Autosomal Dominant Inheritance Flashcards
Why are homozygous dominant mutations not often seen?
They are typically more severe or lethal
What is pure dominant vs incomplete dominant?
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
What are the general pedigree characteristics of autosomal dominant mutations?
- Phenotype appears in every generation
- Normal parents do not transmit condition to their offspring
- Males and females are equally likely to be affected
- Male to male transition is seen readily
What are the exceptions to the rule that the phenotype will appear in every generation for an autosomal dominant mutation?
- De novo mutation
- Incomplete penetrance -> parents had the mutation but didn’t express it
- Variable expressivity -> can result in mislabelling a person as unaffected
What are the exceptions where phenotypically normal parents can transmit the condition to their offspring?
- Incomplete penetrance
- Late age of disease onset -> parent not at age of expression yet
- Gonadal mosaicism -> mutation is in reproductive cells, but rest of cells are without mutation
What are the three types of autosomal dominant mutations?
- Loss of function - less gene product made
- Dominant negative alleles - mutant allele does not function properly and inhibits proper function of wild type protein (dimerization or regulation)
- Gain of function - Elevated gene activity or new gene activation. I.e. protooncogene -> oncogene
What is haploinsufficiency?
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
What is allelic heterogeneity vs locus heterogeneity?
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
What is autosomal dominant hypercholesterolemia an example of?
Locus hetereogeneity - includes 3 loci:
- LDLR
- ApoB
- Proprotein Convertase (PCSK9)
What causes familial hypercholesterolemia? How does the homozygous vs heterozygous condition differ?
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
What are the clinical findings in familial hypercholesterolemia (FH)?
- Increased LDL
- Xanthomas - lipid-filled nodules on skin
- Atheromas in arteries
- Arcus cornealis - white or gray ring found at corneal margin due to fat deposits. Pathologic if <45 yrs
- Premature CVD, earlier in men
(40s) than women (50s)
Why is FH variably expressed? What may influence its penetrance?
Due to diet
Has >90% penetrance, though penetrance may be reduced by modifier genes for instance to ApoA2 which may increase HDL levels.
What is the prevalence of FH and the major defect?
1/500, major defect is the low density lipoprotein receptor in liver, leading to increased plasma LDL levels.
What is the treatment for FH and who responds better?
Statins. Better response by people who have ApoB mutations because you reduce the synthesis of this abberant ApoB which cannot be uptaken
What ethnicities are particularly at risk for FH?
Afrikaners in South Africa, French Canadians, Lebanese, and Finns
What is cascade screening?
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)
What are the clinical findings of Autosomal Dominant Polycystic Kidney Disease (ADPKD)?
- Bilateral renal cysts
- Cysts in other organs, i.e. liver
- Berry aneurysms (intracranial aneurysms) i.e. on Circle of Willis
- Vascular abnormalities i.e dissection of aorta or dilation of aortic root
- Renale hypertension, pain, and renal insufficiency in end stage renal disease
How is the diagnosis for ADPKD primarily made?
Via renal ultrasound
What gene loci are implicated in ADPKD and what is this an example of?
Locus heterogeneity - loss of function mutations
PKD1 (85%)
PKD2 (15%)
What are the functions of polycystin-1 and polycystin-2?
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
How does the site of the PKD1 mutation influence the vascular pathology?
Further towards the 5’ end = more truncated protein = greater vascular involvement
What is the onset of the disease for ADPKD? What’s the treatment?
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.
How is ADPKD most often passed?
95% inherited, but there is some gonadal mosacism possible.
5% are de novo mutations
What are the common clinical findings of NF-1?
- Multiple cafe-au-lait spots
- Axillary and inguinal freckling
- Multiple cutaneous neurofibromas - tumors at end of nerves
- Lisch nodules in iris
- Learning disabilities
What are some uncommon clinical findings in NF-1?
Plexiform neurofibromas, tibial dysplasia, scoliosis
What is pleiotropy?
When a single gene causes two or more apparently unrelated effects, i.e. in Marfan syndrome
Why does NF-1 have variable expressivity? What type of mutation is this?
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.
What is the function of the gene which causes NF-1?
Produces neurofibromin, a gene involved in turning off Ras by exchanging GTP for GDP. There are many possible mutations (allelic heterogeneity)
What surveillance is involved for NF-1?
Annual exams to watch for development of complications
What percentage of NF-1 patients have de novo mutation? Has gonadal mosaicism been observed?
50%
yes, gonadal mosaicism has been observed
What causes segmental NF-1? When will this person be at risk of transmitting it to offspring
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
What is Marfan syndrome caused by?
Caused by FBN1 mutation - Fibrillin-1. It has >1000 possible mutations (allelic heterogeneity)
Connective tissue abnormality affecting multiple systems -> pleiotropy.
What’s the penetrance of Marfan syndrome?
100% penetrance, but variable expressivity
What type of dominant mutation is Marfan syndrome?
Dominant negative - fibrillin-1 mutants will interfere with normal
Why are clinical features crucial for making the diagnosis of Marfan syndrome?
There are individuals with an FBN1 mutation who do not have Marfan syndrome
What are the ocular manifestations of Marfan syndrome?
myopia, ectopic lentis (lens dislocation), retinal detachment
What are the skeletal manifestations of Marfan syndrome?
bone overgrowth and joint laxity, arachnodactyly, pectus excavatum (outgrowth of ribs force chest inward, concave) or carinatum (force chest outward, convex), scoliosis
What are the cardiovascular manifestations of Marfan syndrome? What are the treatments for this?
aortic root enlargement, predisposition for aortic tear and rupture
Treatments include betablockers and blood pressure drugs to prevent hemodynamic stress on the wall
What do Marfan patients need to avoid?
Contact sports, activities causing joint injury, caffeine (stimulates cardiovascular system), LASIK
How often is Marfan syndrome inherited?
75% inherited, 25% de novo. If the FBN1 mutation is known, parents can be checked.
What are the clinical findings of achondroplasia? Include facial and spine features
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
What gene is involved in achondroplasia? What is the normal function of this protein?
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
What is one potentially serious complication of achondroplasia?
Craniocerivcal junction constriction -> a kink at the spinal cord. Limit contact sports
What is the primary genetic etiology of achondroplasia?
Advanced PATERNAL age -> 80% of individuals develop via de novo mutation
20% have at least one affected parent
What does homozygous achondroplasia cause?
Very severe disorder causing respiratory insufficiency and early death due to cervicomedullary stenosis ( achondroplasia = incomplete dominant)
What is double heterozygosity and why is this likely to happen?
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.
