Genetics

Question 1

What is codominance?

Answer 1

When two alleles contribute to the phenotype of the heterozygote, like in blood groups, alpha-1-antitrypsin deficiency or HLA groups.

Question 2

What does variable expressivity means?

Answer 2

That even when the genotype is the same, the phenotype may vary, like in diseases when the severity is different between individuals.

Question 3

What does incomplete penetrance mean?

Answer 3

The phenotype is not always shown.
% penetrance * probability of inheriting = risk of expression in phenotype.
Like the BRCA1 mutation doesn’t always leads to Br of ovarian Ca.

Question 4

What is Pleiotropy?

Answer 4

The fact that a single gene contributes to different phenotypic effects.
In Phenylketonuria (PKU) there are skin, intellectual and body odor alterations.

Question 5

What does Anticipation mean?

Answer 5

The fact that in succeeding generations the severity increases or the onset is earlier.
An example are the trinucleotide repeat diseases like Huntington.

Question 6

What is the loss of heterozygosity?

Answer 6

If someone develops or inherits a mutation in a tumor suppressor gene the other allele has to be mutated/deleted for cancer to develop. It doesn’t apply to oncogenes.
Rb, Lynch Sx, Li-Fraumeni Sx and the “two-hit hypothesis”.

Question 7

What is a dominant negative mutation?

Answer 7

The mutated one that is dominant over a normal gene product.

Question 8

What is linkage equilibrium?

Answer 8

The tendency of alleles at two linked loci to be together more often than expected, might vary in populations.

Question 9

What does moisaicism mean?

Answer 9

Genetically different cells in the same individual.

• Somatic: from mitotic errors after fertilization and goes through tissues or organs.
• Gonadal: mutation on egg or sperm. If parents dont have the mutation, suspect gonadal mosaicism.

Question 10

What is the McCune-Albright syndrome?

Answer 10

Unilateral café-au-lait spots, ragged edges, polyostotic fibrous displasia and at least one endocrinopathy.
Lethal if before fertilization (affecting all cells), survivable in mosaicism.
Caused by a Gs protein activating mutation.

Question 11

What is the locus heterogeneity?

Answer 11

The fact that mutatios at different loci can produce the same phenotype, like in albinism.

Question 12

What is the allelic heterogeneity?

Answer 12

That different mutations in the same locus produce the same phenotype, like in ß-thalassemia.

Question 13

What is heteroplasmy?

Answer 13

The presence of normal and mutated mtDNA, having variable expression in mitochondrially inherited disease.
mtDNA is passed from mother to all children, it has been shown that fathers do too.

Question 14

What is a uniparental disomy (UPD)?

Answer 14

When an individual inherited two copies of a chromosome of a single parent and none from the other.

HeterodIsomy: (heterozygous) is a meiosis I error.

IsodIsomy: (homozygous) is a meiosis II error, postzygotic chromosomal duplication of one pair and deletion of the other.

Individual manifesting a recessive disorder when only one progenitor is a carrier like in Prader-Willi and Angelman syndromes.

Question 15

How does the Hardy-Weinberg population genetics work?

Answer 15

If equilibrium:
p^2 + 2pq + q^2 = 1 and p + q = 1, the value of p and q remains constant from one generation to another.
p^2 = frequency of homozygosity for allele A
q^2 = frequency of homozygosity for allele a
2pq = frequency of heterozygosity (carrier frequency if AR disease)
Freq of an X linked recessive in males is q and in females is q^2.

It assumes:

• No muattion at locus
• Natural selection not occurring
• Completely random mating
• No net migration

Question 16

What is imprinting?

Answer 16

One gene copy is silenced by methylation, only the other one is expressed.

Question 17

What is Prader-Willi syndrome?

Answer 17

A syndrome caused by imprinting (silenciation) of maternally derivated genes, it occurs when the paternal allele is deleted or mutated. 25% are caused by maternal UPD.
Clinically, obesity, hyperphagia, intellectual disability, hypogonadism and hypotonia.
Mutation/deletion of chromosome 15 of paternal origin.
Prader has no Papa.

Question 18

What is AngelMan syndrome?

Answer 18

The paternal UBE3A gene on chromosome 15 is imprinted (silenced) and the maternal one is mutated.
Inappropriate laugh (happy puppet), seizures, ataxia, severe intellectual disability.
5% due to paternal UPD.

Question 19

How does the autosomal dominant inheritance work?

Answer 19

Both sexes, structural genes, often pleiotropic, variably expressive. Must have family history. With an heterozygote parent affected, half the children will be too.

Question 20

How does the autosomal recessive inheritance work?

Answer 20

With two carrier parents, a quarter of children will be affected, a half carriers and a quarter totally healthy.
Enzyme deficiencies, one generation, more severe than dominant, childhood more often.

Question 21

How does the X-linked recessive inheritance work?

Answer 21

Sons of heterozygous mothers have 50% chance, sips generations, no man-to-man.
More severe in females, they must be homozygous to be affected.

Question 22

How does the X-linked dominant inheritance work?

Answer 22

Through both parents, mothers to 50% of daughters and sons, fathers to all daughters but no sons.
The hypophosphatemic rickets (formerly, vitamin D resistant rickets), higher phosphate wasting at proximal tubule, rickets-like.
Fragile X syndrome, Alport.

Question 23

How does the mitochondrial inheritance work?

Answer 23

Only through mother, all offspring affected, variable expression even within a family, heteroplasmy.
Myopathies: myopathy, lactic acidosis, CNS disease (MELAS syndrome), due to failure in oxidative phosphorylation.
Leber hereditary optic neuropathy: cell death in optic nerve neurons, subacute bilateral vision loss in young adults, 90% males.

Question 24

Examples of autosomal dominant diseases:

Answer 24

Achondroplasia, ADPKD, FAP, familiar hypercholesterolemia, h hemorrhagic telangiectasia (Osler-Weber-Rendu sx), h spherocytosis, Huntington, Li-Fraumeni, Marfan, MEN, myotonic muscular dystrophy, NF1 (von Recklinghausen), NF2, tuberous sclerosis, von Hippel-Lindau.

Question 25

What is heteroplasmy?

Answer 25

The presence of more than one type of organellar genome (mitochondrial or plastid DNA) within a cell or individual. Important factor in considering the severity of mitochondrial diseases.

Question 26

Examples of autosomal recessive diseases:

Answer 26

Albinism, ARPKD, cystic fibrosis, Friedrich ataxia, glycogen storage diseases, hemochromatosis, Kartagener sx, mucopolysaccharidoses (exp Hunter), PKU, sickle cell anemia, sphingolipidoses (exc Fabry), thalassemias, Wilson.

Question 27

Examples of X-linked recessive disorders:

Answer 27

Ornithine transcarbamylase def, Fabry, Wiskott-Aldrich, Ocular albinism, G6PD def, Hunter, Bruton agammaglobulinemia, Hemophilia A and B, Lesh-Nyhan, Duchenne and Becker.

[Oblivious Femanle Will Often Give Her Boys Her xLinked Disorders.]

Question 28

What is the X inactivation (lyonization)?

Answer 28

A copy of female X chromosome forms a transcriptionally inactive Barr body, female carriers variably affected, depending on the pattern of inactivation.
Females with Turner (45XO) are more likely to have an X-linked disorder.

Question 29

What is the Duchenne myopathy?

Answer 29

X-linked, frameshift deletion or nonsense = truncated or absent dystrophin = progressive myofiber damage.
Weakness of pelvic girdle muscles, goes upward.
Pseudohypertrophy of calf muscles, fat degeneration.
waddling gait, onset before 5 yo, dilated cardiomyopathy.
Gowers sign.
DMD: dystrophin gene, largest protein coding human gene, high chance of spontaneous mutation, connects the intracellular cytoskeleton (actin) to transmembrane proteins alpha and ß dystroglycan, connected to ECM.
Loss of dystrophin: myonecrosis.
High CK and aldolase confirms dx.

Question 30

What is Becker myopathy?

Answer 30

X-linked, non-frameshift deletion in dystrophin gene (partially functional), ado and early adulthood.

Question 31

What is the myotonic type 1?

Answer 31

AD. CTG trinucleotide repeat expansion in DMPK gene = abnormal myotonin protein kinase expression = myotonia (diff releasing hand from closed, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia.

CTG = Cataracts, Toupee (early blading in men), Gonadal atrophy.

Question 32

What is the Rett syndrome?

Answer 32

Sporadic, only girls because men die in utero or when newborn.
De novo mutation of MECP2 on X chromosome.
Symptoms 1-4 yo, regression (RETTurn) in motor, verbal, cognitive, ataxia, seizures, growth failure, stereotyped handwringing.

Question 33

What is the fragile X syndrome?

Answer 33

X-linked dominant. Trinucleotide repeat in FMR1 gene, hypermethylation, less expression.
Most common cause of inherited intellectual disability, second most common of genetically associated mental def (after Down).
Post puberal macroorchidism, long face with long jaw, large everted ears, autism, mitral valve prolapse.
GGG during oogenesis.

Question 34

Which are trinucleotide repeat expansion diseases?

Answer 34

Huntington, myotonic dystrophy, fragile X sx, Friedrich ataxia.
May show genetic anticipation.

TRY (TRInucleotide) HUNTING for MY FRAGILE cageFREE eggs (X).

Huntington - CAG - AD - Caudate has less Ach and Gaba.

Myotonic dystrophy - CTG - AD - Cataracts, Toupee, Gonadal atrophy.

Fragile X syndrome - CGG - XD - Chin (protrudes), Giant Gonads.

Friedrich - GAA - AR - ataxic GAAit.

Question 35

What is trisomy 21?

Answer 35

Down.Flat facies, prominent epicanthal folds, single palmar crease, incurved 5th finger, gap between first 2 toes, duodenal atresia, Hirschsprung, congenital heart disease, Brushfield spots, early onset Alzheimer, high risk ALL and ALM.
95% due to meiotic nondisjuction (maternal age)
4$ unbalanced Robertsonian trnaslocation 14:21.
1% postfertilization mitotic error.
1:700, most common intellectual dis, viable chromosomal disorder.
First trimester USG, increased nuchal translucency, hypoplastic nasal bone.
HI up: high HCG, Inhibin.
5 A’s: Advanced maternal age, Atresia (duodenal), Atrioventricular septal defect, Alzheimer, AML/ALL.

Question 36

What is trisomy 18?

Answer 36

Edwards. PRINCE edward: Prominent occiput, Rocker-bottom feet, Intellectual disab, Nondisjunction, Clenched fists (overlapping fingers), low set Ears, micrognatia, congenital heart disease, omphalocele.
Death before 1 yo.
1:8000, second most common trisomy in live birth.

Question 37

Whats trisomy 13?

Answer 37

Patau. Severe intellectual def, rocker bottom feet, microphtalmia, microcephaly, cleft liP/Palate, holoProsencephaly, Polydactyly, PKD, cutis aPlasia, Pump (heart) disease, omphalocele. Early death.
1:15,000

Question 38

How are the trisomy markers in screening?

Answer 38

First trimester

21: high ßhCG, low PAPPA
18: both ßhCG and PAPPA low
13: both ßhCG and PAPPA low

Second trimester

21: high ßhCG and inhibin, low estriol and AFP.
18: low ßhCG, inhibin, estriol and AFP.
13: can’t asses.

Question 39

Genetic disorders by chromosome

3
4
5
6
7
9
11
13
15
16
17
18
21
22
X

Answer 39

3: von Hippel-Lindau, renal cell ca
4: ADPKD (PKD2), achondroplasia, Huntington
5: Cri du chat, FAP
6: Hemochromatosis
7: Williams, CF
9: Friedrich ataxia, tuberous sclerosis (TSC1)
11: Wilms tumor, ß-globin gene defects, MEN1
13: Patau, Wilson, RB1, BRCA2
15: Prader Willi, Angelman, Marfan
16: ADPKD (PKD1), alpha globin gene defects, tuberous sclerosis (TSC2)
17: NF1, BRCA1, TP53
18: Edwards
21: Down
22: NF2, DiGeorge (22q11)
X: Fragile X, X-linked agammaglobulinemia, Klinefelter (XXY)

Question 40

What is a robertsonian translocation?

Answer 40

Chromosomal translocation, involves pairs 13, 14, 15, 21 and 22.
One of the most common types.
Long arms of 2 acrocentric chromosomes (centromers near their ends) fuse at the centromere and the short arms are lost.
Balanced translocations usually won’t cause alterations in phenotype, unbalanced can result in miscarriage, stillbirth and chromosomal imbalance (21, 13…)

Question 41

What is cri du chat syndrome?

Answer 41

Deletion on short arm of chromosome 5 (46XX or XY, 5p)
Microcephaly, mod-sev intellectual disability, high-pitched crying/meowing, epicanthal folds, cardiac abnormalities (VSD).

Question 42

What is Williams syndrome?

Answer 42

Microdeletion of long arm of chromosome 7, including the elastin gene.
Distinctive “ELFin” facies, intellectual disability, hypercalcemia, well-developed verbal skills, extreme friendliness with strangers, CV problems.
WILL Ferrell in ELF.