Medical Genetics 2

Front 1

Hemizygous

Back 1

Having half the number of alleles. E.g. males are hemizygous for all X chromosome genes.

Front 2

Expressivity vs penetrance

Back 2

Expressivity: condition is always expressed, but can vary from mild to severe. E.g. neurofibromatosis.

Penetrance: fraction of people who have any (versus no) symptoms. A condition can have reduced, complete, or delayed penetrance.

Front 3

Allelic heterogeneity vs. locus heterogeneity.

Back 3

Allelic heterogeneity: different mutations in the same gene can cause the same clinical syndrome. E.g. cystic fibrosis.

Locus heterogeneity: mutations in differnet genes can cause the same clinical syndrome. E.g. Different forms of deafness.

Front 4

Proband

Back 4

The first AFFECTED person to seek medical help, not necessarily the first person to present with the disease. In a pedigree, a proband is marked with an arrow.

Front 5

Phenotypically normal parents do not transmit autosomal dominant diseases to their offspring. What are the three exceptions?

Back 5

Gonadal mosaicism.
Incomplete penetrance.
Late age of onset (delayed penetrance).

Front 6

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Clinical findings, Dx.

Back 6

Clinical findings: bilateral renal cysts, cysts in other organs such as liver, seminal vesicles, pancreas, and arachnoid mater, intracranial aneurisms, dissection of thoracic aorta.
Renal manifestation include hypertension, renal pain, renal inefficiency.

Dx made by renal ultrasound.

Front 7

Autosomal Dominant Polycystic Kidney Disease

Gene and gene product

Back 7

Gene: two genes have been identified (locus heterogeneity): PKD1 (more common) and PKD2.

Gene product: Polycystin-1 and 2. These interact and are localized to primary cilia (PKD is a ciliopathy). Polycystin in strongly expressed in myocytes of arteries, and cardiac myocytes (reason for vascular complications).

Front 8

Autosomal Dominant Polycystic Kidney Disease

Management and Tx.

Back 8

HTN: ACE inhibitors or angiotensin II blockers and diet modification. Surgical clipping of aneurysms.

Avoidance: long-term NSAID use, caffeine (promote cyst growth), estogen, and smoking.

Front 9

Neurofibromatosis Type 1 (NF1)

Expressivity. Clinical findings.

Back 9

Variable expressivity. 50% of individuals have de novo mutation.

Sx: multiple café au lait spots, axillary and inguinal freckkling, cutaneous neurofibromas, iris Lisch nodules, learning disabilities.
Less common but more serious manifestations include plexiform neurofibromas, optic gliomas, scoliosis, and vasculopathy.

Front 10

Neurofibromatosis.

Gene and gene product. Medical management and Tx

Back 10

Gene: NF1 gene.
Gene product: neurofibromin protein. Function not fully understood, but may act as a tumor suppresor.

Medical management and Tx: symptomatic tx, and refer to specialists for each specific problem.
Surveillance: annual physical exam.

Front 11

Huntington Disease (HD)

Clinical finding.

Back 11

Clinical finding: adult onset result in motor, cognitive, and psychiatric disorders. Involantary movements called chorea in 90% of individuals.
Juvenile HD: onset before 20yo.

Front 12

Huntington Disease (HD)

Gene and gene product. What is considered normal allele? Describe penetrance.

Back 12

Gene: HTT on chromosome 4. Results from trinucleotide CAG repeats, and alleles are characterized by the size of CAG repeats.

Normal allele: <26 CAG repeats.
Intermediate alleles: 27-35 CAG repeats.
HD-causing allele: >36 CAG repeats. More than 40 repeats in full-penetrance. Less than 40 is reduced penetrance.

Gene product: uninterrupted stretch of glutamine residues. This gets cut into toxic fragments and accumulates in neurons.

Front 13

Huntington Disease (HD)

Medical management and Tx. What to avoid?

Back 13

Symptomatic tx.

Avoidance: L-dopa increases chorea (However, L-dopa is used to treat Parkingson's. So make sure you have the correct Dx!). ETOH and smoking are discouraged.

Front 14

Marfan synrome

Clinical findings. Dx. Prognosis.

Back 14

Variable expressivity, but 100% penetrance.
Clinical findings: CT abnormality, myopia, ectopic lentis, retinal detachment, bone ovegrowth and join laxity, extremities too long for hte size of the trunk, pectus excavatum, scoliosis, aortic root enlargement.

Dx: in the absence of family Hx, can use different combinations of sx as dx criteria.

Prognosis: normal life expectancy if managed properly.

Front 15

Marfan syndrome

Gene and gene product. Management and Tx.

Back 15

Gene: FBN1, and several other genes (locus heterogeneity).
Gene product: fibrillin-1.

Management and Tx: symptomatic tx. Avoidance: contact sports, activities causing join injury, decongestant and caffeine, LASIK surgery.

Front 16

Achondroplasia

Clinical finding. Gene and gene product.

Back 16

Small stature, rhizomelic (proximal) shortening of extremities, genu varum (bow legs), kyphosis in infancy, exaggerated lumbar lordosis.

Gene: FGFR3.
Protein: fibroblast growth factor receptor 3. Exact mechanism is unknown.

Front 17

Achondroplasia

Medical management. Genetic counseling.

Back 17

Avoid contact sports due to craniocervical junction constriction. GH administration has little effect. Bone lengthening surgery is an available conbtroversial option.

Genetic counseling: 80% is a result of de novo mutation, which is associated with advanced paternal age. Homozygous achondroplasia is lethal from respiratory insufficiency.