unrelated person 2-3%First cousins 4-5%
P
![Page 56: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/56.jpg)
Risk of birth defect from AR¼ x pC x pC (pC = probability of being carrier)
In this case II1 = ?
P
![Page 57: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/57.jpg)
Risk of birth defect from AR¼ x pC x pC (pC = probability of being carrier)
In this case II2 = ?
P
![Page 58: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/58.jpg)
The probability of being carrier in AR pedigree
ConsiderII1 & II2
I1 & I2 & II3
III2
III3(General Population)
![Page 59: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/59.jpg)
![Page 60: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/60.jpg)
Risk of birth defect from AR¼ x pC x pC (pC = probability of being carrier)
In this case = ¼ x 2/3 x ¼ = 1/24
P
![Page 61: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/61.jpg)
Carrier frequency is approximately equal to
Disease frequency1/2 x 2
For example if incidence of alpha thal is 1/100,the carrier frequency in this population is1/1001/2 x 2 = 1/5
General frequency 1 = N2 + 2ND + D2
N is close to 1 and we know D2 = disease frequency.2ND = Disease frequency1/2 x 2
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Summary of AR pedigree
![Page 63: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/63.jpg)
Autosomal Recessive Inheritance
• Hemoglobinopathies, thalassemias• Cystic fibrosis• Most of inborn errors of metabolism• Spinal muscular atrophy
![Page 64: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/64.jpg)
![Page 65: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/65.jpg)
X-linked Recessive Inheritance
![Page 66: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/66.jpg)
Summarized X-linked pedigree
Who are oligate carriers in this pedigree?
Carrier?2/3
![Page 67: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/67.jpg)
Does X-linkedFemale showPhenotype?
How?
Carrier detection?
![Page 68: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/68.jpg)
X-linked Recessive Inheritance
• Hemophilia A• Hemophilia B• Duchenne muscular dystrophy• Wiskott-Aldrich syndrome (X-linked
immunodeficiency)• X-linked agammaglobulinemia• X-linked adrenoleukodystrophy
![Page 69: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/69.jpg)
![Page 70: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/70.jpg)
X-linked adrenoleukodystrophy
![Page 71: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/71.jpg)
X-linked Dominant Inheritance
![Page 72: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/72.jpg)
X-linked Dominant Inheritance• Affected heterozygous females are seen.• Affected males with normal mates have
no affected sons and no normal daughters.
• Both male and female offspring of female carriers have a 50% risk of inheriting the phenotype.
• The phenotype is about twice as common in females as in males.
![Page 73: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/73.jpg)
X-linked Dominant Inheritance• Affected heterozygous females are seen.• Affected males with normal mates have
no affected sons and no normal daughters.
• Both male and female offspring of female carriers have a 50% risk of inheriting the phenotype.
• The phenotype is about twice as common in females as in males.
![Page 74: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/74.jpg)
Clues
• Pedigree similar to AD, but no male-to-male transmission, with F:M = 2:1
![Page 75: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/75.jpg)
X-linked dominant, lethal in male
• Only female survives
![Page 76: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/76.jpg)
X-linked Dominant Inheritance
• X-linked hypophosphatemicrickets
• Incontinentia pigmenti• Rett syndrome
![Page 77: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/77.jpg)
Y-linked Inheritance• Only males affected• Male to male transmission• Examples:
– SHOXY (Leri-weil, Langer mesomelicdysplasia)
– Testes specific protein– Sex determining region Y– Zinc finger protein Y– Azoospermia factor 2– Azoospermia factor 1
![Page 78: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/78.jpg)
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Summary Mendelian medical disorders
• The family is suffering from a single gene disorder?
• Mode of inheritance• New mutation & germline mosaicism• Penetrance• Variation in expression• Risk calculation• Carrier identification
![Page 81: Single Gene Slide](https://reader033.vdocuments.mx/reader033/viewer/2022051117/55cf867a550346484b980072/html5/thumbnails/81.jpg)