Autosomal Dominant Inheritance

Question 1

Why are homozygous dominant mutations not often seen?

Answer 1

They are typically more severe or lethal

Question 2

What is pure dominant vs incomplete dominant?

Answer 2

Pure - When the homozygous affected has the same clinical picture as heterozygous - very rare

Incomplete dominant - homozygous is a more severe form of disease than heterozygous

Question 3

What are the general pedigree characteristics of autosomal dominant mutations?

Answer 3

1. Phenotype appears in every generation
2. Normal parents do not transmit condition to their offspring
3. Males and females are equally likely to be affected
4. Male to male transition is seen readily

Question 4

What are the exceptions to the rule that the phenotype will appear in every generation for an autosomal dominant mutation?

Answer 4

1. De novo mutation
2. Incomplete penetrance -> parents had the mutation but didn’t express it
3. Variable expressivity -> can result in mislabelling a person as unaffected

Question 5

What are the exceptions where phenotypically normal parents can transmit the condition to their offspring?

Answer 5

1. Incomplete penetrance
2. Late age of disease onset -> parent not at age of expression yet
3. Gonadal mosaicism -> mutation is in reproductive cells, but rest of cells are without mutation

Question 6

What are the three types of autosomal dominant mutations?

Answer 6

1. Loss of function - less gene product made
2. Dominant negative alleles - mutant allele does not function properly and inhibits proper function of wild type protein (dimerization or regulation)
3. Gain of function - Elevated gene activity or new gene activation. I.e. protooncogene -> oncogene

Question 7

What is haploinsufficiency?

Answer 7

A single copy of a wild type allele is insufficient to provide wild type gene activity -> this is the etiology of loss of function dominant mutations

Question 8

What is allelic heterogeneity vs locus heterogeneity?

Answer 8

Allelic - Phenotype can be due to a number of different allelic mutations within a specific gene

Locus - phenotype can be due to mutations at a number of different gene loci

Question 9

What is autosomal dominant hypercholesterolemia an example of?

Answer 9

Locus hetereogeneity - includes 3 loci:

1. LDLR
2. ApoB
3. Proprotein Convertase (PCSK9)

Question 10

What causes familial hypercholesterolemia? How does the homozygous vs heterozygous condition differ?

Answer 10

LDLR mutation
Normal LDL: <130 mg/dL
Heterozygous: >190 mg/dL in adult or >160 in children, early coronary artery disease and lesion onset 30-40 years
Homozygous: >500 mg/dL, MI as early as 18 months and deaths around age 20, lesion onset 6-17 years

Question 11

What are the clinical findings in familial hypercholesterolemia (FH)?

Answer 11

1. Increased LDL
2. Xanthomas - lipid-filled nodules on skin
3. Atheromas in arteries
4. Arcus cornealis - white or gray ring found at corneal margin due to fat deposits. Pathologic if <45 yrs
5. Premature CVD, earlier in men
   (40s) than women (50s)

Question 12

Why is FH variably expressed? What may influence its penetrance?

Answer 12

Due to diet

Has >90% penetrance, though penetrance may be reduced by modifier genes for instance to ApoA2 which may increase HDL levels.

Question 13

What is the prevalence of FH and the major defect?

Answer 13

1/500, major defect is the low density lipoprotein receptor in liver, leading to increased plasma LDL levels.

Question 14

What is the treatment for FH and who responds better?

Answer 14

Statins. Better response by people who have ApoB mutations because you reduce the synthesis of this abberant ApoB which cannot be uptaken

Question 15

What ethnicities are particularly at risk for FH?

Answer 15

Afrikaners in South Africa, French Canadians, Lebanese, and Finns

Question 16

What is cascade screening?

Answer 16

Test all the first degree relatives of the proband first. Whoever among those has the disease, test their first degree relatives as well (since it’s autosomal dominant you can follow it this way)

Question 17

What are the clinical findings of Autosomal Dominant Polycystic Kidney Disease (ADPKD)?

Answer 17

1. Bilateral renal cysts
2. Cysts in other organs, i.e. liver
3. Berry aneurysms (intracranial aneurysms) i.e. on Circle of Willis
4. Vascular abnormalities i.e dissection of aorta or dilation of aortic root
5. Renale hypertension, pain, and renal insufficiency in end stage renal disease

Question 18

How is the diagnosis for ADPKD primarily made?

Answer 18

Via renal ultrasound

Question 19

What gene loci are implicated in ADPKD and what is this an example of?

Answer 19

Locus heterogeneity - loss of function mutations
PKD1 (85%)
PKD2 (15%)

Question 20

What are the functions of polycystin-1 and polycystin-2?

Answer 20

They work together in a functional complex in primary cilia, and are integral membrane proteins.

They are strongly expressed in elastic myocytes, large arteries, cardiomyocytes, and valvular myofibroblasts

Question 21

How does the site of the PKD1 mutation influence the vascular pathology?

Answer 21

Further towards the 5’ end = more truncated protein = greater vascular involvement

Question 22

What is the onset of the disease for ADPKD? What’s the treatment?

Answer 22

Late age onset -> if kid gets it, may still need to test parents

Treatment: ACE inhibitors and Angiotensin II receptor blockers. Surgical clipping of berry aneurysms.

Question 23

How is ADPKD most often passed?

Answer 23

95% inherited, but there is some gonadal mosacism possible.

5% are de novo mutations

Question 24

What are the common clinical findings of NF-1?

Answer 24

1. Multiple cafe-au-lait spots
2. Axillary and inguinal freckling
3. Multiple cutaneous neurofibromas - tumors at end of nerves
4. Lisch nodules in iris
5. Learning disabilities

Question 25

What are some uncommon clinical findings in NF-1?

Answer 25

Plexiform neurofibromas, tibial dysplasia, scoliosis

Question 26

What is pleiotropy?

Answer 26

When a single gene causes two or more apparently unrelated effects, i.e. in Marfan syndrome

Question 27

Why does NF-1 have variable expressivity? What type of mutation is this?

Answer 27

It is a tumor suppressor gene (loss of function mutation). Whole deletions will cause much more severe, debilitating effects. Random tumors arise from mutations in normal allele + the germline mutation, allowing cell proliferation. This is why you don’t have tumors of all nerves.

Question 28

What is the function of the gene which causes NF-1?

Answer 28

Produces neurofibromin, a gene involved in turning off Ras by exchanging GTP for GDP. There are many possible mutations (allelic heterogeneity)

Question 29

What surveillance is involved for NF-1?

Answer 29

Annual exams to watch for development of complications

Question 30

What percentage of NF-1 patients have de novo mutation? Has gonadal mosaicism been observed?

Answer 30

50%

yes, gonadal mosaicism has been observed

Question 31

What causes segmental NF-1? When will this person be at risk of transmitting it to offspring

Answer 31

Somatic mosaicism, where post-zygotic cell develops mutation, and all of its progeny will be affected.

Offspring at increased risk of NF-1 only if gonadal cells contain the mutation

Question 32

What is Marfan syndrome caused by?

Answer 32

Caused by FBN1 mutation - Fibrillin-1. It has >1000 possible mutations (allelic heterogeneity)

Connective tissue abnormality affecting multiple systems -> pleiotropy.

Question 33

What’s the penetrance of Marfan syndrome?

Answer 33

100% penetrance, but variable expressivity

Question 34

What type of dominant mutation is Marfan syndrome?

Answer 34

Dominant negative - fibrillin-1 mutants will interfere with normal

Question 35

Why are clinical features crucial for making the diagnosis of Marfan syndrome?

Answer 35

There are individuals with an FBN1 mutation who do not have Marfan syndrome

Question 36

What are the ocular manifestations of Marfan syndrome?

Answer 36

myopia, ectopic lentis (lens dislocation), retinal detachment

Question 37

What are the skeletal manifestations of Marfan syndrome?

Answer 37

bone overgrowth and joint laxity, arachnodactyly, pectus excavatum (outgrowth of ribs force chest inward, concave) or carinatum (force chest outward, convex), scoliosis

Question 38

What are the cardiovascular manifestations of Marfan syndrome? What are the treatments for this?

Answer 38

aortic root enlargement, predisposition for aortic tear and rupture

Treatments include betablockers and blood pressure drugs to prevent hemodynamic stress on the wall

Question 39

What do Marfan patients need to avoid?

Answer 39

Contact sports, activities causing joint injury, caffeine (stimulates cardiovascular system), LASIK

Question 40

How often is Marfan syndrome inherited?

Answer 40

75% inherited, 25% de novo. If the FBN1 mutation is known, parents can be checked.

Question 41

What are the clinical findings of achondroplasia? Include facial and spine features

Answer 41

Disproportionate small stature, with proximal (Rhizomelic) shortening of arms and legs + redundant skin folds on limbs

Kyphosis in infancy, followed by lordosis around walking age

Protruding forehead, flat midface

Question 42

What gene is involved in achondroplasia? What is the normal function of this protein?

Answer 42

FGFR3 - fibroblast growth factor receptor. There is a net excess of inhibitory signalling in chondrocytes due to this DOMINANT NEGATIVE mutation, which does not allow the receptor tyrosine kinase to dimerize

There are only 2 known mutations, so not a good example of allelic heterogeneity

Question 43

What is one potentially serious complication of achondroplasia?

Answer 43

Craniocerivcal junction constriction -> a kink at the spinal cord. Limit contact sports

Question 44

What is the primary genetic etiology of achondroplasia?

Answer 44

Advanced PATERNAL age -> 80% of individuals develop via de novo mutation

20% have at least one affected parent

Question 45

What does homozygous achondroplasia cause?

Answer 45

Very severe disorder causing respiratory insufficiency and early death due to cervicomedullary stenosis ( achondroplasia = incomplete dominant)

Question 46

What is double heterozygosity and why is this likely to happen?

Answer 46

When two individuals of short stature reproduce due to selective mating, they may have two separate dominant conditions which get inherited and have a very poor phenotype.