Autosomal Dominant, FGFR3 gene, prone to germline mosaicism (gonadal mutation)
Autosomal Dominant, 90% Penetrance
Autosomal Dominant, variable expression, triplet repeat expansion disorder, worse as more expanded (Anticipation). CTG repeats.
Autosomal Dominant, variable expression, pleiotropy as well
Autosomal Dominant, variable expression, (prone to gonadal mosaicism)
Neurofibromatosis Type 1
Autosomal Dominant, mutation in tumor suppressor gene Neurofibromin, small, soft, benign skin growths. 100% penetrance. Some cases of epilepsy and CNS tumors. 50% caused by new mutations.
Acute Intermittent Porphyria
Autosomal Dominant, Pleiotropy, causing several different problems.
Autosomal Recessive, incomplete penetrance, delayed onset
Autosomal Recessive, Arab, Medeitteranean, Asian more common. (Plasmodium Falciparum Resistance) a-Thalassemia Can be splice site mutations. A) loss of splice site, intron added to protein. B) NEW splice site, part of exon lost from protein. Both non-functional.
Bloom Syndrome (Congenital Telangiectasia)
Autosomal Recessive, Due to BLM Helicase gene mutation, due to lots of recombination. Growth deficiency, pigmentation, photosensitivity, erythema (skin telanglectasia), cancer suceptible.
Ataxia Telegiectaxia (ATM)
Autosomal Recessive. ATM initiates repair due to DS breaks. Related to ATR, which repsonds to Hypoxia, UV damage, replication damage. Causes increase in cancer susceptibility, due to lack of repair. Lympomas, tumors, sensitive to radiation.
Fragile X Syndrome
X-linked Dominant, Anticipation (repeat expansion in the mother). CGG repeat causes Methylation of the FMR-1 Gene
X-linked Recessive, FVIII gene, lyonization
X-linked Dominant, so all sons have it and only mothers pass it. Females will get it
Vitamin D resistent Ricketts
Heterogenetity, Autosomal Recessivity. Need Both genes, ROM1 and Peripherin degenerate rods to get this.
Down Syndrome (47, XX, +21)
Wide, slanting forehead (brachycephaly), single simeon crease on hands (Clinodactyly), GI abnormalities, Mental Retardation, Brushfield spots on iris, adult cataracts. Trisomy 21, Nondisjunction in Meiosis I or II, OR Robertsonian Reciprocal Translocation, two satellite chromoesomes join together. Translocation can end up with 3 copies of chromosome 21. (47, XX, +21)
Patau Syndrome (47, XX, +13)
Trisomy 13. Cleft Lip, polydactyly, Microthalmia, mental retardation, lethal heart defects, fatal. Can detect Polydactytly on Ultrasound.
Edward's Syndrome (47, XX, +18)
Trisomy 18. Rockerbottom Feet, Clinched hands, Congenital heart defects, Fatal. Can see Rockerbottom feet on ultrasound, clinched hands, also Exomphalos.
Familial Breast/ovarian cancer
Mutations in BRCA1 and BRCA2 cause breast cancer susception, causing faulty HRR. Has delayed onset
Can be a Promoter mutation, increaing the amyloid precursor protein synthesis. Causes plaques. Dementia, B-amyloid protein mis folding and aggregation due to insolubility. Familial and Sporadic. Familial is < 10%. ALL are early onset <65years. Dominant inheritance. Sporadic, associates with APOE4 Gene on Chr. 19, 25% population is heterozygoing for mutant gene (4X increased risk, 10X in homozygous (2% pop)). Aluminum exposure supposed increase in likelyhood.
clotting factor 9 mutation, promoter mutation, severe deficiency in IX until pubery, when androgens upregulate the synthesis.
Mixed mitochondrial genes, some mutant, some normal. Explains variability in mitochondrial diseases.
Either both normal, or both mutated genes.
Single genes are altered
Whole chromosomes are altered, added or deleted
Whole genome altered, (ex. 3 copies of every chromosome).
Non-Molar placenta. Two sets of maternal chromosomes. ("Di-gina, two ginas.")
Molar. Two sets of Paternal chromosomes. ("Di-andy, two Andy's")
Nondysjunction in Meiosis I, causing germline mosaicism. Causes 2 haploid cells with no copies, and 2 with 2 copies of the chromosome.
Nondysjunction in Meiosis II, causing germline mosaicism. Causes 1 empty haploid cell and one with 2 copies of a chromosome, + 2 normal ones.
Robersonian translocation that results in BALANCED chromosomes, nonviable. Will result in Normal or Downsyndrome in the case of 14/21 R.trans.
Robersonian translocation that results in UNBALANCED chromosomes, nonviable
detects 5Mb mutations
Detects 1.5Mb mutations, understand which mutations will be visible on the karyotype, and which need FISH. Needed for Williams Syndrome, Prader Willi, Angelman, Velocardiofacial Syndrome/Di George's
Amnoitic Fluid aspirated guided by Ultrasound, screened for a-fetoprotein. Can increase miscarraige by 1%
Chorionic Villus Sampling
Remove fetal cells by aspiration from inner surface of placenta, increases possibility of misscarraige. Can be done at 11-12 weeks, sooner than amniocen.
short tandem repeats
Very good marker for DNA fingerprinting using PCR, sequencing, restriction enzymes, Southern Blot Probing. Very variable between individuals, used for forensic fingerprinting. IMPORTANT: Can prove NOT the father with one loci better than is the father. Must use multiple loci to do this.
Deletions, Inversion, dupilications. Most associated with human variability.
The incorporation of a wrong base
Oxidative Damage to DNA
Causes transversion, tautaumerism, damaged G's pair with A's, instead of C.
Single Base Excision Repair
ROS, Alkylation, Deamination, Abasic (depurination/pyrimidization), or single strand breaks due to energy. DNA glycosylates remove the wrong base. Example would be MYH Polyposis.
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Autosomal Dominant. Mutation in gene's for MLH1 on Chromosome 3, or MSH2 on Chromosome 2. (90%). Genetic Predisposition for cancer. Screen with colonscopy starting at age 25. Look for Microsatellite expansions, which will accumulate in those with this mutation. Mutation in MMR (mismatch repair)
Resolves Holiday junctions in Double strand Break, non-homologous end joining repair. (DSB, NHEJ). Also inhibits crossing of of sister chromatids.
Bloom Syndrome (Congenital Telangiectasia)
Autosomal Recessive, DNA Ligase mutation. Due to BLM Helicase gene mutation, due to lots of recombination. Growth deficiency, pigmentation, photosensitivity, erythema (skin telanglectasia), cancer suceptible.
HRR (Homologous Recombination Repair)
BRCA1promotes HR, and BRCA2 stimulates it. BLM helicase resolves the holiday junctions between adjacent chromatids. DNA pol fills in gaps. Uses
Ataxia Telegiectaxia (ATM)
Autosomal Recessive. Mutation in Topoisomerase ATM initiates repair due to DS breaks. Related to ATR, which repsonds to Hypoxia, UV damage, replication damage. Causes increase in cancer susceptibility, due to lack of repair. Lympomas, tumors, sensitive to radiation.
MMR (Mismatch Repair)
HNPCC (colon cancer, MLH1 or MSH2 genes)
NHEJ, HRR (non-homologous end joining, homologous recombination repair)
corrects double strand breaks, like Breast Cancer (BRCA1/2), or Bloom Syndrome (BLM)
BER (Base excision repair)
MYH Polyposis (colon cancer)
NER (Nucleotide excision repair)
Xeroderma Pigmentosum (XPA in japanese, XPC in USA).
Familiar Hypercholesterolemia, one mutation in LDL receptor, other gene cannot make up for it.
Osteogenesis Imperfecta, collagen 1A1 or 1A2, affects dimer/multimer protein, or protein interferes with normal proteins
Gain of function
Huntington's disease, overexpression of CNS proteins, neurological degeneration, usually dominant mutations.
insertion or deletion of bases, that arent multiples of 3. Tay Sach's disease caused by insertion of 4 bases.
ASO (Allele specific oligonucleotide Probes)
Used for point mutations or short aberations
Used for larger aberations. Fragile X is tested with this. You CAN test for CF (3 base deletion). Triplet repeats, like Fragile X and Huntington's needs this.
NEVER use FISH for CF. Used for chromosomal changes and large insertions, deletions.
molar. Two sets of Paternal chromosomes. ("Di-andy, two Andy's")
a mutated proto-oncogene, V-onc is a viral oncogene, causing host cell to become cancerous, and C-onc, a cellular mutation, causing cancer. INCREASE in function genes. DOMINANT mutations.
Translocation of ABL oncogene from Ch. 9 to Chr. 22. Causes a fusion of BRC and ABL proteins, which is permanenely active, overexpressive. Inhibits DNA repair and increases cell cycle.
Translocation of c-MYC gene from Chr.8 to Chr. 14. (90% of cases). Codes for Enhancer boxes, and recruiting histone acetyltransferases. (HAT's and E-boxes). MYC genes related to Cancer, as well as Growth Factors.
Familial Adenomatous Polyposis (FAP)
APC gene on Chr. 5, tumor suppressor gene. Inherited Recessive. Requires a second hit mutation/deletion to cause the cancer.
Genes at multiple loci, polygenic diseases. Cleft Lip, Diabetes, Autism, Schitzophrenia, Neural tube defects, depression, hypertension, cardiac defects.
Liability Curves for Mutifactorial Disorder
Way of explaining inheritance. Multiple factors, graph has a Threshold. The more factors contributing to possible inheritance (people affected, closeness, environmental, etc), the graph is shifted to the right towards the threshold. Above the threshold, the disease is seen in the dividual. Can be faulty, is predicative, not Absolute.
share 1/2 of genes
Grandparents, half siblings, cousins
share 1/4 of genes
1st cousins, Third degree family
share 1/8 of genes
Heritability = (Variance in DZ - Variance in MZ) / Variance in DZ . The proportion of variayion caused by genetic, rather than environmental factors. For a completeley genetic disorder. Should be variance - 1/variance. So, proportion of
Relative Risk (RR)
measures relative risk of getting a disease. The frequency that the individual may contract the disease if the individual has a particular marker for it. Taking in account environment, can predict increase in Risk for particular persons. Percentage of those with a predisposition (allele w/risk /total) : to those without the predisposition (alleles/total). Example was smoker/cancer : non-smoker/cancer = 5.8X more likely.
Odds Ratio (OR)
compares relative odds of occurance. Tells you how much more likely you are of having a disease if you have the allele, vs not having it. Disease w/allele / no disease : disease w/o allele / no disease.
Idiopathic Chronic Pancreatitis
10-40% have 2 mutations in the CFTR gene, but don't have Cystic Fibrosis, however These are modifier genes, since those with CF get a much more severe case because of this.
Triple Test (a-FP, un-estroil down, Gonadotropin UP
chorionic villus sampling