Ch 15. Genetics-2

Question 1

X-Linked Disorders: Lyon Hypothesis

Answer 1

Random inactivation of either paternally or maternally inherited X chromosome occurs in each cell of females
Therefore–normal females are mosaics
X inactivation is regulated by the XIST
gene (Xq13)
The inactivated X is reactivated in germ cells

Question 2

X-Linked Dominant Disorders

Answer 2

Rett Syndrome

Vitamin D Resistant Rickets

Question 3

Rett Syndrome

Answer 3

Mental retardation
Females are infertile
Prenatally lethal in males

Question 4

Vitamin D Resistant Rickets

Answer 4

Normal production and metabolism of Vitamin D
Renal tubular loss of phosphate Interferes with skeletal ossification

Question 5

X-Linked Recessive Disorders

Lesch-Nyhan Syndrome
Complete lack of HGPRT

Answer 5

HGPRT (hypoxanthine guanine phosphoribosyl transferase): involved in the salvage pathway for purine synthesis
It salvages purine bases from the breakdown of nucleic acids
If absent–increased synthesis of purine nucleotides de novo with subsequent increased production of uric acid

Question 6

Lesch-Nyhan Syndrome

Answer 6

Appear normal at birth
May develop normal for months
High uric acid levels
Self mutilation, mental retardation, spasticity
Profound lack of dopaminergic terminals and cells
Gout

Question 7

Duchenne Muscular Dystrophy

Answer 7

Covered in Muscle Disease lectures

Question 8

Multifactorial Inheritance

Answer 8

from combined actions of environment and two or more mutant genes;
Risk of expressing the disorder influenced by the number of mutant genes inherited
; Rate of recurrence is the same for all first degree
relatives; Risk of both identical twins getting disorder

Question 9

Multifactorial Inheritance

Answer 9

Examples:
Congenital heart disease Diabetes mellitus
Cleft lip or palate
Hypertension
Gout

Question 10

Cytogenetic Disorders

Answer 10

Alterations in the number or structure of chromosomes

Question 11

Normal Chromosome

Answer 11

Normal human chromosome complement is expressed as:
46 XX–female
46 XY–male
Euploid: an exact multiple of the haploid
number (23)
Aneuploidy: not an exact multiple of 23

Question 12

Normal Chromosomes

Answer 12

Aneuploidy–Causes Nondisjunction
Anaphase lag
When nondisjunction occurs in gametogenesis, the gametes formed have either an extra chromosome, or one chromosome less.

Question 13

Cytogenetic Disorders

Answer 13

Monosomy of an autosome usually results in the loss of too much genetic material to have a live birth
Monosomy or trisomy of sex chromosomes are compatable with life, but may demonstrate phenotypic abnormalities

Question 14

Mosaicism

Answer 14

Occasionally, mitotic errors in early development give rise to two or more populations of cells in the same individual
Mosaicism affecting the sex chromosomes is relatively common
Autosomal mosaicism is much less common

Question 15

Chromosomal Aberrations

Answer 15

Deletion*
Translocation
Balanced
Robertsonian Fusion Insertion*
Inversion
Ring Chromosome
Isochromosome
* already covered in basic genetics

Question 16

X-Linked Disorders

Answer 16

Majority are X-linked recessive
Fully expressed in males
Heterozygous females may partially express the disease
Carriers

Question 17

Translocation

Answer 17

One segment of a chromosome is transferred to another;
-Balanced reciprocal: single breaks in two chromosomes with exchange of material
-Robertsonian: Also known as centric fusion
A translocation between two acrocentric
chromosomes

Question 18

Inversions

Answer 18

A rearrangement that involves two breaks within a single chromosome with inverted reinsertion of the segment

Question 19

Ring Chromosome

Answer 19

Terminal ends of the chromosome are lost Remaining chromosome circularizes

Question 20

Isochromosomes

Answer 20

Chromosome in which one arm is missing and the other arm is duplicated

Question 21

Cytogenetic Disorders

Trisomy 21 (Down Syndrome)

Answer 21

Most common chromosomal disorder
Major cause of mental retardation
~ 95% of affected individuals have trisomy 21, with a chromosome count of 47
Remainder have normal numbers of chromosomes, but extra chromosomal material is present as a translocation

Question 22

Trisomy 21

Answer 22

Mostcommoncause: meiotic nondisjunction (~95%)
4%–Robertsonian translocation
1%–mosaics
Parents have normal karyotype
Maternal age–strong influence

Question 23

Trisomy 21: Clinical Presentation

Answer 23

Flat face with palpebral fissures and epicanthic folds
Mental retardation (severity varies)
Congenital heart disease
Increased risk for leukemia
Abnormal immune response
Simian crease

Question 24

Trisomy 21: Clinical Presentation

Answer 24

In all most all of those over 40 years of age
Neuropathic changes characteristic of Alzheimer’s disease
Current median age of death: 47 years

Question 25

Trisomy13 (Patau’s Syndrome)

Answer 25

Caused by meiotic nondisjunction Associated with increased maternal age Severe mental retardation Microcephaly, Cleft lip and palate, Cardiac defects Microphthalmia, Rocker bottom feet, Polydactyly

Question 26

Trisomy 18 (Edwards Syndrome)

Answer 26

Mental retardation Rocker bottom feet Low set ears Congenital heart defects

Question 27

Chromosome Deletion Syndromes

Answer 27

Cri-du-Chat Syndrome

Question 28

Cri-du-Chat Syndrome

Answer 28

Deletion of 5p Severe mental retardation | Catlike cry Congenital Heart Disease Hypertelorism Epicanthus Retrognathia

Question 29

Cytogenetic Disorders Involving Sex Chromosomes Klinefelter Syndrome

Answer 29

Male hypogonadism which occurs when there are two or more X chromosomes and at least one or more Y chromosomes Most frequent form of genetic disease involving sex chromosomes

Question 30

Klinefelter Syndrome

Answer 30

Principal cause of reduced spermatogenesis and male infertility Lower mean IQ Mental retardation is uncommon Hypogonadism: consistentfinding High FSH and estrogen, low testosterone

Question 31

Klinefelter Syndrome

Answer 31

Long limbs Gynecomastia (increased risk of breast cancer) Tall, thin Small genitalia Eunuchoid body habitus

Question 32

XYY Syndrome

Answer 32

Tall Phenotypically normal Behavioral difficulties?

Question 33

Turner Syndrome

Answer 33

Results from complete or partial monosomy of the X chromosome Characterized by hypogonadism in phenotypic females ~57% lack an entire X chromosome Remainder: 1/3 lack a portion of one X chromosome 2/3 are mosaics

Question 34

Turner Syndrome

Answer 34

Peripheral lymphedema at birth (severe cases) Congenital heart disease: -Preductal coarctation of the aorta -Bicuspid aortic valve Webbed neck Short stature Broad chest, widely spaced nipples

Question 35

Turner Syndrome

Answer 35

In adolescents and adults: Failure to develop normal secondary sex characteristics Amenorrhea (primary) Increased risk of : Developing autoantibodies to thyroid gland Glucose intolerance Insulin resistance

Question 36

Multiple Modes of Transmission Ehlers-Danlos Syndromes

Answer 36

Defect in the synthesis of fibrillar collagen Mode of inheritance encompasses all three mendelian patterns Typically involves tissues rich in collagen -Skin -joints

Question 37

Androgen Insensitivity Syndrome

Answer 37

46 XY Phenotypically female Mutation in androgen receptor gene No ovaries or uterus Testes within abdomen or inguinal canal X-linked

Question 38

Triple Repeat Mutations Fragile X Syndrome

Answer 38

Xq27.3 Multiple tandem repeats of CGG -Normally 29 repeats; Premutations 50 - 200; Mutations: > 200 Severe MR Enlarged testes Elongated face Large everted ears

Question 39

Fragile X Syndrome

Answer 39

2nd most common genetic cause of MR Most common inherited cause

Question 40

Fragile X Syndrome

Answer 40

Differences from typical X-linked disorders: - Carrier males (AKA normal transmitting males) Clinically and cytogenetically normal Transmit disease to grandchildren through daughters - Affected Females: 30 - 50% of carrier females are affected - Risk of phenotypic effects Depends on place in pedigree - Anticipation

Question 41

Fragile X Syndrome

Answer 41

Gene: FMR1 Normally: ~29 repeats Premutations: 50-200 repeats Full mutations: 200-4000 repeats *During oogenesis (not spermatogenesis) the premutations can be converted to full mutations