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72 Cards in this Set

  • Front
  • Back

Mutation at 17q11.2

NF-1

Mutation in a tumor suppresor that down-regulates Ras in the MAP Kinase pathway

Neurofibromin 1, NF-1



Mutation on Merline gene, at 22q12

NF-2

Mutation on gene that codres for a tumor suppressor protein in Schwann cells

NF-2

Mutation at 15q21.1

FBN-1 gene


Marfan's



Mutation in fibrillin gene

FBN-1


Marfan

Gender effect on threshold example

Pyloric stenosis - Males more commonly affected

Cleft lip/palate, congenital heart defects

examples of congenital malformations

Open neural tube defects (ONTDs)

Congenital malformations example

Spina bifida and anencephaly

Multifactoral condition - congenital malformation


Env (folic acid) + genetic risk

Coronary artery disease

adult onset multifactorial disease example

Thrombosis

adult onset multifactoral disease example

Mutation in this gene increases levels of homocysteine (correlated with risk factor for cardiovascular disease)

MTHFR

Prothrombin 20210A mutation


Factor V Leiden

Increases risk for VTE (venous thromboembolism)



Protein S, C, or antithrombin III deficiency

Genetics factors for thrombosis

Surgery/trauma


Cancer


Chronic conditions (diabetes, obesity, hypertension, high cholesterol)


Smoking


Prolonged inactivity


Hormone: pregnancy, oral contraceptives, estrogen therapy

Environmental factors for thrombosis

BRCA1


BRCA2


p53 gene mutations

Breast cancer genetic risk factors

Nulliparity


Early age of menses


Late age of menopause

Breast cancer environmental risk factors

Mutations in APC, MYH, and DNA repair genes

Colorectal cancer genetic risk factors

Low fiber diet and lack of exercise

Colorectal cancer environmental risk factrs

HLA class II alleles (DR3 and DR4)

Type I diabetes (IDDM)

Some families affected by rare, AD genes, most families exhibit multifactoral inheritance patterns

Type II diabetes (NIDDM)

Schizophrenia (H=70%) and bipolar affective disorder (H=94%)

Heritable psychiatric disorders that are multifactorial

Have the largest impact on specific families (rarer)

Mendelian disorders

Have the largest impact on population as a whole (more common)

multifactorial disorders

Mutation on FMRI gene on Xq27.3

Fragile X Syndrome



Fragile X (FRAXA)


Myotonic dystrophy (MD)


Friedreich ataxia (FRDA)


Fragile X "E" MR (FRAXE)


SCA8, SCA12

Examples of trinucleotide repeat in non-coding regions (introns, promoters, etc.)

Most common form of inherited cognitive impairment

Fragile X syndrome (FMR1 gene - Xq27.3)

Macrocephaly


Large ear


Marco-orchidism


Echolalia


Perseverative speech


Gaze avoidance


2-6% diagnosed with autism

Fragile X Syndrome (FMR1 gene - Xq27.3)

Clinical description of genetic anticipation

Sherman paradox - Fragile X


Increased especially when passed through a female

CGG repeat triplet sequence normally present in the promoter (5' end) of FMR1 gene

Fragile X

>200 repeats of CGG

Result in methylation of promoter and inability to express the FMR1 mRNA/protein


Fragile X

Premutation

Expansion of repeat, but not significant enough to cause phenotype


Also unstable - may expand to full mutation in next gen.

Normal: 0-44


Intermediate: 44-55


Premutation: 55-200


Mutation: >200 CCG repeates

Fragile X syndrome




Stable when passed through males


Unstable and may expand when passed from females

POI/POF, fragile X-associated tremor ataxia (FXTAS)

Due to excess mRNA


Premutation: 55-200 CCG repeats


Fragile X

CTG expansion in the 3'UTR of the DMPK gene

Myotonic Dystrophy (MD)




DMPK gene codes for myotonin protein kinase



35-49 CRG repeaset

MD premutation, no clinical signs

Can expand after maternal transmission, contract after paternal

CTG premutation (MD)

Cataracts, mild myotonia

Mild MD


50 - 150 CCG repeats


Age of onset: 20-70

Weakness, myotonia, cataracts, balding, cardiac arrhythmia, others

Classic MD


100-1000 CCG repeats


Age of onset: 10-30

Infantile hypotonia


respiratory deficits


cognitive impairment

Congenital MD


>2000 CCG repeats


Birth-10

GAA triplet repeat expansion in intron of Frataxin gene (>200)

Friedrich's ataxia (FRDA)




AR disease that causes progressive neurological deterioration

Low expression of frataxin results in mitochondrial dysfunction due to iron accumulation

FRDA

Cerebellar involvement (ataxia, dysarthria, titubation, scoliosis, pes cavus)


Hearing loss, cardiac, endocrine

FRDA

CAG polyglutamine disease

Trinucleotide repeat in coding region


Huntington disease

Full penetrance: 40 + CAG repeats

Huntington's disease

The telomeres get shorter than the general population and correlate with increased risk of ______ cancer at earlier age

BRCA1/BRCA2


breast

Mouse - both maternal pronuclei

embryo develops


placenta is poor

Mouse - both paternal pronuclei

placental develops


embryo is poor

All chromosomes are derived from a single parents

Uniparental diploidy

Human - both maternal pronuclei in the same germ cells

ovarian teratomas or dermoid tumors

Human - both paternal pronuclei are only (or primarily) paternal in origin

Complete mole (46) with ONLY paternal chromosomes - risk of malignancy




Partial mole (triploid, 69) fetal parts can be seen, no malignancy

-neonatal hypotonia


-poor feeding , failure to thrive up to age 2


-short stature, small hands and feet, micro-penis, hypogonadism


-various degrees of cognitive disability


-microcephaly


-obesity


-sometimes albinism


-lack of ability to regurgitate-great with puzzles

Prader-Willi

progressive microcephaly, - severe cognitive delay, lack of speech onset- gait ataxia, at one time referred to as the “happy puppet” syndrome- abnormal EEG , seizures can occur usually by age 3- sometimes also have albinism

Angelman Syndrome

Non functional paternal alleles at 15q11

Prader-willi

Non functional paternal alleles at 15q11

Angelman

Gene mutations in the maternally derived allele of UBE3A

Angelman

Paternal uniparental disomy at 11p15

Results in over-expression of the insulin like growth factor 2 (IGF2)




Beckwith-Weidemann Syndrome

High risk for embryonal tumors (such as Wilm's tumor and/or heptoblastoma)




Neonatal hypoglycedmia


Macrosomia


posterior helical ear pit and creases


abdominal wall defects (omphalocele, diastasis recti, or umblicial hernia)

Beckwith-Weidemann

Intrauterine growth retardation (IUGR), post natal short stature, hemi-hypotrophy, broad forehead with normal head circumfrance, narrow chin, 5th finger clinodactyly

Russell Silver Syndrome (RSS)

Maternal uniparent disomy for chromosome 7

Russell Silver Syndrome

Hypomethylation of paternal chromsome 11p15.5

decreased expression of IGF2 gene




Russell Silver Syndrome

Multiple endocrine neoplasia (MEN2)


Pheochromocytomas


Parathyroid adenoma/hyperplasia


Mucosal neuromas of lips, tongue


Marfanoid habitus

RET proto-oncogene

The Philadelphia chromosome translocation involving 9 and 22 - with breakpoints in the proto-oncogene ABL (9) and BCR (22) genes

Results in a fused gene that changes function of ABL gene




CML and ALL

Hereditary retinoblastoma

Hereditary cancer - 90 risk to heterozygotes

Breast, ovarian, male breast, pancreatic, prostate




Caretaker genes: involved in DNA repair, response to double stranded DNA breaks

Hereditary breast and ovarian cancer syndrome




BRCA1 AND BRCA2

Colorectal, small bowel, stomach, pancreas, thyroid, CNS, liver




100-1000s of adenomas lining the colon and rectum

Familial adenomatous polyposis (FAP)

CHRPE spots


Desmoid tumors


Osteomas


Epidermoid cysts or fibromas

FAP

Colonoscopy/sigmoidoscopy every 1-2 years starting




AD inheritance




APC gene (tumor suppressor)

FAP

Colon, endometrium, stomach, ovary, other (hepatobiliary tract, urinary tract, small bowel, brain/central nervous system)




50% risk of second cancer within 15 years

Lynch syndrome


(HNPCC)

Mismatch repair genes (caretakers): MLH1, MSH2, PMS2, MSH6




MMR GENE





Lynch


MEN2A and MEN2B


RET

Heritable proto-oncogenes