Genetics Flashcards
3 categories of genetic DOs
mutation in a single gene with large effects (Mendelian DOs)
chromosomal DOs
Complex multigenic DOs
Mendelian DOs
rare, high penetrance
Sickle cell anemia: strong selective forces (malaria) maintain mutation in population
Chromosomal DOs
structural or numerical alterations in autosomes and sex chromosomes
uncommon
high penetrance
Complex multigenic DOs
more common
Low penetrance
environment and gene interactions (aka polymorphisms)
no single gene necessary or sufficient to produce disease
Examples of complex multigenic DOs
atherosclerosis, diabetes, hypertension, autoimmune diseases, ht and wt
Mutation
permanent change in the DNA
Germ cell mutations give rise to
inherited disease
Somatic cells give rise to
cancer and some congenital malformations
Point mutations within coding sequence
Missense: alter meaning of sequence of encoded protein (sickle cell–>Glu to Val)
Nonsense: stop codon
Mutations in non-coding sequences
promotor or enhancer sequences
defective splicing of intervening sequences
no translation
transcription factors
3 most common transcription factors
MYC, JUN, p53
Deletions and insertions
if multiple of 3, reading frame is intact–>abnormal protein
Frameshift mutation
deletion or insertion not in a multiple of 3–>altering of reading frame
Trinucleotide repeat
amplification of a sequence of 3 nucleotides
almost all contain guanine and cytosine
Anticipation
a genetic disorder is passed on to the next generation, the symptoms become apparent at an earlier age with each generation
increase in severity of symptoms
Huntington’s disease, myotonic dystrophy
Mendelian disorders
every individual is a carrier of 5-8 deleterious genes, most are recessive and no serious phenotypic effects
Codominance
both alleles contribute to phenotype
Pleiotropism
single mutant gene–>many end effects
Genetic heterogeneity
mutations at several loci may produce the same trait
Autosomal dominant (AD) DOs
manifest in the heterozygous state (only one gene affected) so 1 parent is usually affected
New mutations in AD DOs
seem to occur in germ cells of relatively older fathers
if disease decreases reproductive fitness, then most cases would have to be from new mutations
Incomplete penetrance
positive mutation but normal phenotype
Variable expressivity
all positive traits, but expressed differently
Example of variable expressivity
Neurofibromatosis type 1: can have or not have cafe-au-lait spots, skeletal deformities, and/or neurofibromas
decreased product, dysfunctional or inactive protein produced in AD DOs
Loss of function mutations: familial hypercholesterolemia
Gain of function mutations: huntingtin protein toxic to neurons
2 main patterns of disease with AD
regulation of complex metabolic pathways, subject to feedback inhibition
key structural proteins
LDL receptor in familial hypercholesterolemia
50% reduction in receptor–>secondary increase in cholesterol–>atherosclerosis
Key structural proteins affected in AD DOs
collagen and cytoskeletal elements of the RBC membrane (e.g. Spectrin)
Osteogenesis imperfecta
mutant allele can interfere with assembly of functionally normal multimer
AD DO
Age of onset for AD DOs
delayed; symptoms appear in adulthood (30s-50s)
Pedigree for AD
every generation
equally male and female overall
50/50 chance of getting it every generation
Examples of AD disorders
Huntington's disease neurofibromatosis Marfan syndrome Ehlers-Danlos syndrome Osteogenesis imperfecta Familial hypercholesterolemia
Examples of AR disorders
cystic fibrosis phenylketonuria lysosomal storage diseases glycogen storage diseases Sickle cell anemia
Pedigree in AR disorders
Skips generations
affects males and females equally
both males and females can be carriers
AR DOs
largest
both alleles are mutated
3 features of AD DOs
trait usually NOT affect parents
siblings have 1/4 chance of having trait
if mutation is of low frequency in population, strong likelihood proband product of consanguineous marriage
Differentiation between AR and AD
similar trait/phenotype in AR
complete penetrance common
onset EARLY IN LIFE
new mutations rarely detected clinically
many mutations involve enzymes–>inborn errors of metabolism
decreased normal enzyme of defective enzyme
Cystic fibrosis bacterial pathogens
Staphylococcus aureaus, Haemophilus influenzae, and Pseudomonas aeruginosa
Primary defect in cystic fibrosis
CFTR gene on chromosome 7q31.2
epithelial chloride channel protein
What does cystic fibrosis affect (generally)?
fluid secretion in exocrine glands and in the epithelial lining of the respiratory, GI, and reproductive tracts
abnormal viscous secretions that obstruct organ passages
Main consequences of CF
chronic lung disease (recurrent infections), pancreatic insufficiency, steatorrhea, malnutrition, hepatic cirrhosis, intestinal obstruction, and male infertility
When does CF appear?
at any point in life from before birth to much later into childhood or adolescence
CF pancreas
slightly hyperemic, granular, exaggerated lobulation, rounded edges
cysts, chronic pancreatitis
Bronchiectasis
airway dilation and scarring of bronchus due to persistent or severe infections
signs/symptoms: cough, purulent sputum, fever
Emphysema
airspace enlargement; wall destruction of acinus due to tobacco smoke
signs/symptoms: dyspnea
SI of CF pts
meconium ileus: unable to pass a stool within the first 48 hours of birth due to distended SI
What is the most common lethal genetic disease that affects Caucasian populations?
CF; 1 in 2500 live births
Who has a higher incidence of respiratory and pancreatic disease as compared with the general population?
Heterozygous carriers of CF
Genes other than CFTR modify the frequency and severity of certain organ-specific manifestations such as what?
pulmonary manifestations and meconium ileus
Male urogenital abnormalities and CF
obstructive azoospermia
How to test for CF?
sweat chloride test–>infant will taste salty to the mother
Phenylketonuria (PKU)
Scandinavian descent; NOT AA or Jewish
AR
phenylalanine hydroxylase (PAH) deficiency–>too much phenylalanine
What does PAH convert phenylalanine to?
tyrosine
tyrosine is a precursor for melanin
When does PKU present?
6 months
Signs and symptoms of PKU
severe MR, hypopigmentation of hair and skin, eczema
musty/mousy odor of urine
Treatment of PKU
dietary restrictions
Deficiency of what other enzyme besides PAH can give rise to PKU?
DHPR
X-linked Recessive DOs
Duchenne muscular dystrophy
glucose-6-phosphate dehydrogenase deficiency
Fragile X syndrome
Affects on males of X-linked recessive DOs
infertility, hence no Y-linked inheritance
What is the affect on women with X-linked recessive DOs?
all daughters of affected males are carriers
heterozygous female not express full phenotypic change because of normal paired allel
Pedigree for X-linked recessive DOs
all males; skipping generations
Mitochondrial inheritance
all from mom
affected males do not pass it on
all positive females pass it on to every offspring
Enzyme defecient mendelian DOs
PKU
Tay-Sachs disease
Receptor deficient mendelian DOs
familial hypercholesterolemia
Oxygen ion channels-hemoglobin mendelian DO
Sickle cell anemia
Oxygen ion channels-CFTR mendelian DO
Cystic fibrosis
Extracellular collagen mendelian DOs
Ehlers-Danlos syndromes
Cell membrane mendelian DOs
Marfan syndrome
Mendelian DOs
alterations in a single gene–>abnormal product or decreased normal product
4 main categories of Mendelian DOs
enzyme defects and their consequences
defects in membrane receptors and transport systems
alterations in structure, function, or quantity of non-enzyme proteins
mutations resulting in unusual reactions to drugs
Enzyme mutations
decreased activity or decreased amount of normal enzyme
3 major consequences of enzyme mutations
accumulation of substrate
precursor, intermediate, or alternative product that is toxic
Decreased amount of end product
failure to inactivate a tissue-damaging substrate
Example of accumulation of substrate due to enzyme mutation
Galactosemia: galactose-1-phosphate uridyltransferase deficiency
Example of decreased amount of end product due to enzyme mutation
Albinism: lack of tyrosinase–> decreased melanin
Lesch-Nyhan: increased intermediate product and their breakdown produces toxins
Example of failure to inactivate a tissue-damaging substrate due to enzyme mutation
alpha1- antitrypsin: unable to inactivate neutrophil elastase in lung–>emphysema
Examples of defects in receptors and transport systems leading to mendelian DOs
familial hypercholesterolemia: decreased synthesis of decreased function of LDL receptor–>defective transport of LDL into cells–>secondary increase in cholesterol synthesis
CF: Cl- ion transport in exocrine sweat glands, sweat ducts, lungs and pancreas defective
Sickle cell disease
alteration in structure, function, or quantity of non-enzyme proteins–> defect in structure of globin molecule
Thalassemias
alterations in structure, functions, or quantity of non-enzyme proteins
mutation in globin gene affects amount of globin chains synthesized
Examples of alterations in structure, functions, or quantity of non-enzyme proteins
collagen, spectrin, dystrophin, osteogenesis imperfecta, hereditary spherocytosis, muscular dystrophies
Enzyme deficiencies unmasked after exposure to drug
G6PD deficiency: antimalarial primaquine–>severe hemolytic anemia
Marfan syndrome inheritance and genes/chromosomes
AD
FBN1 chromosme 15Q21.1
FBN2 chromosome 5q23.31 (less common)
1 in 5,000; 70-85% familial
What is defective in Marfan’s?
extracellular glycoprotein fibrillin-1
2 fundamental mechanisms by which loss of fibrillin leads to Marfan’s
loss of structural support in microfibril rich CT
excessive activation of TGF-beta signaling
Clinical features of Marfan’s
Tall, exceptionally long extremities, long fingers and toes, increased flexibility, low lactate levels in lungs, short legs, dolicocephalic (long-headed) with frontal bossing and prominent supraorbital ridges, pectus excavatum
Ectopia lentis
seen in Marfan’s; bilateral subluxation/dislocation of the lens
Usual COD for Marfan’s
aortic dissection; can also overall have mitral valve prolapse, dilation of ascending aorta, passive dilation of the aortic valve ring and root of the aorta
Pt symptoms during aortic dissection
tearing feeling in chest or between scapula
Ehlers-Danlos syndromes (EDS)
defect in the synthesis or structure of fibrillar collagen
skin is hyperextensible, joints are hypermobile
skin is stretchable, fragile, and vulnerable to trauma
Gaping defects
seen in minor injuries in those with EDS; surgical repair or intervention is difficult due to lack of normal tensile strength
Normal COD for EDS pts
rupture of the colon and large arteries (vascular EDS)
Classic EDS internal complications
diaphragmatic hernia
Kyphoscoliosis EDS internal complications
ocular fragility with rupture of cornea and retinal detachment
Classic EDS gene defects
COL5A1, COL5A2
Vascular EDS gene defects
COL3A1
Kyphoscoliosis EDS gene defects
lysyl hydroxylase
Familial hypercholesterolemia
mutation of receptor for LDL
1 in 500 birth have a 2-3 fold increase in cholesterol
Tendinous xanthomas
deposit of cholesterol that looks yellow- seen in familial hypercholesterolemia
Risks of increased cholesterol
premature atherosclerosis, increased risk of MI
Are hetero or homozygotes more severely affected in familial hypercholesterolemia?
homozygotes: 5-6 fold increase in plasma cholesterol levels
Homozygotes in familial hypercholesterolemia risks
skin xanthomas, coronary, cerebral, and peripheral vascular atherosclerosis at early age; MI before 20 y.o.
Sign seen in eyes in homozygotes in familial hypercholesterolemia
arcus cornelius: deposit of material in cornea; usually seen in older pts but can be seen in young pts with this issue
Mutation class I familial hypercholesterolemia
no synthesis of LDL receptor
Mutation class II familial hypercholesterolemia
synthesis, but no transport of LDL receptor
Mutation class III familial hypercholesterolemia
synthesis, transport, but no binding of LDL receptor
Mutation class IV familial hypercholesterolemia
synthesis, transport, binding, but no clustering of LDL receptor
Mutation class V familial hypercholesterolemia
synthesis, transport, binding, clustering, but no recycling of LDL receptor
Lysosomal storage diseases
catabolism of the substrate of the missing enzyme remains incomplete, leading to the accumulation within the lysosomes- primary accumulation
Primary accumulation in LSD
stuffed with incompletely digested macromolecules, lysosomes become large and numerous enough to interfere with normal cell functions
Secondary accumulation in LSD
impaired lysosomal function–>impaired autophagy–>accumulation of autophagic substrates
3 general approaches to treatment of LSD
enzyme replacement therapy
substrate reduction therapy
molecular basis of enzyme deficiency
Primary storage in LSD
defective fusion of autophagosome with lysosome
defective degradation of intracellular organelles
Secondary storage in LSD
accumulation of toxic proteins
accumulation of aberrant mitochondria
Enzyme deficiency in Tay-Sachs disease
Shingolipidoses; hexosaminidase- alpha subunit
Major accumulating metabolite in Tay-Sachs disease
G M2 ganglioside
Gaucher disease enzyme deficiency
Sulfatidoses; glucocerebronsidase
Major accumulating metabolite in Gaucher disease
glucocerebroside
Niemann-Pick diseases: A and B major accumulating metabolite
Sulfatidoses; sphingomyelinase
Major accumulating metabolite in Niemann-Pick
sphingomyelin
MPS I H (Hurler) disease enzyme deficiency
Mucopolysaccharidoses (MPSs)
MPS II H (Hunter) disease enzyme deficiency
Sulfatidoses
Major accumulating metabolite in MPS I and II
dermatan sulfate, heparan sulfate
Tay-Sachs disease
GM2 Gangliosidosis: Hexosaminidase alpha-subunit deficiency
What are GM2 gangliosidoses?
a group of 3 lysosomal storage diseases caused by an inability to catabolize GM2 gangliosides
Chromosome affected in Tay-Sachs disease
mutation in the alpha-subunit locus on chromosome 15–>severe deficiency of Hexosaminidase A
Ethnic group most affected by Tay-Sachs disease
Ashkenazic Jews; carrier rate of 1 in 30
Age of onset of symptoms of Tay-Sachs disease
6 months motor and mental deterioration; obtunded, flaccidity, blindness, and dementia
Affect of Tay-Sachs disease
1-2 yo vegetative state; death by age 2-3 yo
Classic sign for Tay-Sachs disease
cherry red spot in the macula: ganglion cells of retina swollen, especially around macula
GM2 ganglioside accumulates where?
neurons, retina, heart, liver, spleen
Fat stains on what are positive in Tay-Sachs disease?
cytoplasmic inclusions; oil red O and Sudan black B are positive
Tay-Sachs disease on stains
see whorled lysosomes and lipid vacuoles in neuron cytoplasm
Niemann-Pick disease, types A and B
lysosomal accumulation of sphingomyelin due to inherited deficiency of sphingomyelinase
Inheritance of Niemann-Pick disease
AR, Ashkenazi Jews, Chromosome 11p15.4–>maternal chromsome
Type A Niemann-Pick disease
severe infantile form; complete lack of sphingomyelinase; extensive neuro involvement, visceral accumulations of sphingomyelin; progressive wasting
Symptoms onset and death for Type A Niemann-Pick disease
symptoms by 6 months; death before 3 yo
Type B Niemann-Pick disease
organomegaly, NO CNS involvement; reach adulthood
Type C Niemann-Pick disease
most common, NPC1 (95%), transport free cholesterol from lysosomes to cytoplasm
Symptoms of Type C Niemann-Pick disease
progressive neuro damage; ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor regression
Morphology of cells in Niemann-Pick disease
enlarged due to sphingomyelin and cholesterol accumulation; foamy cytoplasm; zebra bodies
Zebra bodies
Niemann-Pick disease; lysosomes with concentric lamellations (EM)
Distinguishing factor of Niemann-Pick disease
massive splenomegaly; accumulation in spleen, liver, LN, BM, tonsils, GI tract, lungs
1/3-1/2 have cherry red spots in retina; vacuolation and ballooning of neurons, brain atrophy
Gaucher disease
Glucocerebrosidase mutation
accumulation of glucocerebroside in phagocytes primarily, CNS also
damage due to accumulation and activation of macrophages
Cytokines released when macrophages are activated
IL-1, IL-6, and TNF
Inheritance of Gaucher disease
AR
Most common lysosomal storage DO
Gaucher disease
Type I Gaucher disease
chronic; 90% of cases; European Jews; NO CNS involvement, spleen and bone symptoms, slight decrease in life span
Type II Gaucher disease
acute neuronopathic: infantile cerebral pattern, progressive CNS involvement, early death, hepatosplenomegaly; NOT JEWISH
Type III Gaucher disease
Intermediate; systemic involvement with progressive CNS disease that begins in adolescence or early adulthood
Morphology of Gaucher disease
distended phagocytic cells- Gaucher cells in liver, spleen, BM, LN, tonsils, thymus, and Peyer’s patches
fibrillary type cytoplasm–> crumpled tissue paper
Distinguishing factor of Gaucher disease
Enlarged spleen–> >10kg; pancyotpenia or thrombocytopenia (BM)
Treatment of Gaucher disease
allogenic hematopoietic stem cell transplant; recombinant enzyme
Mucopolysaccharidoses (MPS)
deficient enzymes degrading glycosaminoglycans
Mucopolysaccharides abundant in ground substance of CT
MPS abundant in CT
dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate
Inheritance of MPS
All AR except Hunter syndrome–>X-linked recessive
Clinical features of MPS
coarse facial features, clouding of the cornea, joint stiffness, MR
Hurler syndrome
MPS I-H: normal at birth, hepatosplenomegaly by 6-24 months, death 6-10 yo
COD for Hurler syndrome
Cardiovascular complications: coronary arterial and valvular deposits; growth retardation, coarse facial features, skeletal abnormalities
Hunter syndrome
MPS II; X-linked; NO corneal clouding, milder clinical course
Distinguishing factor between Hurler and Hunters
No corneal clouding–>Hunters
Corneal clouding–>Hurlers
Where are mucopolysaccharides found?
Mononuclear phagocytic cells, endothelial cells, intimal SM cells, fibroblasts
Balloon cells
clear cytoplasm, multiple vacuoles- swollen lysosomes PAS
MPS morphology
balloon cells, lamellated zebra bodies
Common clinical features to all MPSs
hepatosplenomegaly, skeletal deformities, valvular lesions, and subendothelial arterial deposits, and brain lesions
COD for MPS
MI and cardiac decompensation
Hepatic type of Glycogenoses
Hepatorenal- von Gierke disease (Type I)
Morphological changes in von Gierke disease
hepatomegaly-accumulations of glycogen and small amounts of lipid; intranuclear glycogen
Renomegaly- accumulation of glycogen in cortical tubular epithelial cells
Clinical features of von Gierke disease
failure to thrive if untreated; hepatosplenomegaly and renomegaly Hypoglycemia Hyperlipidemia and hyperuricemia gout and skin xanthomas bleeding tendency
Miscellaneous type of Glycogenoses
Pompe disease (Type II)
Enzyme deficiency in von Gierke disease
glucose-6-phosphatase
Enzyme deficiency in Pompe disease
lysosomal glucosidase (acid maltase)
Morphological changes in Pompe disease
mild hepatomegaly
lacy cytoplasmic patterns in lysosomes
cardiomegaly-glycogen in sarcoplasm
skeletal M. similar to changes in heart
Clinical features of Pompe disease
Major cardiomegaly
muscle hypotonia
cardiorespiratory failure within 2 years
milder adult form with only skeletal muscle involvement, presenting with chronic myopathy
Can you survive von Gierke’s disease if treated?
Yes, develop late complications
Glycogen storage diseases
Glycogenoses
hereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen
Result of glycogen storage diseases
storage of normal or abnormal forms of glycogen, predominantly in the liver or muscle
3 major subgroups of GSD
Hepatic forms
Myopathic forms
Miscellaneous
Hepatic form of GSD
von Gierke type I: Glucose-6-phosphatase deficiency
liver key to glycogen metabolism; increase of storage of glycogen in liver and decreased blood glucose concentrations (hypoglycemia)
Myopathic form of GSD
skeletal muscle; increased glycogen storage in muscle and muscle weakness; muscle cramps after exercise, no increase in blood lactate after exercise due to block McArdle disease (type V): muscle phosphorylase deficiency
Miscellaneous GSD
deficiency of glucosidase (acid maltase) and lack of branching enzyme Pompe disease (type II): acid maltase deficiency-->cardiomegaly associated with glycogen storage in many organs and death early in life
Morphology of Pompe Disease
glycogen filled myocardial cells
Multifactorial inheritance
environmental influences with two or more genes affected
most common genetic cause of congenital malformations
Common malformations for multifactorial inheritance
cleft lip, cleft palate, and neural tube defects (folic acid)
What can reduce the incidence of neural tube defects?
periconceptional intake of folic acid in diet
A range of levels of severity of a disease is suggestive of what?
a complex multigenic disorder
Variable expressivity and reduced penetrance can be found also in what types of mutations?
single mutant genes
What makes it difficult to distinguish between Mendelian and multifactorial disease?
Variable expressivity and reduced penetrance seen in both complex multigenic disorders and single mutant genes
Chromosomal DOs
Euploid, aneuploid, monosomy, mosaicism
Euploid
any exact multiple of haploid number (23)
Aneuploid
NOT an exact multiple of 23
Nondisjunction
aneuploidy; gametogenesis, gametes have +/- 1 chromosome
Anaphase lag
Aneuploidy; during either meiosis or mitosis one chromatid lags behind and is left out of the cell nucleus–>one normal cell and one monosomy cell
Monosomy involving an autosome causes…
loss of too much genetic info to permit live birth or even embryogenesis
Do several autosomal trisomies permit survival?
Yes
Mosaicism
mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement, in the same individual
can affect sex chromosomes
Ring chromosome
break occurs at both ends of a chromosome with fusion of the damaged ends
e.g. 46 XY, r (14)
Inversion
rearrangement that involves 2 breaks within a single chromosome with reincorporation of the inverted intervening segment
Paracentric inversion
inversion involving only one arm of the chromosome
Pericentric inversion
breaks are on opposite sides of the centromere
Isochromosome
one arm of a chromosome is lost, remaining arm is duplicated, resulting in a chromosome consisting of 2 short arms only or 2 long arms only
Translocation
segment of one chromosome is transferred to another one
Balanced reciprocal translocation
single breaks in each of 2 chromosomes, with exchange of material; NO LOSS of material, likely normal phenotype
Robertsonian translocation
centric fusion; translocation between 2 acrocentric chromosomes; typically breaks appear closer to the centromeres of each chromosome
Resulting chromosomes in Robertsonian translocation
1 very large chromosome and 1 extremely small one
small one is usually lost, but because it carries only highly redundant genes–>normal phenotype
Prevalence of Robertsonian translocation
1 in 1000
Trisomy 21
3-4% caused by Robertsonian translocation
q arm of chromosome 21 is translocated onto another chromosome–>46 chromosomes, but 3 copies of the long arm of chromosome 21, which carries all of the functional genes of this chromosome
Clinical features trisomy 21
flat facial profile, oblique palpebral fissures, pericanthal folds, brushfield spots on iris, short, broad hands with simian crease, wide gap between first and second toes
Trisomy 21 (Down Syndrome)
most common chromosomal DO; major cause of MR; 47 chromosomes
Incidence of Down Syndrome
1 in 700; maternal age strong influence
1% of Down syndrome pts are…
mosaics, mixture of cells with either 46 or 47 chromsomes
COD Down Syndrome
40% of pts have congenital heart disease
include AV septal defects, AV valve malformations, ventricular septal defects, ostium primum
Pts with Down Syndrome have a 10 to 20-fold increased risk in developing what?
Acute leukemia
Pts over 40 with Down Syndrome develop changes characteristic to what disease?
Alzheimer disease
Down syndrome and immunity
abnormal immune responses that predispose them to serious infections, particularly of the lungs and thyroid
Trisomy 18
Edwards syndrome 1 in 8000 births micrognathia overlapping fingers renal malformations rocker-bottom feet
Trisomy 13
Patau syndrome 1 in 15,000 cleft lip and palate, polydactyly microphtlamia umbilical hernia renal defects rocker-bottom feet
Chromosome 22q11.2 deletion syndrome
congenital heart defects, abnormalities of the palate, facial dysmorphism, developmental delay, T-cell immunodeficiency and hypocalcemia
Incidence: 1 in 4000
DiGeorge syndrome
Chr 22q.11.2 deletion syndrome
thymic hypoplasia, with resultant T-cell immunodeficiency, parathyroid hypoplasia–>hypocalcemia, cardiac malformations, and mild facial anomalies
CATCH 22
Velocardiofacial syndrome
Chr 22q.11.2 deletion
eyes: narrow palpebral fissures, puffy lids
ears: over-folded helix and attached lobule
Nose: pear-shaped; square nasal bridge
cleft palate, cardiovascular anomalies, learning disabilities
CATCH 22
DiGeorge Syndrome Cardiac abnormality Abnromal facies Thymic aplasia Cleft palate Hypocalcemia/hypoparathyroidism
Sex Chromosome DOs
genetic diseases associated with changes involving the sex chromosomes
more common than autosomal aberrations
Imbalances of sex chromosomes vs. autosome imbalances
much better tolerated than are similar imbalances of autosomes
2 factors that are peculiar to the sex chromosomes
lyonization or inactivation of all but one X chromosome
the modest amount of genetic material carried by the Y chromosome
Lyon hypothesis
only 1 X chromosome is genetically active; other one undergoes heteropyknosis–>inactive
inactivation of the other X chromosome is random during blastocyst stage
inactivation of the same X chromosome persists in all cells derived from each precursor cell
Normal females are in reality what genetically?
Mosaics and have two populations of cells, one with an inactivated maternal X and the other with an inactivated paternal X
Barr body
inactive X that can be seen in the interphase nucleus as a darkly staining small mass in contact with the nuclear membrane
Lyonization
X-inactivation–>Barr body produced
What determines the male sex?
the presence of a single Y
What do sex chromosome disorders lead to?
subtle, chronic problems relating to sex development and fertility
When are sex chromosome disorders diagnosed?
Difficult at birth, usually at puberty
The greater the number of (blank), the greater the likelihood of (blank)
the number of X chromosomes; mental retardation
Klinefelter syndrome
47, XXY
male hypogonadism when greater than 2X or greater than 1Y
Incidence of Klinefelter syndrome
1 in 660 live male births–>hypogonadism diagnosed after puberty
Clinical findings in Klinefelter’s
eunuchoid body habitus with abnormally long legs, small atrophic testes and small penis; gynecomastia; lower IQ
deep voice, beard, and male distribution of pubic hair
Pts with Klinefelters have an increased risk of what other diseases?
Type 2 DM and metabolic syndrome; 50% mitral valve prolapse; osteoporosis and fractures due to hormone imbalance
How does Klinefelter syndrome cause male infertility?
reduced spermatogenesis
Those with Klinefelter’s have 20x increased risk of developing what diseases?
Breast; extragonadal germ cell tumors, and autoimmune diseases such as SLE
Turner Syndrome
45X
complete or partial monosomy of X chr, characterized primarily by hypogonadism in phenotypic females
Karyotypes in Turner syndrome
45, X/46 XX;
45, X/46XY
45, X/47,XXX
Incidence of Turner syndrome
1 in 2500; most common sex chromosome abnormality in females
3 types of karyotypic abnormalities in Turner syndrome
57% are missing an entire X chromosome–>45, XO karyotype
common feature is to produce partial monosomy of X chromosome
mosaic pts have a 45, X cell population plus more than one karyotypically normal or abnormal cell type
Cystic hygroma
infant with edema–>swelling of the nape of the nneck due to lymph stasis
swellings subside but leave bilateral neck webbing and persistent looseness of skin on the back of the neck
related to Turner Syndrome
Turner syndrome and congenital heart disease
25-50% of pts; left-sided CV abnormalities, preductal coarctation of the aorta and bicuspid aortic valve
COD in children with Turner syndrome
CV abnormalities
Clinical features of Turner
shortness of stature, amenorrhea, webbing of neck, cubitus valgus, CV malformations, lack of secondary sex characteristics, fibrotic ovaries, widely spaced nipples
Most important cause of primary amenorrhea
Turner syndrome
Menopause before menarche
Turner syndrome
ovaries are decreased atrophic fibrous strands, devoid of ova and follicles–>streak ovaries
Turner syndrome and the thyroid
develop autoantibodies that react with the thyroid gland; less than half develop hypothyroidism
Metabolic affects in some Turner syndrome pts
glucose intolerance, obesity, insulin resistance
Hermaphroditism
the presence of both ovarian and testicular tissue
Pseudohermaphrodite
disagreement between the phenotypic and gonadal sex
Female pseudohermaphrodite
has ovaries, but male external genitalia
Male pseudohermaphrodite
has testicles, but female-type genitalia
4 categories of single-gene disorders with nonclassical inheritance
trinucleotide-repeat mutatoins
mutations in mitochondrial genes
genomic imprinting
gonadal mosaicism
Trinucleotide repeat DOs
Fragile X syndrome
Huntington disease
Expansions affecting noncoding regions
Fragile X syndrome
Expansions affecting coding regions
Huntington’s disease
Trinucleotide-repeat mutations
expansion of trinucleotide repeats–>neurogenerative disorders
The expansion of a stretch of trinucleotides usually share what nucleotides?
G and C
What does the proclivity to expand in TNR mutations depend on?
sex of the transmitting parent
3 key mechanisms by which unstable repeats case diseases
Loss of function
Toxic gain of function
Toxic gain of function mediated by mRNA
Example of loss of function due to TNR mutations
Fragile X syndrome
non-coding
transcription silencing
Example of toxic gain of function due to TNR mutations
alteration of protein structure
Huntington disease and spinocerebellar ataxias
coding regions
Example of toxic gain of function mediated by mRNA due to TNR mutations
fragile X tremor-ataxia syndrome
noncoding part of gene
Morphological hallmark of TNR mutations
accumulation of aggregated mutant proteins in large intranuclear inclusions
Fragile X Syndrome
second most common genetic cause of MR (Down’s #1)
trinucleotide mutation in the familial mental retardation-1 (FMR1)
CGG repeats–> 200-4000
When does loss of function of the FMR protein occur? (transcriptional silencing)
trinucleotide repeats in the FMR1 gene exceed 230–>leads to abnormal methylation of gene
Incidence of Fragile X syndrome
1 in 1550 for males, 1 in 8000 for females
Clinical features of Fragile X syndrome
males–>MR; long face with a large mandible, large everted ears, large testicles (macro-orchidism), hyperextensible joints, high arched palate, mitral valve prolapse
Most distinctive feature of Fragile X syndrome
macro-orchidism (large testicles)
Carrier males in Fragile X syndrome
20% of males who are clinically and cytogenetically normal
carrier males transmit the trait through all their phenotypically normal daughters to affected grandchildren
called normal transmitting males
What happens to the # of TNR when carrier males pass to their progeny?
small changes in repeat number
What happens to the # of TNR when carrier females pass to their progeny?
dramatic amplification of the CGG repeats–>MR in most male offspring and 50% of female offspring
Premutations of TNR in Fragile X syndrome can be converted via what during the process of what?
converted to mutations by triplet-repeat amplification in oogenesis, not spermatogenesis
Affected females of Fragile X syndrome
30-50% of carrier females are affected
much higher than that in other X-linked recessive disorders
Risk of phenotypic effects of Fragile X syndrome
risk depends on the position of the individual in the pedigree
Ex: brothers of transmitting males are at a 9% risk, but grandsons are at a 40% risk
Anticipation of Fragile X syndrome
Clinical features of fragile X syndrome worsen with each successive generation, as if the mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons and great-grandsons
Huntington Disease (HD)
AD disease
progressive movement disorders and dementia, caused by degeneration of striatal neurons
HD is the prototype of what diseases?
polyglutamine trinucleotide repeat
Gene, chromosome, and protein affected in Huntington’s disease
HTT, 4p16.3, huntingtin
Fatality of Huntington’s disease
Average about 15 years after diagnosis
Anticipiation of Huntington’s disease
repeat expansions during spermatogenesis, so the paternal transmission is associated with early onset in the next generation
Mutations in mitochondrial genes
ova contain numerous mitochondria; spermatozoa contain a few
mtDNA complement of the zygote is only from ovum
Transmission of mtDNA
mothers–>all offspring
daugthers, not sons, transmit the DNA further to their progeny
Heteroplasmy
tissues and individuals harbor both wild-type and mutant mtDNA
Threshold effect
minimum number of mutant mtDNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease
Prototype of mtDNA disorder
Leber hereditary optic neuropathy
Leber hereditary optic neuropathy
neurodegenerative disease that manifests as a progressive bilateral loss of central vision
first noted between 15-35 yo
eventual blindness
Genomic imprinting
imprinting selectively inactivates either the maternal or paternal allele
Maternal imprinting
transcriptional silencing of the maternal allele
Paternal imprinting
paternal allele is inactivated
When does imprinting occur?
in ovum or sperm before fertilization and then is stably transmitted to all somatic cells through mitosis
Deletions in genomic imprinting
gene or set of genes on maternal chromosome 15q12 is imprinted (silenced)
only functional alleles are provided by the paternal chromosome
70% of cases
Uniparental disomy
Prader-Willi syndrome
two maternal copies of chromosome 15
20-25% of cases
Defective imprinting
1-4% of pts
some pts with Prader-Willi–>paternal chromosome carries the maternal imprint
Angelman syndrome–>maternal chromosome carries the paternal imprint
both lead to no functional alleles
Prader-Willi syndrome
Paternal deletion
MR, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, hypogonadism
Gene and chromosome affected in Prader-Willi
chr 15, del(15)(q11.2.q13)
Angelman syndrome
Maternal deletion
born with a deletion of the same chromosomal region derived from their mothers
Clinical features of Angelman
MR, ataxic gait, seizures, inappropriate laughter
happy puppets
Indications for prenatal testing for cytogenic abnormalities
advanced maternal age
parent known to carry a balanced chromosomal rearrangement
fetal anomalies observed on US
routine maternal blood screening, indicating an increased risk of Down Syndrome or another trisomy
Genetic analysis in the diagnosis and treatment of cancer
detection of tumor-specific acquired mutations and cytogenic alterations that are hallmarks of specific tumors
determination of clonality as an indicator of a neoplastic condition
ID of specific genetic alterations that can direct therapeutic choices
determination of a treatment efficacy
detection of drug-resistant secondary mutations in malignancies treated with genetically tailored therapeutics
Diagnosis and management of infectious disease
detection of microorganism-specific genetic material for definitive diagnosis
ID of a specific genetic alterations in the genomes of microbes that are associated with drug resistance
determination of treatment efficacy
What cells are used for prenatal testing?
obtained by amniocentesis, chorionic villus biopsy, or umbilical cord blood
as much as 10% of the free DNA in a pregnant mother’s blood is of fetal origin–>noninvasive diagnostics utilizing this source of DNA
How is testing after birth performed?
peripheral blood DNA and is targeted based on clinical suspicion
When to suspect a genetic syndrome
the presence of one obvious malformation should not limit the full evaluation, because additional, more subtle finding will often be important in that differential diagnosis
VATER association
when to suspect a genetic syndrome vertebral anal anomalies cardiac (VACTERL) treacheo-esophageal fistula renal anomalies limb anomalies
When is real-time PCR used?
monitor the frequency of cancer cells bearing characteristic genetic lesions in the blood or in the tissues or the infectious load of certain viruses
What is used to detect somatic point mutations in oncogenes?
real-time PCR
KRAS and BRAF
Fluorescence in Situ Hybridization (FISH)
uses DNA probes that recognize sequences specific to particular chromosomal regions
What is FISH used to detect?
abnormalities of chromosomes (aneuploidy) or complex translocations that are not demonstrable by routine karyotyping
gene amplification
What to submit for FISH
prenatal sample (amniotic fluid or chorionic villi)
peripheral blood
cytology material (touch prep)
Formalin fixed paraffin embedded tissue
Genomic array technology
detects genomic abnormalities
test DNA and normal DNA are labeled with two different fluorescent dyes
differentially labeled samples are co-hybridized to an array spotted with DNA probes that span the human genome at regularly spaced intervals
Repeat-length polymorphisms
short repetitive sequences of DNA give rise to these; divided based on their length
Minisatellites
10-100 base pairs; repeat-length polymorphisms
Microsatellites
1-9 bp; repeat-length polymorphisms
Epigenetics
the study of heritable chemical modification of DNA or chromatin that does not alter the DNA sequence itself
Example of epigenetic alterations
methylation of DNA and the methylation and acetylation of histones
What diseases involve methylation?
Fragile X syndrome, Prader-Willi, and Angelman syndromes
RNA analysis
HIV and Hepatitis C
mRNA expression profiling–>breast cancer
Assays to detect genetic polymorphisms are important to determine what?
relatedness and identity in transplantation, cancer genetics, paternity testing, and forensic medicine
Genome-Wide Analysis
large cohorts of pts with and without a disease are examined across the entire genome for common genetic variations or polymorphisms that are overrepresented in pts with the disease
Next-generation sequencing (NGS)
newer DNA sequencing technologies that are capable of producing large amounts of sequence dataa in a massively parallel manner
Clinical application of NGS
targeted sequencing–>common genetic diseases or cancers
whole exome sequencing–>looks at the 1.5% of genome that is encoding protein
Whole genome sequencing-cancers
Standard of care in lung cancers
