Autosomal and X-linked Dominant/Recessive Diseases (randomized)

Question 1

Achondroplasia:
Type of inheritance?
What gene(s) is/are mutated?
What other genetic alterations can occur with similar mutations?

Answer 1

AD inheritance, but arises frequently as a new mutation from paternal inheritance (e.g. Tywin Lannister was already an old man when Tyrion was born)

Mutation of FGFR3 (fibroblast growth factor receptor type 3).
Based on the locus of the mutation of the gene, 3 different diseases can occur: achondroplasia, hypochondroplasia, and tanatophoroplasia (example of pleiotropy and allelic heterogeneity)

Question 2

How is hereditary baldness expressed in men vs women?

Answer 2

Men: AD

Women: AR, only in homozygotes with high testosterone level (explained why it’s much rarer)

Question 3

Fragile X syndrome:
Type of inheritance?
What gene(s) is/are mutated?

Answer 3

XD inheritance with variable penetrance

FMR1 aka FRAXA gene which regulates synapses. Trinucleotide CGG repeats: when they exceed 200 repeats, the CpG islands become hypermethylated and inhibit transcription of FMR protein.

Most common cause of male mental retardation, occurs about half as often in women despite X-linked dominant inheritance, as women are more likely to have incomplete penetrance / remain in the “premutation” < 200 repeat stage. But women can still be affected in the heterozygous form, so it’s XD.

Question 4

Congenital adrenal hyperplasia:
Type of inheritance?
What gene(s) is/are mutated?

Answer 4

AR inheritance

Genes related to 21 hydroxylase. Unique mutation of active gene (CYP21A) and inactive psuedogene (CYP21P)

Question 5

Osteogenesis imperfecta:
Type of inheritance?
What gene(s) is/are mutated?

Answer 5

AD inheritance

Different collagen genes mutated. Significant pleiotropy due to abundance of collagen.

Shows strong degree of variable expressivity, especially among heterozygotes. Also, incomplete penetrance for unknown reasons.

Question 6

Autosomal recessive diseases are normally mutations of genes for which type of physiological functions?

Answer 6

Normally they are mutations of enzymes, hemoglobin, or tumor suppressor genes. Cystic fibrosis is the odd one, as it is a regulatory protein (more typical of AD inheritance).

They are usually loss-of-function mutations (nonsense or frameshift), and their heterozygote carriers often have “heterozygote advantage” to sustain the mutation under natural selection

Question 7

Heterozygote carriers of genes for the following genetic diseases may have been protected from which infectious diseases?

• Cystic fibrosis
• Sickle Cell Anemia and beta thalassemia
• Tay-Sachs disease
• Congenital Adrenal Hyperplasia

Answer 7

Cystic Fibrosis: cholera

Sickle cell and Beta Thalassemia: Malaria

Tay-Sachs: Tuberculosis

CAH: Hemophilus influenzae B (meningitis-causing strain)

Question 8

Leber’s optic neuropathy:

Type of inheritance?

Answer 8

Mitochondrial inheritance (maternal)

Note that this maternal pattern is considered “non-Mendellian”

Question 9

Porphyria:
Type of inheritance?
What gene(s) is/are mutated?

Answer 9

Mostly AD inheritance, sometimes AR

Genes coding for enzymes of steps of heme and porphyrins

Question 10

Hereditary Hypophosphatemia:
Type of inheritance?
What gene(s) is/are mutated?

Answer 10

XD inheritance

Mutations of genes that regulate FGF23, which becomes overactive and inhibits vitamin D + increases loss of phosphate from the kidney + activates PTH. Causes “vitamin D-resistant rickets”

Question 11

Hemophilia A and B:
Type of inheritance?
What gene(s) is/are mutated in Hemophilia A?

Answer 11

XR inheritance

Hemophilia A: factor VIII mutation occurs during meiosis, where intrachromosomal crossing over -> inversion of an important intron, causing factor VIII to fall apart. Correlated to older fathers, who give the X to daughter to be carrier, then hemophilia becomes manifest in her son.

(Hemophilia B is factor IX, not sure how it’s mutated)

Question 12

2 examples of sex-limited inheritance

Answer 12

1. Milk production: men won’t ever know if they are good at the lactating, yet they carry genes that can influence their daughters’ milk production
2. Pre-eclampsia also can only be manifest in women, but is affected by paternal genes

Question 13

What type of inheritance is typical for proto-oncogene mutations?

And for mutations of tumor suppressor genes?

Answer 13

Proto-oncogenes usually dominant: just one allele mutated (heterozygous) allows unregulated expression / oncogene formation

Tumor suppressor genes usually recessive (need homozygous form to be affected, Knudson hypothesis) - yet the inheritance pattern appears more dominant, appears in every generation (“vertical family tree”) due to high risk of double-hit

Question 14

Polycystic kidney disease:
Type of inheritance?
What gene(s) is/are mutated?

Answer 14

Both AD and AR inheritance
-AD: polycystin mutation from either PKD1 or PKD2 genes (example of locus heterogeneity). PKD1 mutation is much more common.

-AR: fibrocystin mutation from PKHD1 gene

Question 15

Rett syndrome:
Type of inheritance?
What gene(s) is/are mutated?

Answer 15

XD inheritance

Mutation of methyl-cytosine binding protein (MECP2 gene) - which is used to methylate histones. Results in inability to correctly perform epigenetic modifications.

Men usually die from this, while women suffer frm progressive loss of speech and motor functions, with typical compulsive hand-wringing, ataxia, and seizures

Question 16

Malignant hyperthermia:
Type of inheritance?
What gene(s) is/are mutated?

Answer 16

AD inheritance

Can be caused by at least 6 different gene mutations, maybe only know gene for RYR1, and CACNA1S which is a regulator of RYR1.

RYR1 is a calcium channel in the sarcoplasmic reticulum. Mutation allows too much Ca2+ in the cytosol, causing increased muscle contraction and heat production

Question 17

Cystic Fibrosis:
Type of inheritance?
What gene(s) is/are mutated?

Answer 17

AR inheritance (but not a “classical” AR inheritance like the enzyme or hemoglobin deficiencies)

Mutation of Cl- channel regulatory protein (CFTR). Over 800 different mutations are known, but by far the most common is deletion of triplet from 508th phenylalanine (delta F508)

Question 18

Tay-Sachs disease
Type of inheritance?
What gene(s) is/are mutated?

Answer 18

AR inheritance

Mutation of genes coding for alpha subunit of hexosaminidase, causing toxic buildup of GM2 ganglioside in the lysosomes of neurons

Question 19

Duchenne and Becker Muscular Dystrophy
Type of inheritance?
What gene(s) is/are mutated?

Answer 19

XR inheritance

Mutation of gene for dystrophin cytoskeletal protein (largest known gene, 2.4 Mb, takes an extremely long time to transcribe. high rate of new mutations)

Duchenne: usually a large deletion occurs via frameshift

Becker: in-frame mutation, only a small part is deleted. Milder than Duchenne.
(“allelic heterogeneity” - different mutant alleles of same gene)

Question 20

What is the main disease to know that shows the effect of anticipation?

Answer 20

Huntington’s disease: trinucleotide CAG repeats increase with each generation, making the disease appear at a younger age with each successive generation.

The increase in repeats normally occurs in paternal germline.

Question 21

Huntington’s Disease
Type of inheritance?
What gene(s) is/are mutated?

Answer 21

AD inheritance

The mutated gene codes for Huntingtin, a protein without a clearly known function. Appears to be “gain of malfunction” mutation.

Becomes symptomatic with >40 CAG repeats. Increase in repeat number occurs mostly in paternal germline.

Question 22

Thalassemia:
Type of inheritance?
What gene(s) is/are mutated?

Answer 22

AR inheritance

Many types of mutations to either alpha or beta globin chains of hemoglobin: deletions, frameshift, and splicing mutations.

Question 23

How does X chromosome inactivation complicate the pedigree analysis of X-linked recessive inheritance?

Answer 23

If the product of the gene is a soluble protein, such as clotting factors in hemophilia, the effect is “averaged” - they may actually have reduced clotting factors due to inactivation of some of the dominant/healthy X chromosomes. However, this is not enough to be symptomatic / don’t have phenotype.

If the XR problem is in a given cell type, then mosaicism in that cell may cause symptoms in certain regions. This is the case in hypohydrotic ectodermal dysplasia: sweat glands may be absent in some regions with heterozygous females, whereas it would be generalized in men.

Question 24

Androgen Insensitivity Syndrome (AIS)
Type of inheritance?
What gene(s) is/are mutated?

Answer 24

XR inheritance

Testosterone receptor mutates, making XY genotype people have female appearance with external female genitalia, yet no ovaries/uterus.

Question 25

Why are Barr bodies formed?

Answer 25

Barr bodies are a method of “dose compensation” - with more than 1 X chromosome, the body has to prevent over-expression of X chromosome genes. And so with the process of lyonization, most of one of the X chromosomes is inactivated as heterochromatin, composing a Barr body.

Note that the psuedoautosomal regions (PAR) are never inactivated. PAR1 and PAR2 are homologous in the X and Y chromosome, similarly to the autosomal chromosomes.

Question 26

How are men and women affected differently from X-linked dominant disorders?

Answer 26

Women are affected 2x more often than men (2 X chromosomes vs 1 X), and affected men never give it to their sons while always give it to their daughters

Women may be less affected by the diseases (variable expressivity), due to X inactivation or a recessive allele with some weaker function

Question 27

Sickle cell anemia:
Type of inheritance?
What gene(s) is/are mutated?

Answer 27

AR inheritance

On beta globin chain or Hb, the 6th amino acid glutamine is replaced by valine (occurs via transversion substitution)

Question 28

Glucose-6-phosphate dehydrogenase deficiency:
Type of inheritance?
What gene(s) is/are mutated?

Answer 28

XR inheritance

Mutation of G6PD gene causes insufficient production of G6PD enzyme, which normally protects red blood cells from ROS.

Only becomes symptomatic with environmental changes (ecogenetic), such as infections or some medications. Also eating fava beans, which is why it’s also called “favism”

Heterozygote advantage in malaria

Question 29

Autosomal dominant diseases are normally mutations of genes for which type of physiological functions?

Answer 29

Normally they are mutations of structural proteins, regulatory proteins, receptors, and proto-oncogenes.

They are made more complicated by pleiotropy, variable expressivity, incomplete penetrance, and arousal of new mutations (typically correlated with paternal age)

Question 30

Red-Green Color Blindness
Type of inheritance?
What gene(s) is/are mutated?

Answer 30

XR inheritance

Different genes for opsin pigments in cones are mutated

Because symptoms are mild, men survive and if they have children with a mother who is a carrier for the same mutation, there is a chance that their daughter could be homozygous and thus be affected (rarely occurs in X-linked recessive diseases)

Question 31

Ornithine transcarbamylase (OTC) deficiency:
Type of inheritance?
What gene(s) is/are mutated?

Answer 31

XR inheritance

Mutation of OTC gene, which codes OTC enzyme.

Urea cycle disorder, ammonia accumulates in bloodstream.

Question 32

Phenylketonuria (PKU):
Type of inheritance?
What gene(s) is/are mutated?

Answer 32

AR inheritance

Genes coding for phenylalanine hydroxylase enzyme, causing phenylalanine to be converted to phenylpyruvate (toxic) instead of tyrosine.

Treated with high tyrosine/low Phe diet. Still not enough tyrosine will be available to make melanin, so they have decreased pigmentation in skin, eyes, and hair.

Question 33

Albinism:
Type of inheritance?
What gene(s) is/are mutated?

Answer 33

AR inheritance

Mutation of genes related to tyrosinase enzyme, causing melanin synthesis to be impaired.

Question 34

Marfan syndrome:
Type of inheritance?
What gene(s) is/are mutated?

Answer 34

AD inheritance

Fibrillin gene is mutated. Significant pleiotropy because of fibrillin in various elastic tissue throughout body (lungs, skin, vascular system, cornea, etc). Shows strong variable expressivity.

Correlation between new mutation and paternal age.

Question 35

Xeroderma pigmentosum:
Type of inheritance?
What gene(s) is/are mutated?

Answer 35

AR inheritance

Any of the genes for nucleotide excision repair are mutated (they have names like XPA, XPC, etc.)

Question 36

Kallman Syndrome:
Type of inheritance?
What gene(s) is/are mutated?

Answer 36

XR inheritance

Mutation of gene for a cell adhesion protein which has a role in neuronal migration. Results in ineffective development of both the hypothalamus and olfactory nerves. The gene is in the PAR1 (pseudoautosomal) region. There is a Y chromosomal homologue but it’s an inactive pseudogene.

Suffer from anosmia (lack of sense of smell) + hypopituitarism

Question 37

Waardenburg syndrome:
Type of inheritance?
What gene(s) is/are mutated?

Answer 37

AD inheritance (usually), sometimes AR

Type I: PAX3 mutation. Type II: can be MITF, WS2B, WS2C, etc. Shows locus heterogeneity.

Causes varying degrees of deafness, minor defects in structures arising from the neural crest, and pigmentation changes. / heterochromia of the iris. May have widely-spaced eyes.

Question 38

Incontinentia pigmenti:
Type of inheritance?
What gene(s) is/are mutated?

Answer 38

XD inheritance

Gene: deletion in IKBKG (inhibitor of kappa light polypeptide gene enhancer in B-cells kinase gamma) - regulates nuclear factor kappa-B, which protects cells from apoptotic signals

Shows male lethality with heterozygote females having “Blashko lines” - patchy distribution of skin lesions due to functional mosaicism

Question 39

Hypohidrotic ectodermal dysplasia
Type of inheritance?
What gene(s) is/are mutated?

Answer 39

XR mostly

EDA gene: responsible for signaling between ectoderm and mesoderm, and defect causes poor formation of ectodermal structures (teeth, skin, sweat glands, nails)

Males 100% affected, females regionally affected in the locations where their healthy X chromosome is made into a Barr body