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1
Q

Penetrance

A

-The fraction of individuals with a trait (disease) genotype who show manifestations of the disease. If all persons carrying a mutation have the trait, the condition is 100% penetrant. If some mutation carriers do not show signs of the trait, penetrance is incomplete (

2
Q

Expressivity

A

The degree to which a trait is expressed in an individual (is a measure of severity). Expressivity is analogous to a light dimmer (the light is ‘on’ but the brightness (expressivity) exists along a spectrum (of severity)). The variation in phenotype is explained (in part) by sex influence, environmental factors, stochastic effects, and modifier genes

3
Q

Sex influence and sex limitation

A

Phenotypic expression in some conditions is dependent on the individual’s sex (e.g. gout is more common in males than premenopausal females). Sex limitation occurs if only one sex can express a phenotype (e.g. unicornuate uterus).

4
Q

Stochastic Effects on Mendelian gene patterns

A

Stochastic (random) effects can influence the expression of
phenotypes. This concept pays homage to the fact that some phenotypes may be influenced by chance events/processes absent any obvious genetic/environmental factor.

5
Q

Modifier genes and Mendelian inheritance

A

Genetic factors outside of the genetic locus causing a disease can be important for the expression of Mendelian diseases.

6
Q

Phenocopies

A

Diseases (traits) that are due to non-genetic factors. Example: A thyroid cancer due to radiation exposure cannot always be distinguished from a thyroid cancer due to mutations in RET gene.

7
Q

Pleiotropy

A
Used to describe multiple different phenotypic effects due to mutation(s) in a single gene. Often used, when the phenotypes are seemingly unrelated and/or in multiple different tissues. Example: Neurofibromatosis Type I leads to: café au lait spots (skin), neurofibromas (peripheral nervous tissue), hammartomas in the eyes (ocular),
abnormal freckling (skin again), and learning difficulties (central nervous system).
8
Q

Polymorphism:

A

A genetic variant (mutation) which is common (>1%) in the populations

9
Q

Founder effects:

A

a high frequency of a mutant allele in a population founded by a small ancestral
group when one or more of the original founders was a carrier of the mutant allele

10
Q

Genetic drift:

A

random fluctuation of allele frequencies, usually in small populations

11
Q

Estimating Autosomal dominant mutation rates (direct method)

A

For autosomal dominant conditions with 100% penetrance one can simply count
the number of new cases that occur with no family history. For example, if 12 disease cases are
identified in 100,000 children and 10 of the 12 cases have a negative family history, then the
mutation rate is 10/100,000 children. Since each child actually as 2 alleles for each gene the
theoretical gene ‘mutation-rate’ (μ) is 10/200,000, or 1/20,000 alleles

12
Q

Estimating autosomal dominant mutation rates (indirect method)

A

For an autosomal dominant condition where the reproductive fitness (f) is zero
(i.e. affected persons do not survive to reproduce and/or are infertile) then all cases represent new
mutations. Since each child inherits 2 genes (each could mutate) then the incidence (I) of disease
is really twice the mutation rate  I = 2μ.

13
Q

Mutation rate estimation for nonzero fitness

A
Autosomal dominant: μ= 1/2 F (1-f) 
Autosomal recessive μ= F (1-f) 
X-linked recessive μ= 1/3 F (1-f) 
mu= mutation rate
f=fitness
F=frequency of disease
14
Q

Hardy-Weinberg equation

A

p^2+ 2pq + q^2= 1.
In rare conditions q is small, making q^2
very small so 2pq&raquo_space; q^2. This means that
most copies of the minor allele are found in
heterozygotes.

15
Q

Idealized Assumptions in Hardy-Weinberg Equilibrium (HWE):

A

 Large population mating randomly
 Allele frequencies remain constant over time because:
o No appreciable rate of new mutation
o No selection for/against any allele
o No appreciable immigration/emigration of persons from population with different allele
frequencies

16
Q

Stratification (Non-random mating)

A

refers to populations containing 2 or more subgroups which tend preferentially mate
within their own subgroup. Mate selection is not dependent on the trait/disease or interest.
(Example: sickle cell anemia in African Americans (AAs) has hig

17
Q

Assortive mating

A

refers to when the choice of mate is dependent (in part) on a particular trait (or
sometimes a disease). This occurs because people tend to choose mates who resemble
themselves for (language, intelligence, height, skin color, etc.). This has been observed for
congenital short stature (previously called ‘dwarfism’), blindness, and deafness.

18
Q

 Consanguinity,

A

occurs when persons marry closely-related blood relatives. This, non-random,
mating practice increases matings between carriers of autosomal recessive diseases, thereby
increasing the number of cases of autosomal recessive diseases in the population.2

19
Q

Mendel’s law of segregation

A

Law of Segregation:
At meiosis each allele (2) of a single gene separates/segregates into different gametes –> 50/50 ratio
Basically, all the alleles split up into different gametes

20
Q

Mendel’s law of independent assortment

A

Law of Independent Assortment:
At meiosis the segregation of each pair of alleles in >= 2 genes is independent –> each 50/50 ratio
Separate genes for separate traits are passed along to offspring independently of one another – they’re ‘independently assorted’

21
Q

X-linked recessive inheritance pattern

A

X-linked recessive:

  • if you’re female, will not display phenotype, but will be a carrier
  • if you’re male, and your mother is a carrier, you have a chance of getting it. If your father is a carrier, you will not get it
22
Q

X-linked dominant inheritance

A
  • if the father has it – all daughters will definitely display phenotype. Sons will not.
  • if the mother has it – daughters & sons may get it
23
Q

Three “threats” to mendelian inheritance

A

Penetrance:
Affected/unaffected
(lightswitch)

Expressivity:
Severity
(Dimmer)

Pleiotropy:
Localized or multi-system?
(Lights on in several rooms of house, or just one?

24
Q

Size of human genome

A
  • 3 x 10^9 bp
25
Q

Prevalence of new mutations in an individual

A

~30 new mutations occur in every individual

26
Q

Prevalence of a SNP between two individuals

A

Average of 1 SNP every 1000 bp between any two randomly chosen human genomes.
**Detectable by PCR–> easy to score, widely distributable

27
Q

Indels: Minisatellites

A

tandemly repeated 10-100 bp blocks of DNA

VNTR (variable number of tandem repeats)

28
Q

Indels: Microsatellites

A

-di-, tri-, tetra-nucleotide repeats
->5 x 104 per genome
STRPs (Short Tandem Repeat Polymorphisms)

29
Q

CNV’s

A
  • variation in segments of genome from 200 bp – 2 Mb
  • can range from one additional copy to many
  • array comparative genomic hybridization (array CGH)
30
Q

Gene Poor chromosomes

A

Chr 13, 18, 21 (aneuploidy)

31
Q

Unstable regions of the genome

A

1q21; chr 5q13 (SMA);chr 22q (Digeorge)

32
Q

GC/AT rich portions of genome

A

38%/54%, respectively. Clustering allows bands to appear on karyotypes

33
Q

Status of sequencing of the euchromatic genome

A

99% of the euchromatic genome is sequenced & is accurate to an error rate of 1 event per 100,000 bp

Many (>200) sequence gaps remain in eurochromatic DNA
Many of the remaining gaps are associated with segmental duplications

34
Q

Frequency of categories of genomic DNA sequences

A

1) 1.5% is translated (protein coding)
2) 20-25% is represented by genes (exons, introns, flanking sequences involved in regulating gene expression)
3) 50% “single copy” sequences
4) 40-50% classes of “repetitive DNA”
Sequences that are repeated hundreds to millions of times

35
Q

Human specific pentanucleotide tandem repeat

A

found in heterochromatic regions on chr 1, 9, 16, Y: Hotspots for human-specific evolutionary change

36
Q

Dispersed repetitive elements

A

Alu (short, ~300 bps, ~500k copies)
L1 (long, ~6 kb, ~100k copies)
-Often retrotransposed (insertional inactivation possible)
-Repeats may facilitate aberrant recombination leading to disease

37
Q

Number of human genes

A

25k-30k; includes protein coding genes, RNA encoding genes, and pseudogenes

38
Q

Gene Families

A

. A gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions. Some are clustered, some are dispersed. Gene families arise through gene duplication, a major mechanism underlying evolutionary change.
(when a gene duplicates it frees up one copy to vary while the other copy continues to carry out a critical function)

39
Q

CNV’s

A
  • Possible prevalent because gene duplication has evolutionary advantage
  • CNV loci may cover 12% of genome
  • CNVV regions are often enriched for human specific gene duplications, genome sequence gaps, and human disease
40
Q

CNV regions associated with disease

A

1q21.1(everything, see other card); 9p13.3-9q21.1(Alfi’s syndrome); 5q13.3 (SMA)

41
Q

DUF1220/NBPF sequences

A

deletions or repeats of these sequences in the 1q21 region are associated with disease.
Deletions–>microcephaly, SZD
Duplications–>Macrocephaly, ASD

42
Q

Limitations of Nextgen sequencing

A

Complex, highly duplicated regions are typically unexamined
Such regions are implicated in numerous diseases, e.g. 1q21
Relies on short read sequences, no mammalian genome has been completely sequenced

43
Q

Limitations of GWAS

A

–“Missing heritability” for complex diseases: Many large-scale studies implicate loci (e.g. SNPs) that account for only a small fraction of the expected genetic contribution
– Many regions of the genomes are unexamined by available “genome-wide” screening technologies: is this where the “missing heritability” lies?

44
Q

Triploidy

A

Three of every chromosome (69XXX, 69 XXY, 69 XYY)

Formed when one 2n gamete joins a 1n gamete

45
Q

Trisomy

A

Three copies of one chromosome. (47 XX +21)

46
Q

Monosomy

A

45, X (Turner Syndrome)

47
Q

Mosaicism

A

47, XXX/46,XX

48
Q

Trisomy 18

A

Edwards Syndrome–> intrauterine growth retardation, characteristic faces, severe intellectual disabilities, characteristic hand positioning, congenital malformations (valvular heart disease, posterior fossa CNA maldevelopment, diaphragmatic hernia, renal abnormalities)
Perinatal fatality~90%

49
Q

Trisomy 13

A

Patau Syndrome - Characteristic faces, severe intellectual disability, congenital malformations (holoprosencephaly, facial clefts, polydactyly, renal abnormalities_

50
Q

Polyploidy

A

Having a multiple of all of the chromosomes greater than 23 (Triploid=69, tetraploid= 92–occurs when DNA replication occurs without cell division)

51
Q

Aneuploidy

A

Incomplete set (Trisomy or monosomy)

52
Q

Tissue samples for Constitutional cytogenetic studies

A

Prenatal: Amniotic fluid or chorionic villus
Postnatal: peripheral blood or skin biopsy

53
Q

Tissue samples for cancer cytogenetic studies

A

bone marrow, solid tumor, peripheral blood, lymph node, CNS

54
Q

Genetic cause of Trisomy 21

A

Majority result of maternal meiosis I nondisjunction errors; ~4% are associated with a parental balanced translocation

55
Q

45,X

A

Turner Syndrome

  • Prenatal lymphedema/cystic hygroma
  • Congenital malformations – heart disease (coarctation of aorta), gonadal dysgenesis, short stature, webbed neck
  • 25% have mosaicism, thought to contribute to survival
  • Most severe phenotypes– tiny ring or tiny marker chromosome
56
Q

Cytogenetics of structural abnormalities

A

Structural abnormality must be >5000 kb to be visible on a karyotype

57
Q

Balanced Translocations

A

No loss or gain of genetic material
No phenotypic effect for heterozygote carrier
Exception: breakpoint in a gene, disrupting function

58
Q

Robertsonian Translocation

A

fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (these short arms contain rDNA repeats, so the loss of these is not deleterious)
a. Phenotypically normal, but their offspring may have phenotypic mutations
75% are 13/15 RT’s

59
Q

Reciprocal Translocation (Alternate segregation)

A

From quadrivalent state:
(A) got very lucky; both unbroken chromosomes got transferred to gamete
or
(B)chromosomes get transferred that end up containing complete genetic information

60
Q

Reciprocal translocation (Adjacent 1)

A

From quadrivalent state:

  • Abnormal segregation
  • Adjacent, or next door, non-homologous centromeres go to same pole
  • Most common form of mal-segregation when translocated segments are relatively small
  • results in trisomy and monosomy for some segments
61
Q

Human Acrocentric chromosomes

A

13,14,15,21,22

62
Q

Robertsonian translocations leading to Downs or Patau

A

any RT with a 21 chromosome can lead to trisomy (normal 21 plus RT “analog”) (similar with chr 13)

63
Q

Benign Pericentric Inversions

A
  • 9qh, 16qh,1qh,yqh (constitutive heterochromatin)
  • G-positive band of 9
  • Pericentric region of 2 and 3
  • usually familial
  • not associated with SAB’s, infertility, recombinant offspirng
64
Q

Meiotic outcomes in Pericentric carriers

A

25% normal, unrearranged
25% rearranged, balanced
50% unbalanced-2 complementary recombinants

65
Q

rec(8) infants

A
  • Partial trisomy and monosomy of 8 derived from an inv(8) carrier
  • VSD (ventriculoseptal defect), hypertelorism, thin upper lip, wide face
66
Q

Outcomes of meiosis from Paracentric carriers

A

-~50% dicentric or acentric chromosomes

67
Q

Deletion or Duplication 21q11 syndrome

A
  • Disturbances of neural crest cell migration–> cleft lip/palate defects, thymus defects (T-cell dysfunction, parathyroid defects (hypocalcemia)
  • Critical protein=TBX-1
68
Q

Epigenetic variation

A
  • mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence.
  • Reversible, post-translational modifications of histones and DNA methylation are examples of epigenetic mechanisms that alter chromatin structure, thereby affecting gene expression.
69
Q

MeCP2

A

Protein that binds methylated DNA and facilitates deacytelation and methylation of adjacent histones

70
Q

Imprinting

A

sex-dependent epigenetic modulation of regulatory regions such as promoter sequences.

  • DNA methylation marks are established in the gamete and stably maintained in somatic cells after fertilization
  • Methylation is reversible so it can be reset during gametogenesis
71
Q

Maintenance of methylation markers in somatic cells

A

-Maintenance methyltransferase

72
Q

Genetic cause of Prader Willi

A

del (15q11-15q13) on paternal chromosome (70%)

  • maternal uniparental disomy (28%)
  • 2% imprinting center defect on paternal allele
73
Q

Genetic cause of Angelman syndrome

A
  • del (15q11-15q13) on maternal chromosome (70%)
  • paternal uniparental disomy (4%)
  • mutation in imprinting center on maternal allele (8%)
  • Mutation of UBE3A on maternal chromosome (8%)
74
Q

Symptomes of Prader Willi

A

-short stature, hypogonadism, mild ID, excessive eating

75
Q

Symptomes of Angelman

A

short stature, severe ID, seizures, spasticity

76
Q

Genomic susceptibility to 15q11-13 deletions

A

Large genomic duplications of HERC2 lead to misalignment, which cause repeats flanking the locus

77
Q

Uniparental disomy leading to Prader Willi

A

For example, the maternal gamete could be disomic for Chr 15 (have 2 copies of Chr 15) & paternal gamete is normal. Conceptus will be trisomic, which is normally incompatible with life. However, a mitotic nondisjunction early in gestation rescues lethality. Fetus is viable, but has maternal imprinting only –> no expression of PWS gene, since it is methylated in maternal homologue. Individual will have Prader-Willi Syndrome.

78
Q

Acute lymphocytic leukemia prognosis (precursor B)

A

Low Hypodiploidy or near triploidy–>poor prognosis

Hyperdiploidy (>50)–>good prognosis

79
Q

Function of FISH

A

Specific, cloned DNA sequences can enumerate number of a specific chromosome OR identify
translocation

80
Q

Types of FISH probes (5)

A

Centromere-use for enumeration (ALL panel, prenatal dx)
Locus Specific- deletion/duplication (p53, cancer)
Dual fusion, fusion - translocation (BCR:ABL, PML:RARalpha–> cancer)
Break apart - translocation rearrangement (MLL–>cancer)
Whole Chromosome paint (identifying markers, translocations)

81
Q

BCR/ABL

A

(9,22) translocation leads to novel protein
Detected using Dual Fusion FISH probe
Recurrent in myeloid and lymphoid leukemia

82
Q

ETV6/RUNX1

A

t(12,21) (p13;q22) in ALL can only be detected by FISH

83
Q

Two common causes of specific types of AML

A

t(9;22)–>BCR/ABL fusion. 0.7% frequency. chronic myelogenous leukemia (CML), treatment with tyrosine kinase inhibitor (Gleevec)
t(15;17)–> PML/RARalpha fusion 4.1% frequency. specific Acute promyeloid leukemia (APML) –> treatment with retinoic acid changes the conformation of the novel protein (its receptor) to enable differentiation leading to remission. Auer rods characteristic.

84
Q

DS cancer predisposition

A

DS infants and children have 20-100 fold
Elevated risk for developing ALL or AML
500 x more likely to get AMKL (Acute
Megakaryo-Blastic leukemia

85
Q

How does CMA work?

A

CMA analysis: single-stranded DNA oligomers are placed onto slide or bead. Sample DNA (from peripheral blood) is amplified, labeled, hybridized onto slide/bead, and then the arrays are viewed via an optical scanner. Patient DNA is labeled green, and reference DNA is labeled red. If the two are displayed in equal intensities, spot will be yellow. If spot is more red or more green, displays a deletion or duplication of patient DNA respectively.

86
Q

What is CMA good at detecting?

A
  • CMA detects gains and losses only (but even microscopic ones!) –> no balanced translocations
  • Limited ability to detect mosaicism (10-15%)
  • Runs of homozygosity
87
Q

CMA reports

A

Determine Size and location of deletions/duplications (most >200 Kbp) = further investigation in databases

  • Common CNV/s not reported
  • Genes/functions discussed and known phenotypes
88
Q

Algorithm for testing kids with learning disorders

A
  1. CMA analysis, report
    a. Consult database of genomic variance
  2. If 3 or more oligo clones are deleted or duplicated, and they are not part of CNV, patient & parental chromosomes will be studied with FISH
    a. Parents with a balanced translocation, but no phenotype, are at risk for having offspring with an unbalanced karyotype
89
Q

Features of Prader Willi

A

Early childhood hypotonia, almond eyes, undescended testicles, lighter pigmentation than siblings
Early failure to thrive and feeding difficulties which reverse during preschool age turning to hyperphagia and weight gain
mild/moderate developmental delay
Opthalmologic problems (strabismus/nystagmus)
Obstructive sleep apnea (contradindication to use of growth hormone

90
Q

Developmental and Behavioral Prader Willi

A

Cognitive disability
Behavioral issues: tantrums, throw things, break things, have problems with picking at their skin (obsessive-compulsive quality to their behaviors)

91
Q

Other 15q disorders

A

Maternal deletion in region–> angelman
Interstitial 15q duplications (paternally inhereted)–>NOTHING
Interstitial 15q duplications –> autism, hypotonia, ID, seizures
Supernumerary marker chromosomes: inverted duplicated isodicentric 15q, or IDIC 15(isodicentric isochrome)–> autism, non dysmorphic, often hypotonic, seizures common
**Connection with autism may relate to GABA A gene

92
Q

Prader Willi Diagnosis

A

1) Methylation analysis (to establish disease)

2) FISH or microarray- to figure out the type of mutation

93
Q

Genetic causes of Down Syndrome

A

-Trisomy 21 (95%)
-Unbalanced translocation between 21 and another acrocentric chromosome (2-3%)
Mosaic Tri 21 (1-2%)=> milder phenotype

94
Q

Pharmacogenetics

A
  • the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity
  • variable response due to individual genes
  • genes are selected for study a priori due to knowledge of their role in drug metabolism
95
Q

Pharmacogenomics

A
  • the genomic approach to pharmacogenetics – is concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy
  • variable response due to multiple loci across the genome
96
Q

Pharmacokinetics

A

-the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites
-whether or how much the drug reaches the target
Describes absorption, distribution, metabolism and excretion of drugs (commonly referred to as ADME)

97
Q

Pharmacodynamics

A
  • the response of the drug binding to its targets and downstream targets, such a receptors, enzymes, or metabolic pathways
  • when the drug successfully reaches its target
98
Q

Phase I and II drug metabolism (pharmacokinetics)

A

Phase I: attach a polar group onto the compound to make it more soluble; usually a hydroxylation step

Phase II: attach a sugar/acetyl group to detoxify the drug and make it easier to excrete

99
Q

CYP3A(4)

A
-genetically, is less important than other drug metabolism genes because the population distribution of activity is continuous and unimodal 
Substrates:
o	Cyclosporine (immunosuppressant) 
Inhibitors:
o	Ketoconazole
o	Grapefruit juice
Inducers
o	Rifampin
CYP3A4 participates in metabolism of 40% of administered drugs
100
Q

CYP2D6

A
Substrates:
-Tricyclic antidepressants
-Opioids: codeine (cleaves to morphine)
Inhibitors: 
-Quinidine, fluoxetine, paroxetine
101
Q

CYP2C9 and VKORC1

A

Substrate:

Warfarin

102
Q

NAT

A

N-acetyltransferase

Substrate: Isoniazid for TB

103
Q

TMPT

A

6-mercaptopurine, 6-thioguanine
-1 in every 300-400 children do not have this enzyme – if you give these children with ALL (leukemia) the standard chemotherapeutic dose, you will kill the child due to immunosuppression

104
Q

G6PD

A

-Most common disease-producing enzyme defect in the world – 400 million ppl worldwide
-10% of African-American males are G6PD deficient
-Deficient individuals are susceptible to hemolytic anemia after drug exposures
Substrates
-Sulfonamide
-Dapsone
Mxn: x-linked enzyme

105
Q

If point mutations are more likely to occur in the paternal germline, what impact would that have on the clinical counseling of a family in which a single affected male child has one of the X-linked recessive diseases most frequently caused by point mutations, such as hemophilia B, LeschNyhan syndrome, or ornithine transcarbamylase deficiency?

A

The mother is more likely to be a heterozygote by virtue of her getting an x-chromosome from her more mutation prone father
– If male and female mutation rates are equal in an Xlinked genetic lethal condition, you would expect two thirds of the mothers of an isolated affected male to be carriers.
– However, if point mutations are much more likely in the male germline, she will have a >90% chance of being a carrier

106
Q

Klinefelter Syndrome

A

47 XXY –> Childhood learning disabilities , delayed speech and language, tendency to being quiet, tall stature, small testes, less facial hair, infertility, hypospadias, gynecomastia
1/500-1/1000 boys

107
Q

Jacob’s syndrome

A

47 XYY–> learning disability, speech delay, developmental delay, behavioral difficulties, autism spectrum, tall stature
1/1000 boys

108
Q

Triple X syndrome

A

47, XXX –> tall stature, my have increased risk of learning disability, delayed speech, delayed motor milestones, seizures, kidney abnormalities
1/1000 newborn girls

109
Q

Genetic regulation of sex differentiation

A
  • ovaries and testes result from a common, bi-potential gonad (both gene-directed processes)
  • Gonadal development then determines secondary sex characteristics
110
Q

Embryology of human reproductive organs (4th week)

A

Primordial germ cells form in wall of yok sac

111
Q

Embryology of reproductive organs (5th week)

A

coelomic epithelium becomes genital ridge

112
Q

6th week of human reproductive development

A
  • Primordial germ cells migrate to undifferentiated gonad

- epithelial cells of gonadal ridge proliferate and form primitive sex cords

113
Q

7th week of reproductive development (men)

A

Differentiation of genital ridge into Sertoli cells (–>sperm) and Leydig cells (interstitial cells)

114
Q

8th week of reproductive development (men)

A

Leydig cells produce testosterone
Sertoli cells produce Anti-Mullerian Hormone (AMH)
Primitive sex cords differentiate into testis cords and rete testis (–> seminiferous tubules)

115
Q

7-8th week of reproductive development in women

A

In the absence of SRY and in presence of XX:
primitive sex cords dissociate into irregulary clusters
Medullary (primitive) cords regress and cortical (secondary) cords are formed

116
Q

Initial 2 pairs of genital ducts that form in males and females

A

Mesonephric (wolffian) duct

Paramesonephric (Mullerian) duct

117
Q

SRY and Sox9

A

Responsible for production of AMH, causes regression of paramesonephric duct

118
Q

FGF9

A

Essential for testes differentiation

119
Q

SF1/NR5A1

A

Stimulate differentiation of Sertoli/Leydig

120
Q

Mesonephric duct products

A

Epididymis, seminal vesicles, vas deferens

121
Q

Paramesonephric duct and other things formed due to influence of estrogens

A

uterus, cervix, broad ligament, fallopian tubes, upper 1/3 of vagina

122
Q

WNT4 protein

A

responsible for differentiation of ovaries, inhibited by SOX9

123
Q

DHH

A

Upregulted by WNT4, downregulates SOX9

124
Q

RSP01

A

Coactivator of WNT pathways

125
Q

External genitalia formation (both genders)

A

-At 3 weeks, cells migrate and form genital tubercle and genital swellings
-Both males and females originate from urogenital sinus
Dihydrotestosterone exposure–>penis, scotum, urethral opening
Estrogen from maternal&placental sources–>clitoris, labia majora/minora, lower 2/3 of vagina

126
Q

Clinical algorithm for DSD

A

1) physical exam (Prader Stages)
2) FISH studies for sex chromosome and karyotype
3) Hormone studies (LH, FSH, testosterone, dihydrotestosterone, AMH)
4) Ultrasound study of gonads and uterus
5) surgical consult with urology

127
Q

Primary sex determination

A

Sex is primarily determined from the GONADS (which are in turn determined by chromosomes)
As a general rule, presence of Y–> male
X in absence of Y –> female

128
Q

Androgen Insensitivity Syndrome

A

X-linked, AR

Mutation causes abnormality of androgen receptor. Phenotypes range from milde to full sex reversal

129
Q

5-alpha reductase deficiency

A

decreased ability of body to convert testosterone to dihydrotestosterone
Phenotype: undervirilized male with increased virilization at time of puberty

130
Q

SRY gene disorders

A
  • deletions or absence of gene results in full sex reversal and phenotypically normal female.
  • Ectopic presence of SRY in 46,XX leads to phenotypically normal male
  • Mutations in SRY lead to decreased AMH production and under virilization
131
Q

Denys-Drash and Frasier Syndrome

A
  • Sex reversal with 46, XY
  • Due to mutations in WT1 gene (transcription factor for SRY)
  • Both cause kidney disease
  • Increased risk for wilms tumor
132
Q

Congenital Adrenal Hyperplasia

A

Ambiguous genitalia in 46, XX

  • 21 Hydroxylase deficiency
  • Complicated by salt wasting in first few years of life and times of metabolic stress
133
Q

phenocopy

A

Environmentally caused phenotype that mimics the genetic version of a trait
Ex. thalidomide induced limb malformation vs. rare genetic

134
Q

Definition of heritability

A

How much of the spread or differences among people (measured as statistical variance) is due to genetics
It doesn’t tell you whether there is a genetic component, but can provide an idea of how easy it will be to find a genetic component

135
Q

lambda s (measure of risk of disease in relatives)

A

risk of disease in siblings of affected/risk of disease in general population

136
Q

Allelic heterogeneity

A

Different alleles in different genes can result in different phenotypes or the same phenotype
ex. CF- many alleles have very similar clinical progression, but they can also be grouped based on severity of lung and pancreatic involvement
Other ex. PKU! (enzyme can vary form 20-50% activity)

137
Q

CTFR phenotype/genotype

A

ΔF508/ ΔF508 leads to a severe pancreatic phenotype (stronger correlate)
Different CTFR genotypes also correlate with severity of lung deficiency, but it’s a pretty weak correlation

138
Q

significance tests for linkage analysis

A

chi square, fisher, exact test
If testing multiple variants, must apply multiple-testing correction
In GWAS, p must be

139
Q

SNP’s

A

bi-allelic
1/50-300 bp
used for association, occurrence different between ethnic goups
-Each occurs in a local haplotype

140
Q

Haplotype

A

Local context of surrounding SNP’s

141
Q

CNV’s

A

bi-allelic, multi-allelic, or unique
include common genomic deletions
Huge in size, also differ between populations
Most are not common for human disease

142
Q

Odds Ratio

A

Risk of disease if carrying a given gene variant/Risk of disease if not carrying a given gene variant

143
Q

Haplotype blocks

A

Recombination is not truly random, so very close polymorphism genotypes carried on the same chromosome cluster into ~10-50 kb haplotype blocks in which SNP alleles are in linkage disequilibrium (LD; marker alleles within blocks tend to be co-inherited, because recombination within blocks is uncommon)

144
Q

Unit of genetic distance/recombination

A

centimorgan (cM)

1% recombination between 2 loci per meiosis

145
Q

Statistical measure of linkage

A

LOD (Log of Odds)
Lod= log(likelihood of data if loci linked at x (cM)/likelihood of data if loci unlinked)
>3.0 is considered proof of linkage/gene localization

146
Q

GWAS

A

tests hundreds of thousands of SNP’s across the genome
search for significantly different allele
Still need to match cases and controls ethnically, but can accurately measure and correct for population stratification
You know the number of tests performed genome-wide (solves both problems)

147
Q

Autosomal recessive pedigree

A

Parents of affected child are obligate carriers

Unaffected siblings have 2/3 chance of being a carrier

148
Q

Compound heterozygote

A

an individual who carries two different mutant alleles (Ex. BetaS/BetaC alleles, may show some characteristics of sickle cell and hemoglobin C disease mutant, but symptoms won’t be as bad as someone with 2 sickle cell alleles (?))

149
Q

Alpha1-Antitrypsin (SerpinA1)

A

Suicide inhibitor of serine protease Elastase

150
Q

Two molecular causes of PKU

A

defect of Phenylalanine hydroxylase (PAH)
–98% of cases
Defects in BH4 cofactor –1-2% of cases
BH4 is also involved in 5-HT and DA synthesis

151
Q

Newborn Screening for PKU

A

Mass spec for [F]/[Y], offered 1-2 days postnatally and 10-14 (aiming for the sweet spot where maternal enzyme is gone but damage hasn’t really occurred yet.