Autosomal Dominant inheritance Flashcards
In term of the autosomal dominat diseases, the meaning of incomplete dominance refers to:
It means that homozygotes are more affected that heterozygote carries of this disease.
What does the law of segregation states?
Every individual possess a pair of alleles for any particular trait. Each parent passes a randomly selected copy of only one of these to its offspring.
What is penetrance?
It is the probability that a mutant allele or alleles will have any phenotypic expression at all.
–100% - Any person with a mutation in specific gene will show SOME type of symptom
–<100% - Some people can carry a “mutation” in a gene but not show ANY symptoms
–Often expressed as “reduced” penetrance
Symptoms are Present or Not Present
Achondroplasia
This is an autosomal dominant disease
-It is the most common skeletal dysplasia and it has 100% penetrance. It is caused by new mutation 80% of the cases. Thus, parents with no history of achondroplasia can haev kids like this.
What are the clinical manifestations?
- Small stature
-Rhizomelic limbs (shortening of proximal segements of extremeties)
- Short finger
- *Tridents hands
- *Large head and frontal bossing
- Midfacial retrusion
- Craniocervical instability/small foramen magnum
What is the molecular/biochemical defect?
-The is a mutation in the FGFR3 gene that codes for Fibroblast Growth Factor Receptor 3. This results from a missense mutation.
On what chromosome is the FGFR3 gene found?
Chromosome 4 (4p16.3) nucleotide 1138
What is th eeffect of the mutation?
It is a ****gain-of-function mutation, so the activity of the protein increases and interferes ith skeletal development.
It shows a *Paternal Age effect, which means that the older the fatehr the more likely to cause achondroplasia.
Retinoblastoma
Malignant tumor of the retina
RB1 gene on chromosome 13
- Retinoblastoma Associated protein regulates the cell cycle
- 90% penetrance (thus incomplete penetrance can be observed in pedigree.
Neurofibromatosis Type 1
This is an autosomal dominant disorder with incomplete penetrance.
It is caused by a mutation of neurofibromin a tumor supressor gene on chromosome 17. It is a loss-of-function mutation.
What is the criteria to diagnose it? Two of more of the following:
- 6 or more café-au-lait spots
- 2 or more neurofibromas
- 1 plexiform neurofibroma
- Freckling in the axillary or inguinal area
- Optic glioma
- 2 or more ***Lisch Nodules
- Distinctive osseous lesions
- Affected first degree relative
What is locus heterogeneity?
A mutation in more than one locus causing the same clinical condition
Tuberous Sclerosis
Mutations in the TSC1, TSC2 that encode hamartin and tuberin proteins, which regulate cell growth and proliferation.
Mutations affect chromosome 9 and 16.
Loss of function mutations
Exhibits Variable Expressivity
1/3 inherited; 2/3 de novo
Fully penetrant
What are some clinical findings?
Skin
–Hypopigmented Patches
–Angiofibroma
–**Shagreen Patch
–Ungual fibroma
Kidneys
–Renal Cysts
–Renal angiomyolipomas
Lungs
–Lymphangioleiomyomatosis
•Heart
–**Cardiac rhabdomyoma** (in infants)
•Central nervous System
–**Subependymal nodules
–**Subependymal giant cell astrocytomas (SEGAs)
–Other cortical dysplasias
•Seizures
•Neuropsychiatric Disorders
–Cognitive impairment
–Autism
–ADHD
Osteogenesis Imperfecta
What is the genetic defect?
Mutation in COL1A1 that codes for Collagen type 1 alpha ,on chromosome 7 (q21.3).
It shows variable expressivity.
•Reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half.
What are the clinical presentation?
- *Multiple fractures
- Mild short stature
- *Adult onset hearing loss
- *Blue sclera
Marfan Syndrome
What is the genetic defect ?
Mutation on the FBN1 gene, which coes for fibrillin- extracellular matrix protein. There is a severe reduction in microfibrills.
This occurs in which chromosome?
Chromosome 15 (q21.1)
•***Dominant negative activity mutation (meaning the bad protein induces the good protein to behave bad).
What are the clinical manifestation?
This is a Systemic disorder of *connective tissue (Ocular, Skeletal, Cardiovascular).
Signs used for diagnosis if no family history is present?
-Aortic root enlargement is a key sign
+ Plus one of the following
–Ectopia Lentis
–FBN1 mutation
–Systemic score >7
If the patient has a positive family history any of the followign can be used:
–Ectopia Lentis
–Systemic score of >7
–Aortic root enlargement
*** Pectus excavatum and scoliosis is also seen.
What are trinucleotide repeat disorders?
Expansion of a segment of DNA consisting of three or more nucleotides, for example; CAG-CAG-CAG-CAG-CAG-CAG. This is caused by slipped mispairing and shows anticipation
and parental transmission bias (this means tht when trinucleotide expansion can occur in gametogenesis of the male or female).
It show an AD, AR and X-linked transmission
Fragile X Syndrome and Myotonic Dystrophy show a transmission bias from the___________.
Spinocerebellar ataxia shows a transmission bias from the paternal side.
maternal side (mom)
Huntington Disease
Shows an autosomal dominant pattern. There is a mutation in the HTT gene, coding for Huntingtin protein on Chromosome 4 p16.3
-The expansion of glutamine may cause an altered structure or biochemical property of the proteinRepeat: CAG.
•Parent of origin
–Early onset ––> paternal
–Later onset ————–> maternal
What are the clinical manifestation?
- Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances.
- Age of onset 35-44
- Death approximately 15 years after onset
Myotonic Dystrophy Type 1
Mutation on the DMPK gene, that codes for Myotonic dystrophy protein kinase, on chromosome 19.
This kinase plays important role in muscle, heart and brain cells.
Repeat: CTG
Normal–> 5-34
Abnormal–> >50, full mutation with 100% penetrance.
What are the clinical manifestation?
- Adult onset muscular dystrophy
- Progressive muscle wasting and weakness
- Myotonia
- Cataracts
- Cardiac conduction defects
