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Repro Midterm > Genetics > Flashcards

Genetics Flashcards

1
Q 
Rarest form of CAH
Two genes
Mutations
-Type I (placenta, skin, mammary gland)
-Type II (adrenal gland and gonads)
      -46,XY DSD – male is hypomasculinized
      -46,XX DSD – clitoromegaly
      -Adrenal hyperplasia
A

3B-hydroxysteroid dehydrogenase deficiency

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2
Q

MC cause of CAH
Autosomal recessive
Impaired synthesis of cortisol from cholesterol in adrenal cortex
Virilization in all individuals (androgen excess)
Salt-wasting (due to lack of aldosterone)
Deficiency of cortisol

A

21-hydroxylase deficiency

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3
Q

Males:

  • Premature body hair loss
  • Enlarged penis with small testes
  • Decreased sperm count
  • Short stature

Females:

  • Premature adrenarche/menarche
  • Menstrual abnormalities
  • Balding
  • Excess hair growth
  • PCOS

M & F:

  • Premature growth of body hair
  • Body odor
  • Early rapid growth
  • Acne
A

Non-classical 21-hydroxylase deficiency

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4
Q

Difference between “classic” and “mild/non-classical” forms of CAH:

A

“Classical” CAH:

  • Virilizing form
  • Salt-wasting (newborns at risk for life-threatening crises)

“Mild/non-classical” CAH:

  • Later onset
  • MC than classic – may have normal height, but short when compared to parents
  • Moderate enzyme deficiency – limited glucocorticoid response to stress
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5
Q

Prenatal virilization in females
Postnatal virilization in males and females
Salt-wasting (in 75%)
Cortisol deficiency (in 100%)

A

Classic 21-hydroxylase deficiency

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6
Q

Prenatal virilization absent
Postnatal virilization variable
Salt-wasting absent
Cortisol deficiency rare

A

Non-classical 21-hydroxylase deficiency

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7
Q

Dx confirmation for CAH involves the molecular genetic testing of:

A

CYP21A2

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8
Q

Dx confirmation for CAH may also involve biochemical findings such as elevated serum:

A

17-OHP
17-OHP unable to be converted to 11-deoxycortisol

( >20,000 ng/dL = classic)
(2,000 – 15,000 ng/dL = non-classical)

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9
Q

Tx for classic 21-hydroxylase deficiency CAH:

A

Glucocorticoid replacement therapy

  • Increased during periods of stress
  • Salt-wasting pts – Rx 9a-fludrohydrocortisone and NaCl
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10
Q

An infant with a sibling affected with CAH does not have elevated 17-OHP. What is the probability that this infant is a carrier?

A

66%

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11
Q

Excess adrenal androgens in utero:

  • Before 12 weeks:
  • After 12 weeks:
A

Excess adrenal androgens in utero:

  • Before 12 weeks: Labioscrotal fusion, clitoral enlargement
  • After 12 weeks: Clitoral enlargement
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12
Q

Excess adrenal androgens after birth:

  • Precocious puberty
  • Untreated males:
  • Untreated females:
A

Excess adrenal androgens after birth:

  • Precocious puberty
  • Untreated males: progressive penile enlargement and small testes
  • Untreated females: clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, reduced fertility
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13
Q 
Second MC cause of CAH
Most mutations abolish activity
Females:
-Ambiguous or masculinized external genitalia
-Virilization during childhood
Males:
-Normal external genitalia
-Virilization early
DOC and 11B-deoxycortisol are increased (NO salt-wasting)
HTN*** (distinguishes from 21-OHD)
A

11B-hydroxylase deficiency

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14
Q

What are the two genes associated with 11B-hydroxylase?

A

CYP11B1

CYP11B2

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15
Q

In the zona glomerulosa, 11B-hydroxylase has 3 enzyme activities:

  • 11B-hydroxylase
  • 18-hydroxylase
  • 18-oxidase

All activities are coded for by which gene?

A

CYP11B2

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16
Q

18-hydroxylase and 18-oxidase are involved in the conversion of corticosterone to:

A

Aldosterone

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17
Q

HMG octamer mutations ->
No binding to DNA ->
No male differentiation ->
46,XY female

What gene is mutated?

A

SRY

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18
Q

The Pseudoautosomal Region (PAR) pairs and recombines with X-chromosome. SRY is near but not in PAR. Therefore, Recombination may translocate this gene to the X-chromosome, resulting in 46,XX but phenotypically demonstrating:

A

46,XX with male phenotype

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19
Q

What is required for SRY expression and gonads/adrenal development (sex determination, sex differentiation, steroidogenesis, lipid metabolism)?

A

Steroidogenic Factor 1 (SF1)

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20
Q

Congenital adrenal hypOplasia and hypogonadotropic hypogonadism is due to a mutation or deletion in which gene?

A

DAX1
(normally down-regulated in developing testes but not in ovary)
-Duplication in males -> 46,XY females
-Duplication in females -> no effect

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21
Q

Dosage sensitive sex reversal-Adrenal sensitive sex reversal on the X Chr (DAX1 gene) is important in development of the ovary and down regulation in developing testes. What happens if it is duplicated in males? MoA?

A

Duplicated DAX1 -> 46-XY female

SRY may inhibit DAX1, but in duplicated state, there may be insufficient SRY to repress DAX1 expression

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22
Q
  • Result of SOX9 mutations -> Mullerian ducts do not degenerate (ovary development occurs)
  • Associated with sex reversal due to gonadal dysgenesis in 46,XY
  • Bowing of long bones
  • Shortened long bones
  • Skeletal dysplasia
A

Campomelic dysplasia

“bent limbs”

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23
Q

WT1 and SF1 expression are required for which gene to be expressed?

A

SRY

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24
Q

SRY expression in Sertoli cells up-regulates which gene?

A

SOX9

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25
Q

SRY mutations
SOX9 mutations
DAX1 mutations

All result in:

A

Sex reversal

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26
Q
  • Abnormality of anterior urethral development in which the urethral opening is ectopically located on the ventral side of the penis proximal to the tip of the glans penis
  • Defect occurs between weeks 8-20
A

Hypospadias

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27
Q
  • Both ovarian and testicular tissue in one or both gonads
  • Internal and external differentiation is variable
  • Ovotestis is the MC gonad found
A

Ovotesticular DSD

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28
Q
  • Aromatase (CYP450-aromatase) deficiency
  • Expressed in ovary and testis
  • Tissue-specific promoters
  • Elevated testosterone and androstenedione
  • Masculinization of female genitalia
  • Pubertal failure
A

Female 46,XX DSD

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29
Q
  • Abnormalities of gonad development
  • Cholesterol synthesis defects
  • Testosterone synthesis defects
  • Testosterone metabolism defects
  • Androgen action defects
  • Persistence of Mullerian ducts syndrome
  • Congenital non-genetic 46,XY DSD
A

Male 46,XY DSD

more complicated

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30
Q
  • Prenatal and postnatal growth retardation, microcephaly, moderate to severe mental retardation, and multiple major and minor malformations.
  • Malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes.
  • Clinical spectrum is wide and individuals have been described with normal development and only minor malformations.
A

Abnormal cholesterol synthesis in 46,XY DSD

“Smith-Lemli-Opitz syndrome”

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31
Q

• Impaired Leydig cell differentiation
• Defects in adrenal and testicular
steroidogenesis
• P450scc deficiency
• 3β hydroxysteroid dehydrogenase deficiency
• 17α hydroxylase deficiency
• 17β hydroxysteroid dehydrogenase deficiency (MC)

A

Testosterone synthesis defects in 46,XY DSD

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32
Q

• 46,XY with female external genitalia
• Testes and Wolffian derivatives present
• At puberty – absence of male differentiation – Deepening voice
– Clitoral enlargement – Hirsutism
– Male muscularity
– Breast development

A

17B-hydroxysteroid dehydrogenase deficiency

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33
Q
  • Female genitalia
  • Partial virilization at puberty
  • Elevated testosterone:DHT ratio
A

5a-reductase deficiency
(testosterone metabolism defects)
(46,XY DSD)

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34
Q

• Deficient conversion of testosterone to DHT
– Deficient DHT to bind to androgen receptor
• Two isozymes
– Type 2: Expressed before and after birth
» Prostate, Wolffian derivatives, scrotum, liver
– Type 1: Expressed in non-genital tissues
• Mutation in female - genitalia normal; menarche delayed
• Mutation in male - testes extra-abdominal; usually inguinal – Hypospadic microphallus
– Blind vaginal pouch

A

5a-reductase deficiency
(testosterone metabolism defects)
(46,XY DSD)

35
Q

• Steroid hormone receptor family
• Mediates growth and differentiation in AR responsive tissues
Lipid soluble ligand enters cell ->
Binds to receptor with HSP sequence and displaces HSP ->
Transported into nucleus ->
Binds to hormone response element

What receptor is described?

A

Androgen receptor

46,XY DSD

36
Q

• Androgeninsensitivitysyndrome
– Complete and partial forms
– Mutations in the androgen receptor (Transcription factor)

A

Androgen insensitivity syndrome

46,XY DSD

37
Q
  • Defect in AMH synthesis

* Defect in AMH receptor

A

Persistence of Mullerian duct syndrome

46,XY DSD

38
Q

• Maternal intake of endocrine disruptors

– Chemicals that disrupt the endocrine system

A

Congenital non-genetic 46,XY DSD

39
Q
  • Common cause of male hypogonadism seen in infertility work-up
  • 47,XXY
  • Variants: XXXY, XXXXY, XXYY, and XXY/mosaics
  • Usually from maternal nondisjunction
  • Testicular atrophy, eunuchoid body shape, tall, long extremities, gynecomastia (due to high E:T ratio), female hair distribution
  • May present with developmental delay
  • Increased risk for autoimmune disorders (e.g., diabetes)
  • Presence of inactivated X chromosome (Barr body)
  • Incr LH, Incr FSH, Decr testosterone, Decr sperm count
A

Klinefelter syndrome

40
Q
  • 46,XO
  • Short stature (if untreated), ovarian dysgenesis (streaked ovary), shield chest, bicuspid aortic valve, coarctation of aorta, webbed neck or cystic hygroma, horseshoe kidney
  • MC cause of 1º amenorrhea
  • Menopause before menarche
  • Can result from mitotic or meiotic error
A

Turner syndrome

41
Q

Must have individuals with Turner syndrome karyotype to rule out presence of Y-chromosome because the presence of y-chromosome increases the risk (95%) of:

A

Gonadoblastoma

prophylactic removal of streaked ovaries

42
Q

• “Male Turner” syndrome
• Autosomal dominant
• Mutations in PTPN11 gene (~ half of cases)
– Oncogene regulating RAS/MAPK signaling pathway
• Regulates cell proliferation, differentiation, migration, apoptosis.
• Critical in development of heart, blood cells, bones and other tissues

A

Noonan syndrome

43
Q
  • Delayed puberty
  • Down-slanting or wide-set eyes
  • Hearing loss (varies)
  • Low-set or abnormally shaped ears
  • Mild mental retardation(~25% of cases)
  • Pulmonary stenosis***
  • Ptosis
  • Short stature
  • Small penis
  • Undescended testicles
  • Pectus excavatum
  • Short, webbed neck
  • Fertility problems but fertile**
A

Noonan syndrome

44
Q

List the essential amino acids.

A

“PVT TIM HALL”

Phenylalanine
Valine
Threonine
Tryptophan
Isoleucine
Methionine
Histidine
Arginine
Leucine
Lysine
45
Q

Findings: intellectual disability, growth retardation, seizures, fair skin/hair, eczema, musty/mousey body odor*

Dx?
What enzyme is deficient?
Which AA becomes essential?
What test is used to view PHE levels?

A

Phenylketonuria (type I)

Due to decreased phenylalanine hydroxylase.

Tyrosine becomes essential.

Guthrie test – bacterial inhibition assay
(Now more likely to see Mass Tandem Spec in hospitals)

46
Q
  • Insufficient BH4 (tetrahydrobiopterin cofactor) which leads to BH2 deficiency
  • Due to deficiency of dihydropteridine reductase
  • Major clinical finding: abnormal response to diet
  • Progressive deterioration
  • May respond to BH4 treatments

Dx?

A

Type II Hyperphenylalaninemia

“Malignant PKU”

47
Q
  • Due to deficiency of dihydropteridine synthetase
  • 1-3% of all hyperphenylalaninemia
  • Progressive neuro deterioration
  • May respond to BH4 tx
A

Type III Hyperphenylalaninemia

48
Q
  • Lack of proper dietary therapy during pregnancy

- Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects

A

Maternal PKU

49
Q
  • Autosomal recessive
  • Deficiency of homogentisate oxidase
  • In degradative pathway of tyrosine to fumarate
  • Arthritis
  • Dark colored cartilage
  • Urine turns black on standing
A

Alkaptonuria

50
Q
  • Autosomal recessive
  • Unable to synthesize melanin
  • Hair, skin, eyes affected
  • Associated ocular defects
  • Photophobia
A

Albinism

51
Q
  • Autosomal recessive
  • Failure to thrive
  • Benign, transient defect in TYR metabolism
  • Defect in p-hydroxyphenylpyruvic acid oxidase
  • (+) Guthrie test
A

Neonatal tyrosinemia

52
Q

Defect in tyrosine aminotransferase
Hepatorenal tyrosinemia
Renal obstruction
Liver failure

Dx?

A

Tyrosinemia type II

53
Q

Defect in fumarylacetoacetate hydrolase
Oculocutaneous tyrosinemia
Photophobia
Conjunctivitis

Dx?

A

Tyrosinemia type I

54
Q

Albinism subtype.

Tyrosinase (–)

A

Albinism type IA

55
Q

Albinism subtype.
Tyrosinase (+)
General reduction in pigmentation

A

Albinism type IB

56
Q

Albinism subtype (MC).
Tyrosinase (+)
In pigmented nevi
Hair yellow or light colored

A

Albinism type II

57
Q

Findings: Increased homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus (tall, long limbs), lens subluxation (downward and inward), thrombosis, and atherosclerosis (stroke/MI)

Dx?
Deficiency of what enzyme?

A

Homocystinuria

Deficient enzyme: cystathionine synthase

Methionine and cysteine – sulfur groups*

(See p. 108 in FA)

58
Q
  • Defect in alpha ketoacid dehydrogenase
  • Blocked degradation of branched chain amino acids (elevated leucine, isoleucine, valine)
  • Seizures
  • Mental retardation
A

Maple syrup urine disease

59
Q
  • Absence of galactose-1-phosphate uridyltransferase
  • Autosomal recessive
  • Damage caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye)
  • Sx: failure to thrive, jaundice, hepatomegaly, infantile cataracts*** (due to increased osmotic pressure), intellectual disability

Dx?

A

Classic galactosemia

60
Q
  • Hereditary deficiency of galactokinase
  • Autosomal recessive, relatively mild
  • Sx: galactose appears in blood and urine, infantile cataracts*
  • May present as failure to track objects or to develop a social smile
A 
Galactokinase deficiency
(non-classical galactosemia)
61
Q

TQ
What is the biggest risk factor for breast cancer?

Name some other risk factors..

A 
#1: Increasing age
• Family history
• Mutations in BRCA1 and BRCA2 • Early menarche
• Nulliparity
• Late menopause
• Estrogen use
• Dietary factors
62
Q

Features assoc w/ incr risk of breast and ovarian cancers?

A

BCRA1 & 2 mutation
TP53 mutation
PTEN mutation
HNPCC

63
Q

What is “family clustering” of cancer?

A

-No evidence of Mendelian inheritance
-May be a weaker predisposition
-Non-genetic influences
• Environment
• Socioeconomic factors
• Diet

64
Q

TQ
What are the most common genes known to cause breast and ovarian cancer?

What is their gene function, expression, and mechanism of inheritance?

A

BRCA1 (chr 17) and 2 (chr 13) are tumor suppressor genes:

  • Control cell division (G1/S)
  • DNA repair
  • Apoptosis

Expressed in most tissues (G1-S) and activates p21 CDK inhibitor

65
Q
  • Recognizable motifs (ring-finer and BRCT domain + tandem repeats)
  • Breast ca 50-85% (early age)
  • Second primary breast ca
  • Ovarian cancer (15-45%)
  • Incr risk for prostate and colon cancer

What is the mutation?

A

BRCA1

66
Q
  • Breast Cancer
  • Ovarian cancer
  • Male breast cancer
  • Risk of prostate, laryngeal, and pancreatic cancers

What is the mutation?

A

BRCA2

67
Q

AD

  • cancer predisposition syndrome
  • variety of cancers within the same family
  • risk of multiple primary cancers

What is the mutation?

Ex: Breast + osteosarcoma + brain tumor + leukemia

A

Li-Fraumeni Syndrome
TP53 (chr 17)

90% lifetime cancer risk for women

68
Q
  • Multiple hamartoma syn w/ high risk of benign and malignant tumors of the breast, **thyroid, and endometrium, GI
  • Macrocephaly
  • Trichilemmomas
  • Papillomatous papules by LATE 20s!
  • Hyperkeratosis

What is the mutation?

A

Cowden syndrome
PTEN (chr 10)

Usually problem in tissues that are rapidly turning over (will have GF around PIP3 sensitive)

69
Q
  • multiple colon primary tumors
  • endometrial ca
  • ovarian ca

What is mutated?

A

HNPCC (Lynch syndrome II)
Mismatch repair gene mut
MSH6 MSH2 EPCAM PMS2 MLH1

70
Q

How does micro-satellite instability lead to ineffective repair?

A

Mutations in repair enzymes

Ex: HNPCC

71
Q
  • Early onset BC (<50) yo
  • Early onset BC + ovarian
  • Bilateral dz
  • Jewish
  • Male breast cancer

What is the mutation?

A

BRCA 1 OR 2

AD

72
Q

Same mutation but some individuals may not develop cancer…age of onset and type of cancer also varies…

A

Penetrance! (Breast and ovary)

73
Q

T/F The longer you live w/ a BRAC mutation, the greater your risk of developing breast cancer.

A

TRUE

74
Q

Which population is esp assoc with BRAC1 or 2 mutations?

A
  • Ashkenazi Jews (1 in 100)

- Stabilization of mutation within a population (founder mutations traced back to 600 yrs ago)

75
Q

3 BRCA 1 and 2 mutations account for most breast ca in Jews…

What is the three mutation test?

A
  • Focuses on the 3 specific mutations (certain deletions)

- False negatives

76
Q

If family member of BRCA + individual is tested for a family-specific mutation, and it is absent…are they still at risk?

A

YES just like general population….(1:500 to 1:1000)

77
Q 
TP53-->
Incr p21 (CDK inhib)
Incr GADD45 (DNA repair)-->BAX-->Apoptosis

Is p53 an oncogene or tumor suppressor gene?
Mode of inheritance for LiFraumeni?

A
  • Tumor suppressor gene

- AD

78
Q

Role of PTEN in the cell?
Is it an oncogene or tumor suppressor gene?

Inheritance pattern in Cowden’s syn?

A
  • Dephosphorylate PIP3 to PIP2 to control growth…mutated=no dephos, upreg of oncogenes
  • Tumor suppressor gene
  • AD
79
Q
  • HNPCC
  • Di-nucleotide repeats (CA12, 14, 16)
  • Additions/deletions
  • Defective mismatch repair
A

Microsatellite instabilty

80
Q

GADD45 is assoc w/ what check point in the cell cycle?

A

G1/G2–>apoptosis via BAX

81
Q

BAX=apoptosis pathway

BAX is part of which gene family?
How does it work?

A

BCL2 gene BAX controls mito apoptosis

p53–>BAX–>cyclophilin D–>membrane distruption–>apoptosis
AND
antagonize BCL2

(BCL2=survive, BAX=apoptosis)

82
Q

Microsatellite instability:
Mononucleotide repeat G8 (loss or gain–>G6 or G7)

What does this affect?

A

Decr apoptosis ability by mutation BAX…

83
Q
  • A10 repeat (mononucleotide)
  • Frameshift in HNPCC pts via insertions or deletions

What signaling pathway is the mutated gene involved in?

A

TGFBR2 gene

LAP cleavage–>R1–>R2–>signaling via SMADS*

TGFB=Multifunctional cytokine–>
SMAD–>apoptosis, prolif, or diff

Repro Midterm (8 decks)

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