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GENETIC DISEASES (Cytogenetic Disorders: 1 in 200 newborn infants : some…

- - - - median age death=47; molecular basis:elusive, incr gene dosage of pr coding genes on chromosome 21 /of effects of deregulated miRNA expression?, top culprits: DYRK1A(serine threonine kinase) + RCAN1(reg of calcineurin1)
      - clinical features
        
        diagnostic: flat facial profile, oblique palpebral fissures, epicanthic folds, mental retardation (805 IQ: 25-50)
        
        40%: congenital heart disease, most commonly defects of the endocardial cushion, (atrial septal defects, AV valve malformations, and VSDs); majority of deaths in infancy and early childhood; other congenital malformations: atresias of esophagus and small bowel also common
        
        10-20x risk of developing acute leukemia (lymphoblastic + myeloid)
        
        all >age 40 develop neuropathologic changes characteristic of Alzheimer disease
        
        abnormal immune responses-->predispose to serious infections, particularly of lungs + to thyroid AI
      - forms
        
        95%: 47 chromosomes; most common cause: meiotic nondisjunction
        
        4%: translocation of q arm of chromosome 21 to chromosome 22 or 14
        
        1%: mosaics; mitotic nondisjunction during an early stage of embryogenesis, frequently (but not always) familial, typically robertosonian translocation in carrier parent
    - - clinical features
        
        congenital heart disease affecting outflow tracts
        
        abnormalities of palate
        
        facial dysmorphism
        
        developmental delay
        
        thymic hypoplasia w/ impaired T cell immunity
        
        parathyroid hypoplasia-->hypocalcemia
      - Variations in size + position of \deletion
        
        DiGeorge syndrome: T cell immunodeficiency + hypocalcemia are dominant features; TBX1 loss correlate w/ this
        
        velocardiofacial syndrome: mild immunodeficiency but pronounced dysmorphology + cardiac defects
      - diagnosis established only by FISH
      - are at particularly high risk for psychoses such as schizophrenia + bipolar
  - - - usually reciprocal
      - centric fusion type/robertsonian translocation:involving 2 acrocentric chromosomes; typically occur close to centromere--> one very large chromosome + one extremely small one (are lost, carry highly redundant genes (e.g., rRNA genes) ) + carrier has 45 chromosomes
  - - - Turner Syndrome
        
        charac: (diagnosis:at birth/early in childhood) primary hypogonadism Fig 6-16; CardioV abnormalities most common cause of death in childhood; mental status u. normal, but subtle defects in nonverbal, visual-spatial info processing; 50% develop clinical hypothyroidism. In adults: short stature + primary amenorrhea: strong suspicion for Turner; diagnosis established by karyotyping; mosaics / deletion variants may have almost normal appearance + present only w/ primary amenorrhea.
        
        cause: partial/complete monosomy of short arm of X
        
        pathogenesis: (normal fetal: ovaries have 7 million oocytes; by menarche: 400,000; menopause: <10,000 remain) In Turner: absence of second X: accelerated loss of oocytes, complete by age 2yrs--> “menopause occurs before menarche,” + streak ovaries); short stature homeobox (SHOX) gene at Xp (remain active in both X + unique in having an active homologue on short arm of Y)-->1 copy: short stature.
      - Klinefelter Syndrome
        
        charac: in some only hypogonadism, but most: distinctive body habitus w/ incr in length btw soles + pubic bone--> elongated body. Also: eunuchoid body habitus, Reduced facial, body, pubic hair, gynecomastia, testes sometimes only 2 cm--> serum testosterone levels <normal + urinary gonadotropin levels
        elevated.
        
        cause: at least two X + >=1 Y. Most: 47,XXY (results from nondisjunction of sex chromosomes during meiosis, extra X M/P origin. ~15%: mosaic patterns (46,XY/47,XXY, 47,XXY/48,XXXY) 46,XY line in mosaics: milder
        
        most common cause of hypogonadism in males; rarely fertile (mosaics w/ large proportion of 46,XY cells); cause: impaired spermatogenesis, sometimes total azoospermia. (hyalinization of tubules, Leydig cells prominent (hyperplasia / apparent incr related to loss of tubules); may be associated w/ mental retardation (typically mild, and in some not detectable) correlated w/ # of extra X; associated w/ higher frequency of several disorders (breast cancer (20x normal males), extragonadal germ cell tumors, and AI diseases like SLE)
    - - small amount of genetic information on Y chromosome: male differentiation; gene for male differentiation (SRY, sex-determining region of Y chromosome) on short arm
      - lyonization of X chromosomes: in females, only one X chromosome genetically active (P/M random) (21% of genes on Xp + 3% on Xq, escape X inactivation). X inactivation occurs early in fetal life (~16 days after conception); females are mosaics;
  - - - trisomy
        
        autosomes
        
        sex chromosomes
      - monosomy
        
        autosome: incompatible with life,
        
        sex chromosomes
- - - - 900 different mutations, divided into 5 categories.
        
        Class I: uncommon, associated w/ complete loss of R synth.
        
        Class II: most prevalent form, R pr synth, but its transport from ER to Golgi impaired due to defects in pr folding.
        
        Class III: Rs transported to cell surface but fail to bind LDL normally.
        
        Class IV: Rs fail to internalize within clathrin pits after binding to LDL
        
        Class V: Rs bind LDL + internalized but trapped in endosomes because dissociation of R + bound LDL does not occur.
        
        auto dominant.
        
        Hetero: 2-3x elevation of plasma cholesterol levels; although cholesterol levels elevated from birth, remain asymptomatic until adult life, when they develop cholesterol deposits (xanthomas) along tendon sheaths + premature atherosclerosis.
        
        homo: 5x; develop cutaneous xanthomas in childhood + often die of myocardial infarction <age of 20.
        
        among most common mendelian disorders; freq: 1 in 500; mutation in LDLR gene--> accumulation of LDL cholesterol in plasma (reduced catabolism) + impairs transport of IDL into liver (--> greater proportion of plasma IDL converted into LDL (excessive biosynthesis))--> excessive levels of serum cholesterol--> marked incr of cholesterol traffic into monocyte-MQs + vascular walls mediated by scavenger R--> skin xanthomas + premature atherosclerosis.
    - - PATHOGENESIS
      - MORPHOLOGY
        
        Pancreatic abnormalities: in 85-90%;
        
        milder cases: only accum of mucus in small ducts, w/ some dilation of exocrine glands.
        
        advanced (u. seen in older children/adolescents) : ducts totally plugged--> atrophy of exocrine glands + progressive fibrosis--> impairs fat absorption--> so avitaminosis A--> squamous metaplasia of lining epithelium of ducts in pancreas, which are already injured by inspissated mucus secretions.
        
        Intestines: Thick mucus plugs may be found in small intestine of infants; Sometimes--> small bowel obstruction (meconium ileus)
        
        pulmonary: most serious complications; bronchioles often distended w/ thick mucus + marked hyperplasia/trophy of mucus-secreting cells (submucosal glands). Superimposed infections--> severe chronic bronchitis + bronchiectasis; Development of lung abscesses common; Staph aureus, H influenzae, and Pseudomonas aeruginosa: 3 most common organisms responsible for lung infections. Even more sinister: incr frequency of infection w/ another pseudomonad, Burkholderia cepacia: particularly hardy + associated w/ fulminant illness (“cepacia syndrome”).
        
        Liver: Bile canaliculi plugged + ductular prolif + portal inflammation; Hepatic steatosis common; cirrhosis develops--> diffuse hepatic nodularity (in <10%)
        
        Azoospermia + infertility in 95% of males surviving to adulthood; bilateral absence of vas deferens frequent (In some this may be the only feature suggesting an underlying CFTR mutation)
      - Clinical Course:
        extremely varied; range from mild to severe, from presence at birth to onset years later, and from confinement to one organ system to involvement of many
        Advances in management: median life expectancy: 36 yrs
      - most common lethal genetic disease affecting whites; uncommon among Asians (1 in 31,000 live births) + African Americans (1 in 15,000 live births).
      - autos recessive + doesn't affect carriers; however bewildering phenotypic variation resulting from diverse mutations in CF-associated gene, tissue-specific effects of loss of this gene’s function, + influence of newly recognized disease modifiers.
      - a disorder of epithelial transport affecting fluid secretion in exocrine glands + epithelial lining of respiratory, GI, and reproductive tracts--> abnormally viscid mucous secretions blocking airways + pancreatic ducts--> 2 most imp: recurrent and chronic pulmonary infections + pancreatic insufficiency
      - exocrine sweat glands structurally normal (and remain so throughout the course of this disease) but a high level of NaCl in sweat is a consistent + characteristic biochemical abnormality in CF.
  - - - -in converting Gal to Glc: Gal-1phosphate uridyltransferase (GALT) homozygous mutations--> Gal-1-phosphate and other metabolites (galactitol) accumulate in many tissues, including liver, spleen, lens of the eye, kidney, and cerebral cortex. The liver, eyes, and brain bear the brunt
      - -early-onset hepatomegaly is due largely to fatty change, but in time widespread scarring closely resembling cirrhosis of alcohol abuse may supervene
        -Opacification of lens (cataract), probably bc lens absorbs water + swells as galactitol accumulates + incr its tonicity.
        -Nonspecific alterations in CNS: loss of nerve cells, gliosis, and edema.
      - -Almost from birth, affected infants fail to thrive. Vomiting + diarrhea appear within few days of milk ingestion. Jaundice + hepatomegaly usually evident during 1st week. aminoaciduria. Fulminant Escherichia coli septicemia w/ incr frequency.
      - -diagnosis:
        demonstration in urine of a reducing sugar other than Glc, but tests that directly identify deficiency of transferase in leukocytes + RBCs. Antenatal diagnosis: assay of GALT in amniotic fluid cells / determination of galactitol level in amniotic fluid supernatant.
      - prevention / amelioration: early removal of Gal from diet for at least 1st 2 yrs: permits almost normal development nonetheless older patients frequently affected by a speech disorder + gonadal failure (esp premature ovarian failure) and, less commonly, by an ataxic condition.
    - - Mucopolysaccharidoses (MPSs: dermatan sulfate, heparan sulfate, keratan sulfate, and (in some cases) chondroitin sulfate):
        Most of MPSs secreted into ground substance, but a fraction degraded within lysosomes. Multiple Es involved
        
        -Several clinical variants (classified from MPS I to MPS VII each resulting from deficiency of one specific E)
        all except one: auto recessive; the exception: Hunter syndrome, (X-linked recessive)
        
        -MPS type I (Hurler syndrome)
        -affected children life expectancy: 6-10 yrs + death often due to cardiac complications.
        
        deficiency of α-L-iduronidase.
        
        Accumulation of dermatan + heparan sulfate in cells of mononuclear phagocyte system, fibroblasts, and within endothelium + smooth muscle cells of vascular wall--> swollen + clear cytoplasm (accumulation of material + for periodic acidSchiff staining within engorged, vacuolated lysosomes) Lysosomal inclusions also found in neurons--> mental retardation.
        
        MPS type II (Hunter syndrome): absence of corneal clouding, often milder clinical course.
        
        deficiency of L-iduronate sulfatase
        
        accumulation of heparan + dermatan sulfate
        
        Hepatosplenomegaly, skeletal deformities, lesions of heart
        valves, and subendothelial arterial deposits (particul in coronary arteries), and lesions in brain, in all of the MPSs. In many of more protracted syndromes, coronary subendothelial lesions--> myocardial ischemia--> myocardial infarction + cardiac decompensation important causes of death. Most cases: coarse facial features, clouding of the cornea, joint stiffness, and mental retardation. Urinary excretion of accumulated MPS often incr.
      - Gaucher Disease:
        
        accum in mononuclear phagocytic cells--> Gaucher cells particularly in liver, spleen, lymph nodes, and bone marrow.
        
        cause: burden of storage material + *MQs (High levels of MQ-derived cytokines, (IL-1, IL-6, TNF) found in affected tissues)
        
        3 auto recessive variants
        
        type I (chronic nonneuronopathic form): 99% of cases
        charac: clinical or radiographic (Marrow replacement + cortical erosion may produce visible skeletal lesions + reduction in formed elements of blood) bone involvement (osteopenia, focal lytic lesions, and osteonecrosis; caused by MQ cytokines) in 70-100% of cases + hepatosplenomegaly (spleen fills entire abdomen) + absence of CNS involvement; most common in Ashkenazi Jews; unlike other variants, compatible w/ long life.
        
        type II (acute infantile neuronopathic form): more severe type III (chronic neuronopathic form): appear later + milder Although liver + spleen also involved, clinical features in types II and III dominated by neurologic disturbances (convulsions, progressive mental deterioration)
        
        diagnosis + detection of carriers: level of glucocerebrosides in leukocytes / cultured fibroblasts
        
        therapy
        
        current: lifelong E replacement by infusion of recombinant glucocerebrosidase.
        
        newer: reducing substrate (glucocerebroside) by oral administration of drugs that inhibit glucocerebroside synthase.
        
        on the horizon: glucocerebrosidase gene therapy (infusion of autologous HCS cells transfected w/ normal gene)
      - Niemann-Pick Disease: Estimation of sphingomyelinase activity in leukocytes / cultured fibroblasts used for diagnosis + detection of carriers. Antenatal diagnosis: E assays / DNA probe analysis
        
        B: organomegaly but no neurologic manifestations.
        
        C: quite distinct + more common than types A + B combined. Mutations in NPC1 (most case) + NPC2: Both in transport of free cholesterol from lysosomes to cytoplasm;
        Affected cells accumulate cholesterol + gangliosides
        clinically heterogeneous: most common form: in childhood + marked by ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression.
        
        A
        
        bc of high phagocytic content--> organs most severely affected are spleen, liver, bone marrow, lymph nodes, and lungs. striking splenic enlargement, entire CNS involved (neurons enlarged + vacuolated).
        
        manifests itself in infancy w/ massive visceromegaly + severe neurologic deterioration
        
        accumulates in all phagocytic cells + in neurons. Electron microscopy: vacuoles are engorged secondary lysosomes often containing membranous cytoplasmic bodies resembling concentric lamellated myelin figures ("zebra” bodies)
      - Tay-Sachs Disease
        
        molecular basis: if misfolded prs not stabilized by chaperones-->apoptosis--> molecular chaperone therapy: use of small molecules that incr chaperone synth / reduce degradation of misfolded prs by proteosomes
        
        most common acute infantile variant: appear normal at birth, but motor weakness begins at 3-6 mths, followed by neurologic impairment, onset of blindness, and progressively more severe neurologic dysfunctions. Death: within 2 or 3 yrs
        
        most common among Ashkenazi Jews; carriers reliably detected by estimation of level of hexosaminidase in serum / by DNA analysis
        
        brain principally affected bc it is most involved in ganglioside metabolism; storage of GM2: neurons, axon cylinders of nerves, glial cells throughout CNS (including the spinal cord), peripheral nerves, autonomic nervous system; retina u. involved as well, swollen ganglion cells in peripheral retina--> pallor--> contrasting “cherry red” spot in relatively unaffected central macula
      - features common to most diseases in this group
        
        Frequent CNS involvement + neuronal damage
        
        Cellular dysfunctions bc: storage of undigested material + cascade of secondary events triggered (ex MQ* + release of cytokines)
        
        Storage of insoluble intermediates in mononuclear phagocyte system--> to hepatosplenomegaly
        
        Patient population: infants + young children
        
        Autos recessive
    - - inborn error of metabolism (inability: phenylalanine-->tyr; In normal children: <50% intake of phenylalanine necessary for pr synth, remainder converted to tyrosine by phenylalanine hydroxylase system) that affects 1 in 10,000 live-born white infants.
      - classic phenylketonuria: most common form quite common in persons of Scandinavian descent + distinctly uncommon in African American + Jewish populations.
        -Homozygotes: classically have a severe lack of E phenylalanine hydroxylase (PAH)--> hyperphenylalaninemia + PKU.
      - infants normal at birth--> within few ws: rising plasma phenylalanine level--> impairs brain development, by 6 mths: severe;
        -<4% of untreated phenylketonuric children have (IQs)> 50 or 60. 1/3: can't walk 2/3: can't talk. Seizures, other neurologic abnormalities, decr pigmentation of hair and skin, eczema often accompany mental retardation in untreated children.
        -prevention: restriction of phenylalanine intake early in life;
      - maternal PKU: many females w/ PKU reach child-bearing age + clinically normal--> Most have hyperphenylalaninemia, bc dietary treatment is discontinued after reaching adulthood--> Btw 75-90% of children born to such women: mentally retarded + microcephalic, +15% have congenital heart disease, even though they're heterozygotes.
        -results from teratogenic effects of phenylalanine/metabolites; presence + severity directly correlate w/ maternal phenylalanine level
      - -When phenylalanine metabolism blocked
        -minor shunt pathways--> several intermediates excreted in large amounts in urine + sweat--> strong musty / mousy odor to affected infants.
        -lack of tyrosine (a precursor of melanin)--> light hair+ skin
      - mutations: 500 mutant alleles of PAH gene been identified, only some cause severe deficiency; lack of PAH activity: classic features of PKU; those w/ 6% residual activity present with milder disease; some result in only modest elevations of blood phenylalanine levels w/o associated neurologic damage= benign hyperphenylalaninemia
      - molecular diagnosis not feasible + measurement of serum phenylalanine levels is necessary to differentiate benign from PKU; levels in latter typically are 5x (or more) higher than normal.
        98% of cases of PKU: mutations in PAH; 2%: cofactor tetrahydrobiopterin (patients can't be treated by dietary restriction)
    - - Type II glycogenosis (Pompe disease)
      - Myopathic type
      - Hepatic type
  - - - MORPHOLOGY:
        lesions described are typical but not seen in all cases bc different allelic mutations in FBN1 gene
        
        Skeletal abnormalities: most obvious feature; slender, elongated habitus w/ abnormally long legs, arms + fingers (arachnodactyly); a high-arched palate; and hyperextensibility of joints. A variety of spinal deformities, such as severe kyphoscoliosis, may be present. chest: either pectus excavatum (i.e., deeply depressed sternum) or a pigeon-breast deformity.
        
        ocular: most characteristic ocular change: bilateral dislocation, or subluxation, of the lens secondary to weakness of its suspensory ligaments (ectopia lentis).
        
        Most serious: cardiovascular system. Fragmentation of elastic fibers in tunica media of the aorta--> aneurysmal dilation + aortic dissection. These changes, called cystic medionecrosis, not specific for Marfan syndrome, similar lesions occur in hypertension + aging. cardiac valves, esp mitral, may be excessively distensible + regurgitant (floppy valve syndrome)--> mitral valve prolapse + congestive cardiac failure. Death from aortic rupture may occur at any age + is in fact most common cause of death. Less commonly, cardiac failure is the terminal event.
      - auto dominant (mutant fibrillin pr must act as a dominant negative by preventing assembly of normal microfibrils); (GP that's a major component EC matrix; Microfibrils: scaffolding for deposition of tropoelastin)
        particularly abundant in aorta, ligaments, and ciliary zonules that support the ocular lens; prominently affected in Marfan syndrome.
      - Mutations in FBN1 gene (15q21) found in all patients. However, molecular diagnosis not yet feasible, bc >600 distinct causative mutations in the very large FBN1 gene have been found.
        prevalence: 1 per 5000. (70-85% familial, rest are sporadic, mutations in germ cells of parents)
      - some features ex overgrowth of bones difficult to relate to simple loss of fibrillin.
        loss of microfibrils--> abnormal + excessive activation of TGFβ (normally sequestered)--> deleterious effects on vascular smooth muscle development + integrity of EC matrix (mutations in TGF-β type II R--> a related syndrome, Marfan syndrome type 2 (MFS2)); angiotensin R blockers, which inhibit activity of TGF-β, improve aortic + cardiac function in mouse models of Marfan syndrome
    - - diseases charac by defects in collagen synth / structure. All single-gene disorders auto dominant + recessive (~30 distinct types of coll--> clinical heterogeneity; at least 6 variants recognized)
      - certain clinical features common to all variants: tissues rich in coll (skin, ligaments,joints,..) frequently involved in most; skin is hyperextensible + joints are hypermobile--> contortions (bending thumb backward to touch forearm + bending knee upward to create almost a right angle); predisposition to joint dislocation; skin is extraordinarily stretchable, extremely fragile, and vulnerable to trauma. Minor injuries: gaping defects, and surgical interventions w/ great difficulty because of lack of normal tensile strength. serious internal complications: rupture of colon and large arteries (vascular EDS); ocular fragility, w/ rupture of cornea + retinal detachment (kyphoscoliotic EDS); and diaphragmatic hernias (classical EDS), ...
      - molecular bases for 3 more common variants:
        
        • Kyphoscoliotic EDS: Deficiency of lysyl hydroxylase: in types I + III coll, interferes w/ formation of cross-links; auto recessive
        
        • Vascular EDS: Deficient synth of type III coll resulting from mutations affecting COL3A1 gene; auto dominant; weakness of tissues rich in type III coll (e.g., blood vessels, bowel wall), predisposing them to rupture.
        
        • Classical EDS: Deficient synth of type V coll due to mutations in COL5A1 and COL5A2; auto dominant
- - - - FISH: DNA probes recognizing sequences specific to chromosomal regions>100 kb; probes labeled w/ fluorescent dyes + applied to metaphase spreads / interphase nuclei;
        ability of FISH to circumvent need for dividing cells is invaluable when a rapid diagnosis is warranted, such analysis can be performed on prenatal samples (e.g., cells obtained by amniocentesis, chorionic villus biopsy, or umbilical cord blood), peripheral blood lymphocytes, and even archival tissue sections;
        Use: detection of numeric abnormalities of chromosomes
        (aneuploidy); subtle microdeletions or complex translocations not detectable by routine karyotyping; for analysis of gene amplification (e.g., NMYC amplification in neuroblastomas); and for mapping newly isolated genes of interest to their chromosomal loci.
      - Array-Based Genomic Hybridization:
        unlike FISH doesn't need previous knowledge of what aberrations may be
        Newer generations of microarrays using SNPs provide even higher resolution (with more than 1 million SNPs from the human genome on a single microarray!) and are currently being used to uncover copy number abnormalities in a variety of diseases, from cancer to autism
- - - - males: moderate to severe mental retardation. physical: (not always present / may be quite subtle): long face w/ large mandible, large everted ears, (in at least 90% of postpubertal males): large testicles (macroorchidism).
  - - - maternal: transcriptional silencing of maternal
      - paternal: transcriptional silencing of paternal
    - - charac: mental retardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism
      - cause: paternal
        
        60-75%: interstitial deletion of band q12, del(15)(q11;q13) detected
        
        loss of function of several genes located on chromosome 15 btw q11 and q13
        
        w/o a detectable cytogenetic abnormality: FISH analysis --> smaller deletions within same region
        
        both copies of chromosome 15 derived from mother. (Inheritance of both chromosomes of a pair from one parent: uniparental disomy)
    - - charac: mental retardation, ataxic gait, seizures, inappropriate laughter.
      - cause: maternal chromosome deletion
        
        15q12 deletion
        
        Angelman syndrome gene (UBE3A): encode a ligase in ubiquitin-proteasome proteolytic pathway; expressed primarily in specific regions of normal brain—hence the neurologic manifestations.
        
        uniparental disomy of parental chromosome 15
- - - - missense: in β-globin chain of hemoglobin--> sickle cell anemia
      - nonsense: in most cases RNAs rapidly degraded (nonsense mediated decay)
  - - - critical during
        
        development: Physiologic epigenetic silencing during development: imprinting
        
        homeostasis of fully developed tissues
      - mechanisms
        
        methylation of cytosine residues at gene promoters: heavily methyl: inaccessible to RNA polymerase
        
        Histone pr: variety of reversible modifications (e.g., methylation, acetylation)--> secondary and tertiary DNA structure--> gene transcription
    - - miRNAs: inhibit translation of target mRNAs (Posttranscriptional silencing of gene expression); # of miRNA<<those that encode prs--> a given miRNA can silence many target genes
      - lncRNAs (ncRNAs>200n length); roles of lncRNAs in various human diseases, from atherosclerosis to cancer
        
        many mechanisms, ex:bind to regions of chromatin, restricting access of RNA polymerase
        
        XIST: tanscribed from the Xchromosome, essential role in physiologic X chromosome inactivation, itsself escapes X inactivation, but forms a repressive “cloak” on the X chromosome from which it is transcribed--> gene silencing.
      - small interfering RNAs (siRNAs): Unlike miRNA, siRNA precursors are introduced by investigators into the cell. Their processing by Dicer and functioning via RISC are essentially similar to that described for miRNA.
    - - SNPs: variation at single isolated nucleotide positions and are almost always biallelic; may occur anywhere (but <1% of SNPs occurs in coding regions)
        
        could alter gene product + predispose to a phenotypic difference / disease
        
        Much more commonly: just a marker that is co-inherited w/ a disease-associated gene as a result of physical proximity (the SNP and the causative genetic factor are in linkage disequilibrium)--> SNPs could serve as reliable markers of risk for multigenic complex diseases (type II diabetes, hypertension,..)
      - CNVs: variation consisting of different #s of large contiguous stretches of DNA (1kbp-millions).
        
        these loci are
        
        complex rearrangements of genomic material, w/ multiple alleles
        
        biallelic and simply duplicated or deleted
        
        50% involve gene coding sequences; nificant overrepresentation of certain gene families in these regions (immune + nervous system)