* threadlike strx in cell of nucleus that contains genetic material

* Each consists of dsDNA coiled in helix attached to histone

*2 arms of each chromosome attach to centromere (p=short arm; q=long arm)

*hereditary unit; sequence of chromosomal DNA req for production of fxnl protein

*sequence of nucleotides and appears as paired alleles in humans

extra pices of DNA that do not appear in mRNA that the gene encodes and do not become part of the protein

"non-coding DNA"

results in genetic variation by shuffling of maternal and paternal chromosomes and crossing over

*no daughter cell formed during meiosis is identical to mom or dad

Genetic variations that change the function of a gene

* may have a cuase, be random or inherited

Not all mutations are expressed

Possible chromosome abnormality

3+ miscarriages

Other family members affected

High risk ethnic group

Insest relationship

Requires 2 afected homologous genes for disease to occur.

Individuals w/ 1 normal and 1 mutated are CARRIERs

Requires only one affected gene for disease to occur

AD homozygotes are usually lethal

occurence of 2+ cell lines w/ different genetic or chromosomal constitutions.

mutations of confined portion of germ cell

mutation can be transmitted to offsprin

Normal and abnormal cell lines w/in cells of body

Mutations can not be transmitted to offspring unless present in germline.

gene alteration present for the first time in one family member

Common in: AD and x-linked disorders as well as advanced maternal age

*Xlinked recessive

*mutations in Xp2.2 dystrophin gene.  Dystrophin is absent or partially functioning

*progressive myopthay, gowers maneuver, inability to walk

affected gene is on x-chromsome

Male is affected, female w/ 1 recessive is carrier and with 2 is affected

diseased gene is on x chromosome

homozygous male and female is usually lethal

1 copy of gene

ex: x & y in males or unbalanced chromsomes

technique using enzymatic procedure to synthesize DNA chains of varying length in four different reactions

*finds a mutation anywhere along given gene

"last decade" sequencing

Used for gene by gene mutations

mapping gene by hybridization of cloned DNA sequence labeled by radioactive fluorescence. 

used in microdeletions (William syndrome, 22q11.2), micro translocations(wolf hirschhorn) and tumor studies

Not diagnostic-gives individualized risk estimate

1st tri-trisomy 21 & 18

2nd tri-trisomy 21, 18 & neural tube defects

Combined screen-trisomy 21, 18 & neural tube defect

9-13wks+6days

nuchal translucency - 1st trimester

level II ultrasound - 2nd trimester

15-22 weeks gestations

use quad over triple when available

Alpha-fetoprotein (AFP)

unconjugated estriol (uE3)

Beta-human chorionic gonadotropin (b-HCG)

dimeric inhibin-A (DIA) - quad only

Most common autosomal chromosomal syndrome

only autosomal trisomy compatible w/ adult life

not hereditary ?95% of time

almost always trisomy 21

47, XXY

gynecomastia

Monosomy X

70% due to error in paternal gametogenesis

Most common chromosomal cause of spontaneous abortion

X-linked disorder

most common cause of mental impairment

diagnosis made by DNA blood test

3 DNA bases: CAG CTG CGG repeated in varyin lengths.

Increased length of repeats linked to Fragile X, Huntingtons, Myotonic dystrophy and Friedrichs Ataxia

Non-traditional pattern of inheritance

FMR-1 gene

carriers CGG repeats 50-200x

Affected CGG repeats 200-1000 times

mutation in CFTR gene located in 7q31.2

Large gene containing 27 exons (230kb)

Autosomal recessive

Dx: IRT, Sweat chloride test (>90% sensitive; gold standard), transepithelial potential difference, genetic testing

inherited more commonly from both parents who express or carry thet trait.

Problems begin >6 mos

1000 babies/year die

aka DiGeorge or Velocardiofacial syndrome

deletion in 3Mb.  Too small to be detected by karyotype so usually detected using FISH.

7-10% of parents have deletion and recurrence risk is 50%

AD, Cr 4, FGFR3 gene

normal growth of trunk and head but shortening of limbs

defect in coverting cartilage>bone

assoc w/ advanced paternal age

AR, Cr5, SLC26A2 gene

disorder of cartilage and bone development

limb shortening, hitchhikers thumb, normal skull

spinal deformities

early onset osteoarthritis and contracture of large joints

Hereditary breast & ovarian cancer

HNPCC

FAP

Long QT

Cardiomyopathy

Alzheimers

5-10%

~85% is sporadic, 15-20% in family clusters

2+ 1st or 2nd degree relatives

unclear pattern of inheritace

risk could be up to 2-3x general population

bilateral tumors in paired organs, male breast cancer, multiple cancers in on eindividual, generation to generation affecetd

monthly self breast exam begining at age 20

clinical breast exam every 6 months strating at age 25

anual MMG & breast MRI at age 25

BSO when child bearing is complete or by age 35-40 (1) or 40-45 (2)

CA-125 blood test, TAH-BSO

Colonoscopy every 3-5 y >50yoa, Pancreatic screening, Annual pap >18yoa, annual PSA & DRE >40-45yoa

72 years

(90% of cases occur >50yoa)

95% of HNPCC associated tumors have MSI.

Polyps progress much quicker to cancer if MSI is present.

condition manifested by damaged DNA due to defects in the normal DNA repair process

5 specific markers are used.

MSI-H - instability in 2+

MSI-L - instability in 1

MSS - no instability

Early onset (45yoa)

R sided predominate

extra-colonic cancers

test protein expression and tags Ab to the proteins of interest

Looks for lack of expression in genes MLH1, MSH2, MSH6 and PMS2.  Lack of these genes is a positive result which highly correlates with gene mutation

colonoscopy and upper endoscopy by age 25 or 5 y befpre earliest family onset

repeat every 1-2 y until age 40 and then per year after that.

If family member is diagnosed, subtotal colectomy is recommended

CA-125 blood test and transvaginal US starting at 35y

anual endometrial aspirate starting btw 25-35

prophylactic TAH-BSO after childbearing or at menopause for HNPCC confirmed

Individuals with multiple adenomatous polyps (multiple being anywhere from 20 to 1000s)  or a 1st degree relative with polypsis

Avg onset is 35 yoa

Full sequencing of APC gene looking for AD, or mutations with FAP

Large deletions/dups of APC gene

MYH7 testing which mimics FAP, AR and has 2 common mutations

AD (heart problems only)

AR (multi-system)

Heart rhythm disorder

Mutations in 10+ genes or some meds cause

Flags: Near drowning events, exercise or emotional stress, SIDS

LV enlargement, thin wall, depressed LV systolic fxn

40% is idiopathic

20-50% of IDC is found in more than one family member and termed FDC

>90% are AD, 5-10% are x-linked and 1-2% are AR

Phenotype-incomplete age-dependent penetrance and variable expression

Genotype-locus heterogeneity and allelic heterogeneity