Gen/Neonat Week 1

location on a chromosome

different sequences of a gene

2 or more clearly different phenotypes being maintained at heterozygote frequency of >2%

Alleles that are classified as rare (<1%) or common

• Combination of the allelic consitution of multiple loci on a chromsome
• ie A/a and 1/2 could be A2, a2, A1, a1

• The product of the GALT gene (galactose 1-phosphate uridyl) converts galactose to glucose. A normal range of enzyme activity here is 120% to 50% and includes the N, L, D, and A alleles
• Galactosemia results from homozygous G alleles

• Begin with a ceramide. H-transferase adds carbohydrates onto this to form H antigen. In the next step, a specific transferase adds a sugar onto the antigen to form the end product
• A transferase adds N-acetylgalactosamine to form A antigen
• B transferase adds galactose to form B antigen
• A frameshift mutation (result of a deletion) at the allele causes there to be no functional transferase formed. H antigen remains and is called type O blood

• The CD-CV model holds that a disease stems from the additive effects of low risk common variants, of which no one is sufficient to cause the disease by itself.
• The CD-MRV model holds that disease is caused by a single devastating rare variant, but that multiple different variants could mutate to cause the same disease (locus heterogeneity). This is the currently held model

the single strand DNA breakage and bridging between ajacent strands that occurs during genetic recombination

• Linkage during crossing over depends on the physical proximity of two genes. Genes that are closer together will have a higher chance of remaining on the same chromosome after recombination.
• centiMorgan=1% recombination frequency

• Single nucleotide polymorphism
• determine a person's genetic predisposition to develop a disease
• Most disorders caused by these polymorphisms are rare, but altogether, the prevalence is ~2%

finding new drugs using expanding knowledge of the human genome

the study of heritablity in drug response

• CYP2D6; controls the clearance of 20% of drugs; part of the cytochrome p450 family; highly polymorphic; amplification and diminishing of activity leads to ultra rapid metabolizers and poor metabolizers
• The majority of humans are extensive metabolizers

Interplay of diet, environment, and polymorphisms in drug metabolizing enzymes, transporters, etc.

Different polymorphisms occur at different frequencies in different ethnic populations; this can affect drug metabolism and activities

• One drug can be activated by a metabolic process that is inhibited by another drug (i.e. Terfenadine must be converted to Fexofenadine by CYP3A4 to be active. Erythromycin and other drugs compete for and inhibit this enzyme)
• May also compete to be metabolized by the same enzyme
• Drugs can build up to toxic levels within the body

Enzyme expression levels can be induced to change by diet; this alters the dose that the patient eneds to take to achieve therapeutic level (i.e. char on outside of steak increases enzymatic activity so that you will never reach maximum drug activity and the drug will wear off faster)

Single gene, usually looking at mutations that have large effects on the phenotype; follow a characteristic pattern of inheritance in families; only autosomal and x-linked conditions

mutant alleles at the same locus, each capable of producin an abnormal phenotype

Mutations at different loci causing the same, or very similar phenotypes (diseases)

conditions expressed in heterozygotes; only one copy of the mutant allele is sufficient to express the mutant copy; expressed in every generation of a family; males and females have equal chance of inheriting (50%) and passing on the disorder (in autosomal); no carriers; usually due to defects in non-enzyme proteins

Condition expressed in homozygous individuals; two copies of the mutant allele are required to express the disorder; can have carriers; in autosomal, males and females are equally likely to inherit (25% if 2 carrier parents) and equally likely to pass on the disorder; not usually present in more than one generation (skips); usually due to defects in enzyme proteins; disorders usually appear earlier in life

• the likelihood that a characteristic will manifest itself
• 100% penetrance is all or none

different degrees of expression with the same genotype

Autosomal dominant disorders

• Autosomal dominant
• Mutation in gene coding for fibrillin (component of microfibrils); causes connective tissue weakness; also a carrier protein and important modulator of inflammatory reactions
• Classic clinical features, DNA is diagnostic >90%
• Skeletal-->tall, lean, lanky, long digits, scoliosis, sternum abnormality, dolichocephaly (long, narrow head)
• Ocular-->dislocation of lens, myopia, retinal detachment
• CV-->dilation of ascending aorta, dissection/rupture of aorta, mitral valve prolapse
• Most patient shave an affected parent; 25-30% from new mutation; 1/10,000 people in US

• Autosomal dominant
• Gain of function mutation in FGFR3; the increased activity inhibits normal growth plate development
• 80% new mutations; usually paternal when family history is there; can be associated with increased paternal age; 1/15,000 births; complete penetrance (no such thing as mild achondroplasia); if both parents have it, 50% risk of having it, 25% risk of homozygous (lethal), 25% riskk of normal stature
• Short proximal extremities, normal spine length, macrocephaly with mideface hypoplasia

• Autosomal dominant
• 50% new mutations; 100% penetrance, but great variable expressivity; 1/3500 people in US
• Condition of the nervous system
• Cafe au lait (hyperpigmented macule), axillary freckling, neurofibroma (benign subcutaneous tumors), Lisch nodules (small pigmented lesions of the iris), learning difficulties, optic nerve glioma, CNS tumors

Autosomal recessive disorders

• 1/2500, but carrier rate is 1/25; onset is anywhere from birth to adult
• Epithelial ion transporter (CFTR) mutations; transmembrane conductance regulator gene; pancreas enzymes don't absorb food very well; over 1000 alleles lead to this, most are extremely rare; 80% caused by deletion of Phe at 508 (7q21-34)
• Meconium ileus (thick fetal stools); malabsorption due to exocrine pancreatic insuficiency; epithelial inflammation and chronic infection in respiratory tract; excessive salt in perspiration (dysfuntional exocrine sweat glands); and male infertility (>95%; caused by congenital absence of vas deferences and obstructive azoospermia)

• 1/100,000; higher incidence in Ashkenazi-Jewish population
• Hexosaminidase A deficiency leads to lysosomal storage disorder; lysosome swells, cells lose function, organ dysfunction; hexo is responsible for GM2 (present in plasma membranes) degredation; most prominent effect in neurons (brain and retina) because of GM2 accumulation
• Whorled myeling figurs within lysosomes is characteristic; cherry red spots on macula of eye
• Normal at birth, but increased startle response at 5-6 months; progressive weakness, loss of skills by 6-24 months; death by 2-4 years

Newly diagnosed or suspected genetic condition; child with multiple congenital anomalies; family history of genetic condition; genetic testing for late-onset condtion; prenatal diagnosis for old pregnant women or loss of pregnancy; teratogen exposure; infertility; consanguinity

• First person in the family brought to the physicians attention with the disease
• The person ebing studied in the pedigree

• Hardy-Weinberg says p^2 + 2pq + q^2=1 and p + q=1
• Given the frequency, calculate q, then p, then 2pq

• The population is large
• Random mating
• Locus autosomal (M and F have similar frequencies)
• No mutations, no migrations
• Equal fitness of individuals

• Name, relationship, birth date
• Date of death, cause if known
• Current age or age at death
• Number of siblings (including those who died at birth or infancy)
• Pregnancy losses
• Symptoms and health conditions of each individual

A mathematical method to calculate recurrence risks combining information from genetics, pedigree, and test results

Through the X chromosome

• Several different mutations at the same locus cause the same phenotype (disorder)
• There are lots of things that can go wrong in the same spot on the chromosome to cause these disorders

• No male-male transmission
• All daughters of an affected man are carriers (phenotype depends on whether it's dominant or recessive and the pattern of X-inactivation in the daughter)

• Most X-linked conditions are recessive
• Carried by unaffected mother (heterozygous) and expressed in sons
• Affected relatives must be related through the mother of the proband

• Relatively few
• All daughters of an affected man will have the condition; none of his sons
• Daughters and sons of an affected female have a 50% chance of having the disorder
• Typically lethal to the male
• Tend to be less severe and more variable in females
• Pedigrees resemble autosomal dominant, but no male-male transmission

Environmental modifiers, oligomeric disease (locus heterogeneity or extreme variable expressivity), sporadically lethal, and male lethality

• X-linked dominant trait or
• onely one X is active in a given cell; random inactivation of X leads to variable expressivity of disorders in females or
• Turner Syndrome (Single X)

X-linked Recessive disorders

• 1/3500 males; XLR
• No dystrophin produced; muscle degeneration and replacement with fat cells (causes the pseudohypertrophy of the calves)
• Normal babies; late to walk; Gower manuever (can't get up from 4 point stance); wheelchair bound by 11 years; 20% with MR; death in late teens
• Diagnose with elevated CK levels and muscle biopsy

• 1/3500 males; XLR
• Some dystrophin produced
• Normal babaies, able to walk into second decade; no MR; live past 21 years
• Diagnosis: elevated CK levels and muscle biopsy

• Huge gene (2300 kb)
• Multiple different mutations associated
• 90% of the mutations are detectable

• 1/10,000 males; XLR; 50% family history (50% de novo)
• Deficiency in the blood clotting factor VIII
• Excessive or spontaneous bleeding; severity depends on where mutation is and whether you form any protein at all
• Severe form (low factor VIII activity) leads to bleeding into joints, muscles and internal organs; spontaneous head bleeds in infants
• Mild form (moderate factor VIII activity) leads to prolonged bleeding after injury or surgery
• Treatment with Factor VIII infusions leads to prolonged life, but severe arthritis and deformed joints
• Diagnosis: Excessive bleeding or prolonged PTT time

X-linked dominant conditions

• Very rare; usually lethal to males
• Hypophosphatemic
• Short stature; bowed legs (unless placed on Vitamin D and phosphate prior to weight bearing)

• Most common cause of MR in males, and significant cause in females
• Triple repeat expansion which occurs during gametogenesis
• Long face, prominent jaw and forehead, large everted ears, hypergonadism, MR, hyperactive behavior, tendency to avoid eye contact, large body size overall

• Gender, disease status, name, DOB, age of death (or current), country of origin/ethnicity
• Disease (age of onset and diagnosis, original site of cancer, site of metastasis, cause of death)--make sure you confirm the pathology of the disease

Conditions in multiple generations involving severla siblings, early onset of disease, sudden death in seemingly healthy relative, individual or couple with more than 3 pregnancy losses, the cousin thing

• incomplete penetrance
• variable expressivity
• gonadal mosaicism (2 different kinds of DNA in sperm)
• lyonization (X-inactivation)
• Non-paternity
• New mutations
• Locus and allelic heterogeneity
• Environmental factors

• Mitochondrial (if mom has it, all of kids will have it)
• Chromosomal
• Multi-factorial
• Sporadic

• Polygenic traits (determined by the combined effects of many genes)
• Multifactorial traits (determined by multiple genes and environmental factors)
• Most inherited traits are multifactorial or polygenic

Complex non-Mendelian inheritance

• A mixture of mitochondria, some with normal DNA and some with abnormal DNA coexisitng within a single cell
• An individual inherits more than just 1 abnormal mDNA; certain threshold must be crossed to have clinical effects; depending on the type of mutation, may only be present in certain tissues
• Female with heteroplasmic mtDNA may transmit variable amount to her offspring

37, as compared to 25,000 by nDNA

• No typical presentation; odd combinations are common
• Most common is diabetes mellitus, cardiac problems, ptosis (drooping of the upper eyelid), and other eye problems
• Blot tests are best way to diagnose (difficult with heteroplasmy)
• Treat with Riboflavin (complex I and II disorders) and other supplements (carnitine)

• Continuously variable have a normal distribution in the population; typically measurable traits like height; small effects of many genes plus environmental factors
• Threshold traits are caused by the additive effects of genes to a threshold prior to clinical effect; the phenotype is typically all or none

Population risk squared (higher if more than one family member affected or if defect is severe)

Multifactorial complex disorders in adults

• Germline mosaicism is 2 or more genetic or cytogenetic cell lines confined to the precuros (germline) cells of the egg or sperm; formerly called gonadal mosaicism; recurrence risk is generally 1-5%; increase in spontaneous germline mutations in sperm of father with increasing age
• Somatic mosaicism is characterized by a patchy distribution of genetically identically altered somatic cells; non-hereditary

• UPD: usually comes from trisomy where paternal are excluded (maternal UPD) or maternal are excluded (paternal UPD); begins with a trisomic zygote with 47 chromosomes; undergo trisomy rescue and loss of a trisomic chromosome; causes an abnormal phenotype when the genes of one chromosome are imprinted
• Imprinting: usually involves either the maternal or paternal copy of a gene being turned on, but not both

• Maternal imprinting: faulty gene copy is switched off (imprinted) when passed to the baby. Children on mother have a 50% chance of being a carrier, but there will be no affected children. Her male children will have 50% affected children (no carriers). Her female children will have 50% carriers (no affected). With males, it gets turned back on during gametogenesis and is not inhibited.
• Paternal imprinting: faulty gene copy causing disorder is turned off (imprinted) when passing to offspring (only carriers); remains active when passed by a carrier mother to her children

Prader-Willi Syndrome; Angelman syndrome; Transient neonatal diabetes; and Beckwith-Wiedman syndrome

• mUPD15; loss of function mutation
• Hypogonadism in boys; uncontrollable increase in appetite; possible MR

• pUPD15; loss of function mutation
• Autistic features; development delays; seizures (epilepsy)

Abnormally large allels resulting from too many trinucleotide repeats; unstable and highly polymorphic

• MELAS (mitochondrial)
• Fragile X and Huntington's (TRE)
• Hemophilia and Duchennes MD (Sometimes germline mosaic)
• Prader-Willi and Angelman (UPD)

the study of genetic defects, especially congenital malformations

Patterns of birthd efects that occur together with high frequency

• abnormal embryogenesis that occurs within 11 weeks of gestation; the tissue or organ never had the chance to develop normally
• Major has functional significance
• Minor has no functional significance; most people have 1 or 2 of these

external forces secondarily deform the tissue; tissue would have developed normally had not the outside force acted on it; i.e. amniotic bands

The secondary breakdown of tissue; fetal tissue is growing normally, but then growth is arrested by something that comes in and disrupts growth

• Malformations
• None of these are indicative of a syndrome by themself, but when paired with others, could indicate the presence of a disorder

• Teratogens
• Monogenic disorders (AR, AD, XLR, XLD) and Non-Mendelian (mitochondrial and UPD)
• Chromosomal
• Polygenic and multi-factorial
• Unknown; shrinks as our knowledge increases

• Infections (toxoplasmosis, rubella, cytomegalovirus, herpes, and syphilis)
• Ionizing radiation
• Metabolic imbalance (alcoholism, diabetes, folic acid deficiencies, hyperthermia, PKU)
• Drugs and Environment (worst are 13-cis-retonoic acid, isotretinoin (Accutane), Warfarin, ethanol)

• Susceptibility depends on genotype and interactions with environment
• Varies with developmental age
• Agents act in specific ways
• Access to developing tissues depends on nature of agent
• Four manifestations of deviant development (death, malformation, growth retardation, and functional defect)
• Deviant development increases with frequency and dosage

Inner canthal and outer canthal distance both increased (distance between eyes)

• baby will either have PKU or be a carrier
• Microcephaly; growth and development retardation; congenital heart disease
• Better control by mom leads to decreased risk of this

• baby does not get diabetes
• macrosomia; hypoglycemia; hypoparathyroidism; polycythemia; transient cardiomyopathy; congenital heart disease; nergvous system abnormalities; skeletal abnormalities
• Better maternal control leads to decreased risk

• Microcephaly, hairy face, learning problems, thin pilthum, thin upper lip, large forehead, small eyes
• no genetic testing yet

Spina bifida and anenecephaly; most common nervous system anomalies and completely preventable

Take folic acid; get a check-up prior to preg.; eat right and maintain healthy weight; stop smoking; stop drinking; no illegal drugs; avoid infections; limit exposure to hazards; learn about genetics; avoid stress and get fit

• chromosome analysis
• metaphase analysis after culturing, so you need living cells; get lymphocytes from peripheral blood smear, hematopoeitic cells from bone marrow or blood, or tissues from lymph nodes and solid tumors
• Advantages: You can view the entire genome easily
• Disadvantages: limited resolution and need viable cells to grow in culture
• Detection: chromosome abnormalities (numeric and structural)

• No culturing needed; any cell suspension of paraffin-embedded tissue; don't need living cells
• Detection: constitutional microdeletions, aneuploidy, translocations, amplifications, and deletions

• Chromosomal imbalances (gains or losses); must use isolated DNA
• Mix patient DNA with control DNA; they compete for hybridization; when there is gain, more patient, more green
• Disadvantages: takes a long time
• Detection: gains or losses; use this when there is a small gain or loss (difficult to see on metaphase analysis), developmental delay, intellectual disability, multiple congenital anomalies, autism spectrum

• 1/700-800; most common cause of moderate MR
• Occurs through nondisjunction in meiosis; trisomy survives if fertilized, monosomy does notp; risk increases with maternal age though 2/3 cases are women under 35
• Upslanting palperbral fissure; epicathal fold; flat nasal bridge; low set ears; protruding tongue; Simian crease; congenital heart disease; leukemia; Alzheimer like lesions; MR

• 1/8000 births
• prominent occiput, rocker bottom feet, clenched fists, receding jaw, MR, heart defects, death by 1 year

• 1/20,000 births
• More severe than 18, probably because it's a bigger chromosome
• Cleft palate, polydactyly, rocker bottom feet, microcephaly, severe MR, severe heart defects, death by 6 months

• t(14;21) is most common; whole arm translocation between acrocentric chromosomes (13,14,15,21,22; the ones with the short p arms)
• Person with Robertsonian is just a carrier (45 chromosomes; 1/6 chance)
• 3/6 chance of SAB
• 1/6 is totally normal
• 1/6 is trisomy 21 (Downs); accounts for 4% of all Down's cases
• Not associated with maternal age

• 1/500-1000 males; XXY
• Tall, hypogonadism, gynecomastia, dysgenesis of testes, atrophic tubules, infertile, lack of androgens leading to elevated follicle stimulating hormone; no germ cell production (shooting blanks)
• Diagnosed at puberty or in fertility clinics

• 1/2500 females; XO (45)
• They have phenotypic anomalies because the inactivated X in normal females is not completely silent
• Short stature, webbed neck, lymphedema, low hairline, wide spaced nipples, streak gonads, cardiac abnormalities, horseshoe kidney, visual/spatial and math problems (no MR)
• Diagnosed at birth

Typically normal; problem comes in meiosis (either SAB or children with multiple congenital anomalies)

To look for translocation, amplifications, etc.

• 5p deletion (cry of the cat)
• High pitched cry; MR

t(9;22); CML

t (8;14) myc gene

t(14;18) BCL2 gene

t(11;22)

• abnormal maternal blood screening
• Family history of a genetic disorder
• Ethnicity-based screening
• Abnormal ultrasound

• Ultrasounds, maternal serum screens
• If abnormal, then CVS, amniocentesis, and targeted ultrasound

Maternal serum screen: AFP (neural tube), diametric inhibin (DIA), Conjugated estriol (UE3), or HCG

thickened nuchal fold, congenital heart defects, clinodactyly, absent nasal bone, choroid plexus cyst, echogenic cardiac foci, renal abnormalities

Rocker bottom feet, congenital heart defects, neural tube defects, choroid plexus cysts, clenched hands

• Biopsy of tissue from the villi of the chorion
• Done transcervically or transabdominally
• 1% risk of miscarriage

• Removal of amniotic fluid to retrieve fetal cells
• Transabdominally with ultrasound
• 0.2% risk of miscarriage

severe disease; natural history of disease is understood; effective treatment depends on early diagnosis; enough incidence to make it reasonable; specificity and sensitivity; available to the at risk population; follow-up of positive results available; cost-benefit worthy

Heel blood sample; tandem mass spec (AA disorders); isoelectric focusing; enzyme assays; DNA tests

amino acid deficiency, organic acid, fatty acid, hemoglobinopathies, hypothyroidism, biotinidase, congenital adrenal hyperplasia, galactosemia, CF, and hearing

• PKU (MR, seizures, eczema)
• Maple Syrup Urine Disease (Metabolic acidosis)
• Homocystinuria (long digits, tall, lens dislocation, strokes)
• Tyrosinemia (liver failure and cancer)
• Argininosuccinate lyase deficiency (sepsis like, hyperammonemia, lethargy, coma)
• Citrullinemia (same as above)

• The analytes are acylcarnitines; you get metabolic acidosis, sepsis-like, coma, and death
• Methylmalonic acidemia and methylmalonyl-CoA mutase and Vitamin B12 deficiency

• The analytes are acylcarnitines; you get hypoglycemia, seizures, hypotonia, hepatomegaly, cardiomyopathy
• Medium chain acyl-CoA dehydrogenase deficiency
• Look for fatty liver on autopsy

• decreased activity, jaundice, hoarse cry, coarse facial featues, macroglossia, cool, dry skin
• Treat with iodide supplementation, levothyroxine

• seizures, hypotonia, ataxia, developmental delay, vision problems, skin rash, deafness, metabolic acidosis
• Treat by giving biotin

Site of action in the adrenal gland; you have accumulation of the substrate 17-hydroxyprogesterone

Jaundice, liver failure, MR, direct hyperbilirubinemia

Follow with a diagnostic hearing test; if this is inconclusive, look to genetic testing (connexins)

• Movements (chorea)
• Cognition
• Behavior and mood