Cystic Fibrosis
CFTR, autosomal recessive
1 in 2000 - 2500 white children
progressive pulmonary disease, exocrine pancratic insufficiency, obstructie azoospermia, elevated sweat chloride concentration, growth failure, meconium ileus
Neurofibromatosis
NF1, autosomal dominant
penetrance: 100% in adults; <50% in children
cafe au lait spots, neurofibromas; Lisch nodules (hamartomas) in the iris; mental retardation
Turner syndrome
45, X
short stature, swelling, broad chest, webbed neck, low hairline, low-set ears
cognitive deficits: visuospatial, mathematical & memory
typically sterile, amenorrhea (non-working ovaries)
Edwards syndrome
Trisomy 18
Intrauterine growth retardation
Hypertonicity - clenched hands, narrow hips
CNS abnormalities - posterior fossa anomalities, severe intellectual disabilities, seizures
Congenital heart disease
Patau syndrome
Trisomy 13
Normal or deficient growth
CNS abnormalities - holoprosencephaly, severe intellectual disabilities
Facial clefts, polydactyly, renal dysplasia, congenital heart disease, omphalocele, dermal defects
Klinefelter syndrome
47 XXY
Tall, hypogonadism, underdeveloped secondary sexual char., gynecomastia, usually in fertile, language impairment
1/1000 live births
50% of cases = patetnal meiosis I failure of recombination in pseudoautosomal regions
15% of cases = mosaicism (46, XY / 47, XXY)
47 XYY syndrome
Indistinguishable physically / mentally from normal males
1/1000 live births
inc. risk of behavioral & educational problems; delayed speech / language
Charcot-Marie-Tooth Disease
Duplication of 17p11.2 which contains the gene for peripheral myelin protein-22 (PMP-22)
weakness of the foot and lower leg muscles
foot deformities (hammer toes)
weakness & muscle atrophy of the hands (late in the disease course)
all forms of the disease affect peripreal nerves.
*of note, due to dosage differences, deletion in the same region of chr 17p leads to a different peripheral myelin disease HNLPP (p. 97)
List the various mechanisms that lead to Down Syndrome.
- Meiosis I nondisjunction
- Robertsonian Translocation
- Isochromosome
- Mosaic Down Syndrome
- Partial trisomy 21
Velo-Cardio-Facial syndrome
del(22q11.2)
cleft palate, lateral nasal buildup, cardiac septal defects
“Contiguous Gene Syndrome”
DiGeorge syndrome
del(22q11.2)
absent or hypoplastic thymus (T-cell abnormalities = a lot of infections) & parathyroids, congenital heart disease (outflow tract)
List at least 4 contiguous gene syndromes (as discussed in class)
DiGeorge syndrome
Prader-Willi syndrome
Velo-Cardio-Facial syndrome
Angleman syndrome
Chronic Myelogenous Leukemia
genotype…
46, XX t(9;22)(q34;q11.2) (95% of patients)
Reciprocal Translocation between chromosomes 9 and 22.
Philadelphia chromosome: BCR gene from chrom. 22 and the ABL gene from chrom. 9 fuse. BCR-ABL fusion gene is a tyrosine kinase.
Chronic Myelogenous Leukemia
pathophys…
Cancer of the white blood cells
unregulated growth of myeloid cells in the bone marrow
accumulation of these cells in the blood
treated with tyrosine kinase inhibitors (imatinib, gleevec)
For DiGeorge syndrome remember CATCH-22
Cardiac abnormality Abnormal facies Thymic aplasia Cleft palate Hypocalcemia/Hypoparathyroidism Chromosome 22 del(22q11)
Beckwith-Wiedmann syndrome
Uniparental Disomy for a portion of chr 11
large at birth, enlarged tongue, protrusion of the umbilicus
severe hypoglycemia, malignant neoplasms of kidney, adrenal and liver
see p. 79; also a focus of “ghost in your genes” video recommended by Dr. Johnson
Huntington Disease - genetics
HD allele - expansion of a polyglutamine encoding repeat (CAG) in exon 1 of the HD gene
normal allele has 10-26 CAG repeats
mutant allele has >36 CAG repeats
Age at disease onset inversely proportional to # CAG repeats in HD gene
Reduced penetrance for 36-41 CAG repeats in HD gene
80% juvenile pts inherit from father
Mean age of onset is 35-44 years
Median survival after diagnosis is 15-18 years
Huntington Disease - clinical presentation
Progressive motor, cognitive and psychiatric abnormaities
Motor: voluntary and involuntary movement disturbances; Chorea
Cognitive: language (later onset), behavioral social disinhibition, aggression, outbursts, apathy, sexual deviation, increased appetite
Psychiatric: personality changes, affective psychosis, schizophrenia
Ellis-van Creveld syndrome
Autosomal recessive
Ex. of the Founder Effect in Old Order Amish populations
short-limbed dwarfism, polydactyly, abnormal nails & teeth, heart defects
Type I Tyrosinemia
Autosomal recessive
Ex. of Founder Effect in French-Canadian region: Lac Saint Jean in Quebec
Hepatic failure, renal tubular dysfunction - deficiency in fumarylacetoacetase (enzyme in the degradation pathway of Tyrosine)
1/685 in Lac Saint Jean region of Quebec
1/100,000 in other parts of Quebec, Sweden and Norway
Osteogenesis Imperfecta genetics…
Type-1 collagen deficiency (most common)
8 types in all from different genetic mutations
Most common mutations in COL1A1 or COL1A2 autosomal dominant; 60-100% de novo mutations
(some autosomal recessive versions exist)
1/20,000 live births
Sickle Cell Anemia genetics…
SNP of Beta-globin gene Glu6Val
Beta-globin gene is located at 11q15.4
Confers Heterozygous Advantage against malaria
Common in regions with more malaria
*(E6V glutamic acid at position 6 changed to valine; GAG -> GTG; A to T mutation
MODY-3
HNF1-alpha mutation
Mature Onset Diabetes of the Young - 3 most common (70%) of all MODY's HNF1-alpha is a homeobox trxn factor (important for differentiaton of beta cells) Different mutations within the HNF1-alpha gene lead to variable expressivity of onset age is a considered a type 2 diabetes but insulin dependence eventually develops late (after many years with disease, beta cells deteriorate)
treat with sulfonylureas
Duchene Muscular Dystrophy
X-linked recessive Gower maneuver giant calves muscle wasting, extra connective tissue progressive loss of respiratory function (diaphragm)
Becker muscular dystrophy
less severe - point (in frame mutation)
same gene location (Xp) as duchenne m.d.
Achondroplasia
autosomal dominant
chr. 4, fibroblast growth factor receptor
FGFRc - inhibits proliferation of chondrocytes
mutation leads to shortening of the long bones –> short stature
1 in 25,000
