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General Flashcards

1
Q

If a parent has balanced translocation, which type of segregation leads to phenotypically normal offspring? Chromosomally?

A

Alternate -> phenotypically normal, 50% chromosomally normal

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2
Q

G6PD heterozygote advantage

A

malaria resistance

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3
Q

Common severe HFE variant, second variant

A

Cis282Tyr

His63Asp (homozygote unaffected)

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4
Q

What does HFE do?

A

Regulate hepcidin signalling - iron response hormone that tells body to stop absorbing

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5
Q

When do you treat hemochromatosis

A

Ferretin > 300 for men or 200 for women

  • Goal <50
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6
Q

Why does Factor IV leyden resolve with puberty?

A

mutation is on promoter which activates with hormone changes after puberty

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7
Q

What gender is hirschsprung more common in?

A

Males

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8
Q

Uplifted ear lobes, hirschsprung

A

Mowat Wilson

ZEB2

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9
Q

HTT repeat expansion location and cutoffs

A

exon 1

Normal 10-25

At risk 26-35

Low penetrance 36-39

Classic 40-59

Juvenile 60

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10
Q

What type of proteins do the most common HCM mutations affect?

A

Sarcomere or Z disk

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11
Q

What does having DR3 and DR4 alleles place someone at increase risk for? Why?

A

Insulin dependent diabetes

They are linked with DQB1*0201 and DQB1*0302 alleles (antiben binding clefts in pancreatic island cells)

DR2, which is linked with DQB1*602 is protective

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12
Q

Which 2 genes account for 80% of long QT

A

KCNQ1 and KCNH2

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13
Q

What do you need to offer relatives of patients with Jervell and Lange-Nielsen syndrome?

A

EKG. Jevell and Lange Nielsen is AR, but allelic with Romano Ward syndrome (AD long QT)

KCNQ1 and KCNH2

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14
Q

MSH2, MLH1, MSH6, PMS2

A

Mismatch repair genes -> Lynch Syndrome (HNPCC)

GI cancer (Colon, stomach, intestine, pancreas)

Endometrial/ovarian Ca

Renal Cancer

NO breast/lung ca

MSH6 and PMS2 low penetrance

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15
Q

Lynch syndrome surveillance

A

Age 20: Colonoscopy (or 5 years before earlierst family hx)

Age 30: Endometrial biopsy every 1-2 yrs, Urine cytology

Age 40: Gastric - EGD every 3-5 yrs

Age 50: MRCP for Pancreatic CA annually

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16
Q

What % of marfan mutations are de novo

A

~25-33%

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17
Q

What is the skeletal features of marfan

A

Tall with long arms/long legs: Arm span to height > 1.05, Upper to lower segment

arachnodactyly

Pectus

Scoliosis

joint laxity

narrow palate

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18
Q

Management of Marfan

A

Annual TTE (root, mitral valve), eye exam

Follow ortho

B-blocker

? Ace/Arb

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19
Q

How is increased nuchal thickness defined?

A

3mm in 1st trimestery, 6mm in 2nd trimester

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20
Q

What is the most common FAOD?

A

MCAD

ACADM gene

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21
Q

17p.13 deletion

Brain dysgenesis

A

Miller-Dieker

Key gene: LIS1

Platelet activating factor acetylhydrolase 1 (PAFAH1)

  • Lisencephaly (LIS1) + dysmorphic features (unknown genes)
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22
Q

Recurrence risk for miller dieker

A

17p13.3 deletion

80% de novo (usual germline mosiacism risk)

20% translocation: 25% abnormal (either del or dup), 25% miscarriage

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23
Q

Mt8344G>A tRNAlys

A

MERRF

Myoclonic epilepsy with RR fibers

Complex I and IV reduced - mostly synthesized within mitochondria

  • Heteroplasmy
  • Can also cause multisystemic diasese
  • Mutant mitochondrial accumulate with age (mtDNA has 10x mutaton rate vs chromosomal DNA)

Tx: CoQ10 and Carnitine

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24
Q

What % of NF patients have a de novo mutation?

A

50% - NF has a very high mutation rate

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25
Q

Pima Indian Tribe (Arizona)

A

Type 2 DM, MODY

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26
Q

Which type of diabetes have more twin concordance?

A

Type 2

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27
Q

What is the most common extra renal manifestation of ADPKD?

A

Colonic Diverticula

  • PKD1 and PKD2 genes -> encore parts of multimer compled that affect how cilia sense flow

+ Heptaic, biliary, pancreatic, ovarian, splenic cysts

Mitral/Aortic insufficiency

+ 10% have aneurysms in brain

PKD1 and TSC are next to each other on Ch16

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28
Q

Almond shaped eyes, triangular mouth, small hands and feet, narrow bifrontal diameter + OCD, hyperphagia

A

Prader Willi

15p11 paternally expressed genes

70% pat deletion, 25% maternal UPD, <5% imprinting defect

+ obesity 2/2 hyperphagia,

Tx: growth hormone can normalize height

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29
Q

How often is RB1 germline mutation found in a patient with unilateral retinoblastoma?

A

40%, but only 10% of patients have a family history.

  • All patients with bilateral retinoblastomas have germline RB1 mutations
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30
Q

What is the function of RB1

A

Cell cycle regulatory element

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31
Q

What secondary neoplasms can be seen in patients wtih RB1 mutations?

A

Retinoblastoma + osteosarcoma, soft tissue sarcoma, melanoma

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32
Q

Where do nearly half of RB1 mutations occur?

A

CpG dinucleotide (CG island, often methylated motif)

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33
Q

What genes cause RETT syndrome or similar phenotype?

A

MECP2 (classic for females or males with XXY)

CDKL5 (XL)

FOXG1 (AD)

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34
Q

Normal at birth -> decelerating head circumference

Cortical and cerebellar atrophy without neuronal loss (densely packed neurons on path)

A

RETT syndrome - MeCP2

Clinical spectrum from neurodevelopmental to neurodegenerative disease

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35
Q

What is the most common cause of disorders of sexual differentiation

A

SRY

80% of 46XX males (transloction to X chromosome) - tx with androgens to complete virilization

30% of 46XY females (deletion/mutation - LOF) - tx with estrogen at 14, progesterone for periods, remove gonads to avoid gonadoblastoma

  • also regulates sperm formation (Azoospermia factors AZFa, b, c)
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36
Q

Glu6Val - B Globin gene

A

SSD

  • Can also be caused by compound heterozygousity in sickle cell mutation w/ B thal (non-expression) or Hg C (Glu6Lys)
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37
Q

What is HgbC?

A

Glu6Lys on B globulin gene -> affects solubility and can cause mild splenomegaly/anemia but not sickling

  • Can cause SSD phenotype when compound het w/ Glu6Val (SS mutation)
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38
Q

What do you do if SSD is seen on NBS?

A

Antibiotic prophylaxis due to 11% mortality from sepsis in first 6 month of life.

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39
Q

What is the prior probability for female mother of one son who is affected w/ XL-R disorder to be a carrier?

A

2/3rd

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40
Q

What phase of the cell cycles do cells spend the most time in?

A

Interphase

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41
Q

Phase of cell cycle where cellular contents are duplicated?

A

G1 (part of interphase)

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42
Q

Phase of cell cycles where chromosomes are duplicated?

A

S (part of interphase)

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43
Q

Phase of cell cycle when cell gets split into 2

A

Cytokinesis

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44
Q

The cell is 2n, 4c entering ___ phase of mitosis. After ___ cells are 2n, 2c again

A

Prophase, cytokinesis

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45
Q

After what phase of the cell cycle are meiotic cells 2n, 4c?

A

Interphase (after S)

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46
Q

After what phase of meiosis are cells 1n, 2c

A

meiosis 1

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47
Q

After which phase of mieosis are cells 1n, 1c

A

Meiosis 2

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48
Q

When do meiotic cells become haploid

A

After meiosis 1

Haploind = 1n

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49
Q
A
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50
Q

When are homologous chromosomes separated in meiosis?

A

Anaphase 1

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51
Q

When are sister chromatids separated in meiosis?

A

Anaphase 2

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52
Q

What are the stages of prophase 1?

A

Leptotein - chromosomes condense

Zygotene - synapsis form

Pachytene - bivalent + crossing over

Diplotene - Synaptonemal complex dissolve

Diakinesis - nuclear membrane fragment

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53
Q

Which stage of meiosis do bivalents form and crossing over occur?

A

Prophase 1 -> pachytene

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54
Q

What are chiasma?

A

point between homologous chromosomes across which exchange of genetic maternal occur

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55
Q

When does meiosis start in males?

A

puberty

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56
Q

At what stage of meiosis does Oogenesis arrest in? Until what times?

A

Prophase 1 until puberty

Metaphase 2 until fertilization

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57
Q

What charactersitics must a cell have to be usable for karyotyping?

A
  • have a nucleus
  • spontaneously divide (marrow, prenatal tissue, skin) or can be induced to divide (blood)
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58
Q

What cell type(s) can be available for metaphase analysis immediatly? After 3 days? After 2 weeks?

A

Immediately: Bone marrow

3 days: Blood

10-14 days: amniotic fluids, CVS, skin

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59
Q

How many metaphases are counted in routine karyotype? When would you count more?

A

Routine = 20

Do more when looking for mosiacism (50)

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60
Q

Level 1 mosiacism

A

Only single cell is seen in multiple cultures

  • Most likely artifact (pseudomosiacism)

NOT reported

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61
Q

When does level 2 mosiacism get reported?

A

2 or more abnormal cells in the sinple flask, or a single abnormal colony in culture among many - usually pseudomosaicism

Report if:

  • additiona studies inadequate
  • fetal anomalies identified
  • well recognized anomaly in mosaic state
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62
Q

What is level 3 mosiacism

A

multiple cells/colonies in independent cultures/dishes share same anomaly -> true mosaicism

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63
Q

What are the advantages of FISH analysis?

A

Rapid turnaround, high sensitivity

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64
Q

When would you choose a dual color break apart FISH probe instead of a dual-fusion probe?

A

When there are many possible translocation targets

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65
Q

What is an emumeration probe in FISH

A

Centromere control + target probe to look for amplification

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66
Q

Name 6 common tumor suppressor genes

A

RB1 - retinoblastoma

TP53 - Li frameni

APC - FAP

VHL

BRCA1/2 - familial breast/ovarian ca

MLH1 and MLH2 - Lynch

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67
Q

Which agent is used to prevent coagulation in cultures of liquid tumor cytogenetic analysis?

A

Sodium Heparin

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68
Q

What translocation is associated with CML?

How do you detect it?

A

t(9:22) - philadelphia chromosome

  • BCR-ABL fusion expressed in der22
  • detect w/ dual fushion FISH
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69
Q

What cytogenetic anomaly is seen in Polycythemia vera?

A

Trisomy 9 (JAK2 is on 9)

Polycythemia also seen in JAK2 GOF mutations

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70
Q

What ca is t(8:21) seen in?

A

AML

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71
Q

What is the only STAT cytogenic lab cancer case

A

Acute promyelocytic leukemia

t(15;17)

  • Patients may go into DIC
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72
Q

What is the purpose of testing for Her-2 amplification?

A

Poor prognostic factor in invasive cancers, but also target for therapy (Trastuzumab)

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73
Q

t(8:14), t(8:22), or t(2:8)

A

Burkitt lymphoma - MYC is on 8

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74
Q

What type of tumor is associated with each translocation?

9: 22
8: 21
15: 17
11: 14
14: 18
8: 14
8: 22
2: 8

A

9: 22 - CML - BCR-ABL
8: 21 - AML
15: 17 - APML (Promyelocytic)
11: 14 - Mantle cell
14: 18 - Follicular
8: 14/8:22/2:8 - Burkitt (MYC)

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75
Q

Pleuroplumonary blastoma, pulmonary cysts, thyroid ca, ovarian ca, cystic nephroma

A

DICER 1

  • also CNS sarcoma, pituitary, embryonal rhabdo
  • Monitor w/ chest CT/CXR at birth and Thyroid/pelvic/abd US at age 8
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76
Q

Which populations have increased incidence of Tay Sachs?

A

Ashkenazi Jews, (1/30 carrier risk)

French Canadians,

Louisiana Cajuns,

Pennsylvania Amish

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77
Q

Which populations are at risk for HbH and Hydrops?

A

Southeast Asia and Mediterranean Basin - carreirs of a-globin deletions in cis

Hb H = 1 of 4 funcitonal a-globin genes

Hydrops = 0 of 4

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78
Q

High HbA2 and HbF

A

B thal trait

HbA2 = α2δ2

HbF=α2γ2

  • Both use alternative proteins from B globin cluster
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79
Q

TPMT (thiopurine methyltransfarse)

A

Pharmacogenomic test for azathioprine toxicity -> catalyzes methylation/inactivation of drug (prevents myelosuppression)

TPMT*1 = wt

TPMT*2, *3A, *3C homozygotes = hematopoetic toxicity -> decrease dose to 10% of usual

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80
Q

What is the pathophys of FV Leiden and Protein C?

A

Factor V leiden - Arg506Gln = GOF - removal of preferred clevage site by protein C -> reduced inactivation of activated FV -> prothrombus formation

Proctein C = LOF - inability to cleave activated Factor V -> prothrombus formation

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81
Q

What % of turner syndrome patients are mosaic?

A

25%

50% 45, X

25% structural abnormality involving X

25% Mosaic

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82
Q

What % of 45, X conceptions result in a livebirth?

A

<1%

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83
Q

How is Turner Sydnrome managed?

A

GH until bone age 15

Estrogen after 15 to promote 2nd sexual characteristics

Progesterone to promote menses

TTE monitoring for root dilation (2/2 bicuspid AV)

Monitor for Diabetes and renal disease

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84
Q

Nucleotide excision repair

A

Xeroderma Pigmentosum

Photosensitivity, freckling, photophobia -> premature skin again

  • Actinic keraotsis + skin ca (melanoma, BCC, SCC)

+ ocular abnormlaities, neurodegeneration

(Also Trichothiodystrophy but no skin ca)

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85
Q

What are the 3 disorders of UV damage DNA repair

A

XP, Cockyne, and Trichothiodystrophy

XP, TTD = nucleotide excision, CS = transcription coupled repair

All three: thin skin w/ photosenstivity + neurodegeneration

XP = skin Ca

Cockayne = RP, deafness

TTD = brittle hair/nails, ichthyosis

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86
Q

What is the incidence of single gene disorders? prevalence?

A

Incidence 1:300 live borns

1:50 lifetime prevalence

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87
Q

How many genes are in the human genome?

A

~20,000 protein coding

~20,000 noncoding RNA

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88
Q

what are the componnents of the nucleo some complex?

A

4 core histones (H2A, H2B, H3, H4)

~140bp DNA

Histone H1 bind to DNA at edge of nucleosome in spacer region.

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89
Q

How much genetic variation is between 2 randomly selected individuals?

A

~0.5%

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90
Q

What is G0 in cell cycle?

A

Permanently arrested phase for cells that have stopped dividing. (neurons, RBCs)

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91
Q

What are the 5 phases of mitosis

A

Prophase - DNA condense, centromere form

Prometaphase - Nuc membrane dissolves

Metaphase - Chromosomes align

Anaphase - Separation

Telophase - Decondence/cytokinesis

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92
Q

When does crossing over occur?

A

Prophase 1 of meiosis

  • Zygotene = homologous choromsomes align in “synapsis”
  • Pachytene = meiotic crossing over
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93
Q

When is meiosis I compelted for Oocytes?

A

Just before ovulation (pause at metaphase II until fertilization

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94
Q

What enzymes initiates trancription at start site?

A

RNA polymerase II

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95
Q

What sequence specifies the location of polyadeenylation on 3’ end of mRNA

A

AAUAAA

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96
Q

Which two amino acides are only specified by a single unique codon?

A

Met (AUG) - start codon - establishes reading frame

Trp (UGG) - UAA, UAG, and UGA are STOP codons

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97
Q

What are the stop codons?

A

UAG, UGA, UAA

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98
Q

What strand of DNA is used as the template for Transcription?

A

Noncoding/antisense in 3’->5’ direction

Sense/coding strand is identical to mRNA transcript but NOT used as template

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99
Q

What is the TATA box

A

region rich in A and T ~25bp upstream of start codon ipmoratnt for initiation.

-CAT box further upstream

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100
Q

What are CpG islands?

A

CG rich areas found in promoter regions that are sites for methylation

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101
Q

What are enchancers, promotors, and locus control regaions?

A

Promoters: regulate transcription initiation for small distance upstream; same orientation as gene, 5’ UTR

Enchancer: regulate from a distance (can be any orientation/location)

Locus control: regulate chromatin context needed for expression

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102
Q

What chemical reaction happens in dna methylation

A

Cytoseine -> 5-methylcytosine

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103
Q

Which allele is XIST expressed in?

A

Only the inactivated X

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104
Q

What are the 2 classes of splicing mutations?

A

Mutations that interfere w/ normal RNA splicing (donor/acceptor site)

Mutations that creat alternative splice site

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105
Q

What is the mutation rate in a dominant gene?

A

affected cases/ (total births x2)

  • x2 for both parent alleles
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106
Q

Average genome has ___ of de novo mutations? LOF variants? inactivated genes?

A

75 de novo, 200 LOF, 25 inactivated genes

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107
Q

What is the resolution of karytyping w/ banding?

A

~1 million bp

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108
Q

What is the most commonly used tissue for karyotyping? Why?

A

T lymphocytes

Accessible, can be culture and stimulated to divide, then arrested in metaphase

3-4 days

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109
Q

What is the incidence of chromosome abnormalities among livebirths? Stillbirths? Infant deaths?

A

Livebirths <1%

Stillbirth, Infant death ~10%

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110
Q

What FISH probes are used to ID chromosome copy number?

A

α-satellite family of centromere repeats

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111
Q

What are the 5 acrocentric chromosomes?

A

13, 14, 15, 21, 22

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112
Q

What are 2 diadvantages to microarray?

A

1) VUS
2) does not reveal structure (ie translocation)

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113
Q

What kind of inversion is more likely to result in abnormal offspring?

A

Pericentric

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114
Q

What causes partial hydatidiform mole?

A

Triploidy with extra paternal chromosome set - abnormal degenerative placenta

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115
Q

Aneuploidy is seen in ___ % of recognized pregnancies?

A

5%

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116
Q

What is the most common autosome aneuploidy?

A

Trisomy 16

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117
Q

What is the most common aneuoploidy?

A

45 X

(Trisomy 16 is second)

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118
Q

In a balanced translocation, what kind of segregation results in normal phenotypic offspring?

A

Alternate

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119
Q

What is the most common type of chromosome arrangement?

A

Robertsonian

rob(13;14)(q10;q10) and rob(14;21)(q10;q10) are first and second

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120
Q

What is i(X)q(10)

A

isochromosome X

Most common isochromosome, seen in Turner syndrome often

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121
Q

Which type of inversion involved in centromere

A

PerIcentric -> Includes the centromere

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122
Q

What causes terminal deletion and duplication within the same chromosome

A

PerIcentric inversion

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123
Q

What is the most common abnormalitity in abortuses?

A

45, X

  • 20% of chromosomally abnormal abortuses

<1% chromosomally abnormal liveborns

Trisomy 16 is #2

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124
Q

What are the most common chromosomal abnormalities in liveborns?

A

1) Balanced rearrangement
2) extra sex chromosome (XXY, XYY, XXX)
3) trisomy 21

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125
Q

What are the most common chromosomal abnormalities in abortuses?

A

1) 45X
2) Trisomy 16
3) Trisomy 21

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126
Q

Who should you screen for aneurysms in ADPKD?

A

People with a positive family history (Aneurysms cluster in familites)

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127
Q

What is the most common mechanism for the second hit in RB1

A

Deletion or isodisomy

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128
Q

When is the high risk age for developing retinoblastoma in RB1

A

Until age 7

Most patients develope in first 3 years

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129
Q

What type of SRY variant is seen in 46XX males? 46XY females?

A

80% of 46XX males (translocation to X chromosome) - tx with androgens to complete virilization

30% of 46XY females (deletion/mutation - LOF) - tx with estrogen at 14, progesterone for periods, remove gonads to avoid gonadoblastoma

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130
Q

What do breakpoints of aneusomies (segmental duplicatons/deletions) cluster?

A

Low copy repeated sequences (aka segmental duplications)

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131
Q

Microcephaly, hypertelorism, epicanthal folds, low set ears, micrognathia, high pitched cry

A

Cri Du Chat

5p15 deletion syndrome

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132
Q

What are the 3 most common mechanisms of Prader Willi syndrome?

A

1) Pat 15p11 del - 70%
2) Mat UPD - 25%
3) Imprinting defect

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133
Q

What are the 5 most common mechanisms for Angelman syndrome?

A

1) Mat 15q11 deletion - 70%
2) UBE3A point mutation - 10%
3) Pat UPD - 7%
4) imprinting defect - 3%
5) Unknown - 10%

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134
Q

Which X chromosome is preferentially inactivated when a balanced translocation involving X is present? What about an unbalanced offspring?

A

Balanced: normal X preferentially inactivated -> this allows for the other translocated part to be expressed.

Unbalanced: Normal X active

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135
Q

Which autosomal gene is the effector (up-regulated) by SRY?

A

SOX 9 (causes campomelic dysplasia)

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136
Q

What is the offspring prognosis for a male with an X-Y translocation involving SRY?

A

All children will have sex reveral:

XY offsping will look female (SRY deleted)

XX offspring will look male (SRY present)

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137
Q

Male with infertility, hypotonia, decreased bone density, low-normal IQ, androgen deficiency

A

Klinefelters

47 XXY

Many can look normal. ALWAYS infertile (germ cell does not develope)

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138
Q

What are the most common chromosomal abnormalites in oocytes and sperm?

A

Oocytes: aneuploidy (~20% of total)

Sperm: Sturctural rearrangement (~10% of total)

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139
Q

What is the most common error (stage of meiosis and parent) that leads to aneuploidies?

A

Maternal meiosis 1

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140
Q

Which anueploidy is usually a maternal meiosis II error

A

Trisomy 18

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141
Q

Which aneuoploidies are most likely to be due to paternal meiosis error?

A

XXY - 50% pat MI

X - 75% pat

XYY - 100% pat MII

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142
Q

What is the predominant mechanism of aneuoploidy in females?

A

Premature separation of sister chromatids (BEFORE anaphase) during M1

Males have more classic nondysjunction

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143
Q

What is the most common autosomal trisomy in a SAB?

A

Trisomy 16 (30% o f SABs)

25% of all SABs are due to autosomal aneuploidy

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144
Q

What are the most common karyotype findings in Down syndrome?

A

95% trisomy

4% Robertsonian translocation - t(14:21) usually

1% mosaic/structural rearrangements

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145
Q

What are the most common Karyotype findings in Edwards syndrome

A

97% maternal nondisjunction (usually Meiosis II)

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146
Q

What are the most common karyotype findings in Patau syndrome?

A

75% trisomy 13

20% robertsonian translocation - der (13;14)

5% mosaic

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147
Q

What is anaphase lag?

A

Failure of chromosome to attach to spindle or migrate to pole during meiosis -> thus not included in nucleus of daughter cell

Mechanism of chromosomal mosciacism in addition to nondysjunction

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148
Q

Isochromosome 12p

A

Pallister Killian

isochromosome -> tetrasomy 12 p

  • Always mosaic (can be detected on amnio, but not always CVS)
  • DD, seizures, high hairline, diaphgramatic hernia
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149
Q

Which Chorionic villus tissue is MOST likely to have save genetic makeup as fetus? (least likely to be confined moasicism)

  • Cytotrophoblast
  • Syncythiotrophoblast
  • Mesenchymal core
A

Mesenchymal core (in cultured prep only)

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150
Q

What does finding confined placenta mosiacism mean for fetus?

A
  • most like normal
  • high risk for iUGR, pregnancy loss
  • 2% risk for UPD
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151
Q

What do Chromosomes 6, 7, 11, 14, 15, 20 have in common?

A

Imprinted

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152
Q

What is the most common interpretation for trisomy 16 seen on CVS vs amnio

A

CVS - usually confined placental mosiacism

Amnio - usually fetus is mosiac

True trisomy 16 not viable

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153
Q

What is the most common chromosomal abnormalities in SABs

A

Monosomy X

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154
Q

Which 45X patients are at risk for gonadoblastoma?

A

When there is mosaic 46XY cells

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155
Q

What causes partial hydatiform mole?

A

Paternal triploidy (2 sperm, 1 egg)

  • AFP, hCG elevated
  • Hydropic villi + normal villi + small fetus
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156
Q

Maternal triploid fetus

A

Small placenta, small fetus with large head

  • AFP, hCG low
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157
Q

What is the difference between maternal (digyny) and paternal (dispermy) triploidy?

A

Paternal -> partial mole, large villi, small fetus, high AFP, hCG

Maternal -> small plaenta, small fetus w/ large head, low AFP, hCG

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158
Q

What is the difference between partial and compelte hydatiform mole?

A

Partial = triploid w/ 2 paternal chromosome sets -> large villi w/ small fetus

Complete = diploid w/ 2 paternal chromosome sets (NO mat chromosomes) -> NO fetus

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159
Q

Which X chromosome will be nonrandomly inactived if a structually abnormal X is present?

A

abnormal X

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160
Q

Which X will be nonrandomly inactived if there is a balanced translocation?

A

normal X

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161
Q

Which X chromosome will be nonrandomly inactivated when there is an unbalanced tranlsocation involving X?

A

Abnormal X

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162
Q

Which X is usually missing in Turner syndrome?

A

paternal

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163
Q

What are the 3 more common karyotypes in Turner Syndrome?

A

45, X - 15%

46, X, i(Xq) - 15% - missing most PAR genes in Xp

45X/46,XX mosaic - 15%

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164
Q

Why is it important to look for marker chromosomes in Turner syndrome?

A

Marker Y -> risk for gonadoblastoma

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165
Q

What are the most common robertsonian translocations?

A

t(13:14) - 75% - can cause patau syndrome if unbalanced

t (14:21) - 8%

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166
Q

What is a trivalent

A

3 aligned chromosomes due to a robertsonian translocation carrier

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167
Q

In a trivalent, which segregation leds to normal offspring?

A

Alternate

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168
Q

What is the difference between adjacent 1 and adjacent 2 segretation?

A

Adjacent 1 -> chromosomes with different centromeres go together in daughter cell -> more common

Adjacent 2 -> chromosomes with same centromere go together in daugher cell -> very rare

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169
Q

What segregation might produce offspring with down syndrome if a parent is a carrier for t(14:21)?

A

Adjacent 1 -> different centromeres go together, more common and more likely to be viable

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170
Q

What are the clinical consequences of having a balanced X-autosome translocation?

A

Females: decreased fertility (oogenesis needs both X); may also lead to abnormal offspring due to skewed inactivtion in oogenesis

Male: almost always infertile

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171
Q

What is the most common isochromosome?

A

Xq (seen in turners) - NOT Xp because p is where most PAR genes are

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172
Q

What type of inversion is most likely to lead to abnormal offspring?

A

Pericentric -> del and dup in terminal ends of same chromosome

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173
Q

Which type of inversion will almost always result in normal offspring?

A

Paracentric -> recombinant version acentric or dicentric -> not viable

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174
Q

How does size of inverion affect offspring risk in pericentric inversions?

A

Small inversions are not likely to cross over-> low risk of viable abnormal offspring

Large inversion -> more like to cross over AND del/dup are smaller -> more likely to have viable abnormal offspring

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175
Q

What does ring chromosome look like on microarray?

A

if normal chromosome number: terminal deletions on both ends

If additional ring: partial trisomy in middle but not the ends of chromosome

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176
Q

Name the following syndromes:

5q35 del

7q11 del

15q11 del

17p11 del

17p12 del

17p12 dup

22q11 del

A

5q35 del - Sotos

7q11 del - Williams

15q11 del - PWS/Angelman

17p11 del - Smith Magenis

17p12 del - HNPP

17p12 dup - CMT type 1A

22q11 del - VCF/Digeorge

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177
Q

What is the mechanism for recurrent chromosomal rearrangements?

A

non-allelic homologous recombination in low copy repeat (LCR; aka segmental duplications)

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178
Q

What is the mechanism for non-recurrent structural chromosomal rearrangements?

A

Nonhomologous end joining

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179
Q

How many copies of each alleles are present in isodicentric chromosomes?

A

2x in most cases

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180
Q

When is there risk to fetus after a marker chromosome is found?

A

If parent is phenotypically normal, non-mosaic, and a carrier

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181
Q

idic(22)

A

Isodicentric 22 -> if present patient has tetraploidy of ch 22

Cat eye syndrome: Iris coloboma, CHD, ear tags, anal atresia w/ normal intellect

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182
Q

what is r(20) associated with?

A

Ringed chromosome 20

  • usually mosiac

May be fused at telomere so no loss of termianl DNA - need to do FISH/karyotype

-intractable epilepsy

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183
Q

What is a haplotype

A

A set of alleles at two or more neighboring loci on ONE of two homologous chromosomes

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184
Q

What is the difference between penetrance and expressivity

A

Penetrance is chance ANY phenotype is expressed

Expressivity is the severity of phenotype

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185
Q

Semidominant (incompete dominant) vs codominant

A

Semidominant: Homozygotes are more severely affected than heterozygotes

Codominant: both alleles expressed togehter in compound heterozygotes

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186
Q

What is the genetic risk of offpring of first cousin marriages?

A

3-5% (background 2-3%)

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187
Q

What is reprodutive fitness?

A

(# Offspring of affected individuals that survive to reproductive age)/(#Offspring of unaffected)

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188
Q

For X linked disorder with fitness of 0, what % of cases should be de-novo?

A

<50%; since allele is partially protected from selection in female carriers

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189
Q

For an AD disorder with fitness of 0, what % of cases should be de novo?

A

100%

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190
Q

In HD, which parent is more likely to pass along an expanded allele?

A

Father

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191
Q

In Fragile X, which parent is more likely to pass along an expanded allele?

A

Mother

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192
Q

What is allelic heterogeneity?

A

Different Mutations (same gene) -> same phenotype

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193
Q

What is locus heterogeneity?

A

Different genes -> same phenotype

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194
Q

What is clinical/phenotypic heterogeneity?

A

same gene (different mutations) -> different phenotype

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195
Q

What is the difference between allelic, locus, and clinical heterogeneity?

A

Allelic: Different variants (same gene) -> same phenotype

Locus: DIfferent genes -> same phenotype

Clinical/phenotypic: Same gene (different variants?) -> different phenotypes

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196
Q

What is the relative risk ratio?

A

Measure of familiam aggregation

Lamda = prevalence in relatives of affected/prevalence if general population

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197
Q

What does a Heritabilty (H2) of 1 mean?

A

Heritability = fraction of phenotypic variance of quantitative trait due to allelic variance

1 means completely attributed to genetics

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198
Q

How is Heritability (H2)calculated?

A

Subtracting coefficient of correlation in dizygotic twins (50% IBD) from monozygotic twins (100% IBD) and multiplying by 2

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199
Q

What is the difference between ascertainment and recall bias?

A

Ascertainment bias = affected more likely to come to researcher’s attention

Recall bia = affected more likely to be aware of disease than controls

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200
Q

Name 2 modifier genes for cystic fibrosis.

A

1) MBL2 - mannose binding lectin (binds pathogens) - lower levels -> worse outcome
2) TGFB1 - cytokine transforming growth factor B (promotes scarring) -high level -> worse outcomes

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201
Q

What is the most common gene seen in Hirschsprung?

A

RET

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202
Q

Which gender is at higher risk for dementia?

A

females

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203
Q

How does the APOE gene modify alzheimer risk?

A

3 alleles (E2, E3, E4)

Baseline risk 10% by age 80

If one E4 risk is 40% by age 80

If 2 E4 risk is 60% by age 80

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204
Q

Which chromosomes cannot be distinguished by centromeric FISH?

A

13, 14, 21, 22 -> common robertsonian translocations; too similar sequences

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205
Q

What is the advantage of using FISH to test for aneuoploidy?

A

Fast - only 1-2 days vs weeks for CMA/karyotype

Often used prenatally

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206
Q

When would you want to do interphase instead of metaphase fish?

A

when looking for tandem duplications (easier to see when stuff is less condensed)

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207
Q

When would you use Dual-fusion FISH vs Break-apart FISH?

A

Dual fushion - when both translocation breakpoints are known

Breakapart- when looking at loci with multiple rearrangement partners

208
Q

What are reasons to use FISH after a CMA

A
  • confirm result with different modality
  • Find locations of duplications
  • Help find structural rearrangements
209
Q

ΔCCR5 allele

A

Resistance to AIDS - CCR5 = cytokine receptor that in entry point for HIV. Deletion prevents expression

210
Q

What are the Hardy Weinberg Assumptions?

A
  • random mating
  • large population
  • no new mutation
  • same fitness
  • no migration
211
Q

How is observed allele frequency calculated?

A

(2x homozygotes + 1x heterozygotes)/ Total possibilities

212
Q

What is hardy weinberg for X- linked cases?

A

Males: p+q=1

Females p2+2pq + q2

213
Q

What is stratification? How does it affect HW allele frequencies?

A
  • non fandom mating where subgroups remain genetically separated (ie culture, religion, class, etc)
  • It results in excess of homozygotes
  • does NOT affect autosomal dominant disease frequencies
214
Q

Which type of disorders are most affected by new mutations?

A

Dominant and X linked

215
Q

What is fitness (f)

A

Likelihood of affected individual’s offspring to survive to reproductive age

216
Q

What is coefficient of selection? (s)

A

s = 1-f

f = fitness

217
Q

Which type of disorder is LEASE susceptible to selection?

A

Autosomal recessive -> since only homozygotes (usually small portion) are exposed to selective pressure

218
Q

How are mutation rates, selection, and allele frequency related in autosomal dominant diseases?

A

allele frequency = mutation rate/selection

u=sq, q=u/s

Mutation rate must accound for all cases that are lose due to selection

219
Q

How are mutation rates, selection, and allele frequency related in X linked diseases?

A

u=sq/3 (only 1/3rd of q is in males, the rest are in unaffected females at equilbirum)

If s is 1 (fitness is 0) new mutation rate is 1/3q

220
Q

How do you tell if an allele is under selective pressure?

A

Compared observed allele frequencies to hardy weinberg frequences.

221
Q

What gene protects against trypanosomiasis (t brucei) in heterozygotes but cause increased risk for FSGS (nephropathy) in homozygotes?

A

APOL1 (apolipoprotein 1)

222
Q

What are AIMS (ancestry infromative markers)

A

alleles that show large differences in fequency among populations from different parts of the word -> used to track migration

223
Q

Whats the difference between CGH array and SNP array?

A

CGH: control + patient sample with oligos - you choose coverage

SNP: patient hybridize to 2 sets of SNPs representing alleles

Most CMAs now do both

224
Q

What an SNP arrays detect that CGH arrays cannot?

A

Can get genotype information such as runs of homozygosity and triploidy

  • But SNPs are not evenly distributed and you cannot control where they are
225
Q

What are the advantages of microarray vs karyotype?

A
  • higher resolution (5KB)
  • does NOT need metaphase/culturable cells (useful in products of conceptrion)
  • Can detect UPD (isodisomy)
226
Q

What are the major limitations of CMA

A
  • No structural infromation
  • does not locate extra material
  • cannot detect uniparenal heterodisomy
227
Q

In CGH array, what does a log 2 ratio of infinity mean?

A

Nullizygous deletion (CN = 0)

228
Q

In CGH array, what does a log 2 ratio of -1 mean?

A

heterozygous deletion (CN = 1)

Log2 of 1/2

229
Q

In CGH array, what does a log 2 ratio of 0 mean?

A

normal

Log2 of 2

230
Q

In CGH array, what does Log 2 ratio of 0.6 mean?

A

Duplication

Log2 of 3/2

231
Q

In CGH array, what does a Log 2 ratio of 1 (or more) mean?

A

amplification

Log2 of >4

232
Q

What is the difference between SNP allele difference track and B allele frequency track?

A

Different ways to look at SNP array data

Allele difference: arbitrary flourescence of haploid locus set to 0 (AA = 1, AB = 0, BB = -1)

B frequency: arbitrary floursecence of haploid locus set to 0.5 (AA = 0, AB = 0.5, BB =1)

233
Q

What is the output of the CGH array?

A

A Log2 ratio since it compares hybridization of patient vs control

234
Q

What is the output of a SNP array?

A

Allele difference or B allele frequency tracts

235
Q

What is the difference in output of a CGH array vs SNP array?

A

CGH = Log 2 ratio

SNP = Allele difference or B allele frequency track

236
Q

What does duplication and deletion look like on SNP array?

A

Duplication: 4 combinations instead of 3

Deletion: 2 combination instead of 3

237
Q

What is the difference between coefficient of consanguinity and coefficienct of inbreeding?

A

Coefficient of consanguinity = % genome shared between the parents

Coefficient of inbreeding = % homogyzous genome in offspring

Parents are consanguinous, Offspring are inbred

238
Q

What percent of genome is expected to be IBD in offspring of a first cousin mating? What is the coefficient of inbreeding? What is the coefficient of consanguinity?

A

6.25% IBD

Co of Inbreeding = 1/16

Co of consanguinity = 1/8

239
Q

If you see loss of heterozygosity on CMA, when should you think about UPD instead of inbreeding?

A

Think about UPD when:

  • ROH (runs of homozygosity) is blocked (in inbreeding ROH are interspersed throughout genome)
  • ROH is large - entire chromosome or arm
  • ROH is terminal and >10MB or interstitial > 20MN
240
Q

What should you do next if you see many ROH interspaced throughout genome in a CMA?

A

Likely inbreeding, look for AR disorders on exome

241
Q

What should you do if you suspect UPD in a non-imprinted chromosome on CMA?

A

= exome for AR disorders

  • karyotyping to rule out robertsonian translocation or isochromosome
242
Q

What should you do if you suspect UPD in chromosomes 6, 7, 11, 14, 15, or 12?

A

These are chromosomes with imprinted regions

  • MS-MLPA (methylation specific) can determing parental origin without parental samples
  • Get trio data to determine parent of origin
243
Q

What does triploidy look like on CGH and SNP array?

A

CGH array - normal (data gets normalized)

SNP array - 4 lines of probes instead of 3 (every locus has 3 possible combinations instead of 4)

244
Q

According to ACOG, when should you use CMA

A
  • Replace karyotype if there is an US abnormality
  • karyotype OR array if there are no US abnormalities
  • NOT age-related - can offer to anyone
  • Recommend in POC, IUFD, or stillbirth
245
Q

What features make CMA abnormalities more likely to be pathogenic?

A
  • Del > duplications
  • Larger (>1MB)
  • gene density
  • OMIM genes
  • Evidence of dosage sensitivity
  • De novo
246
Q

What does this CMA depict?

A

Supernumery Ring 20

  • Pericentromeric duplication
247
Q

What does this CMA depict

A

Ring X (replaced normal X)

  • Distal monozomy of pter and qter
248
Q

What does this CMA show?

A

Unbalanced translocation

  • Terminal gain and loss in different chromosomes
249
Q

What does this CMA show?

A

recombinant chromosome from parental pericentric inversion

  • Terminal gain/loss in the same chromosome
250
Q

What is del(5)(p15.3)

A

Terminal deletion in p arm of ch5

251
Q

What is del(13)(q21.3q33)

A

interstitial deletion in Ch 13

252
Q

What is dup(15)(q11.2q13.1)

A

Interstitial duplication in Ch 15

253
Q

What is inv(9)(p11q13)

A

Pericentric inversion in Ch 9

254
Q

What is inv(9)(q11q13)

A

Paracentric inversion in Ch 9

255
Q

What is 46,XX,t(11,22)(q23.3;q11.2)?

A

46,XX,t(11,22)(q23.3;q11.2)

Balanced translocation (no Der) between Ch 11 and 22. Breakpoint 11 at first locus, breakpoint 22 at second locus

256
Q

What is 47,XY,+der(22)t(11;22)(q23.3;q11.2)

A

47,XY,+der(22)t(11;22)(q23.3;q11.2)

47 chromosomes, extra chromosome contains centromere of c22 -> this extra chromosome is the result of a 11;22 translocation

  • Remaining 22 and 11 assumed normal
257
Q

What is 45,XY,der(13;14)(q10;q10)

A

45,XY,der(13;14)(q10;q10)

Robertsonian translocation - balanced

  • derivative chromosome that is the result of 13:14 translocation where p arms are lost is present
258
Q

What is 46,XY,+13,der(13;14)(q10;q10)

A

46,XY,+13,der(13;14)(q10;q10)

Robertsonian translocation - unbalanced

  • EXTRA material from 13 is present; a derivative 13;14 is present
  • Assume 2 normal ch13s in addition to derivative since extra material is from 13
259
Q

What is ish 17p13.3(RP11-806J5x2)

A

ish 17p13.3(RP11-806J5x2)

ish = metaphase FISH

  • probe RP11-806J5 which targets 17p13.3 was seen x2
  • This is NORMAL result
260
Q

What is nuc ish (RP11-806J5x2)

A

nuc ish (RP11-806J5x2)

Nuc ish = interphase FISH (done in nucleus, not during mitosiss)

  • Proble RP11-806J5 was seen twice
  • This is NORMAL FISH result
261
Q

What is ish del(17)(p13.3)(RP11-806J5-).nuc ish(RP11-806J5x1)

A

ish del(17)(p13.3)(RP11-806J5-).nuc ish(RP11-806J5x1)

  • On metaphase (ish) FISH probe RP11-806J5 (which targets 17p13.3) is missine one copy; this means there is a deletion
  • On interphase (nuc ish) FISH the same probe is seen only once
  • These results are concordant and both point to missing genetic material at that locus
262
Q

What is ish t(X;16)(q28;q12.1)(RP11-811K14-,RP11-368M4+; RP11-368M4-,RP11-811K14+)

A

ish t(X;16)(q28;q12.1)(RP11-811K14-,RP11-368M4+; RP11-368M4-,RP11-811K14+)

  • Metaphase FISH
  • Translocation of X and 16 detected
  • RP11-811K14 probe which targets Xq28 is missing on copy in chX and gained one copy in ch16
  • RP11-368M4 probe which targets 16q12.1 gained a copy in chX and is missing a copy in ch16
263
Q

What is nuc ish(ABL,BCR)x2

A

nuc ish(ABL,BCR)x2

On interphase (nuc ish) FISH both ABL and BCR probes were seen twice

  • this is a normal result
264
Q

What is nuc ish(ABL,BCR)x2(ABL con BCRx1)

A

nuc ish(ABL,BCR)x2(ABL con BCRx1)

On Interphase FISH both BCR and ABL are each seen twice, a ABL connected to BCR is seen once

  • This represents a BCR/ABL fushion found using a dual-fusion probe
265
Q

What is nuc ish (p1,p2)x2(p1 sep p2x1)

A

nuc ish (p1,p2)x2(p1 sep p2x1)

Interphase FISH saw each of two probes seen twice. One P1 probe was separated from one P2 probe

  • This represents a translocation found using a break apart probe
266
Q

arr(X,Y)x1,(1-22)x2

A

arr(X,Y)x1,(1-22)x2

Normal Male

267
Q

arr(X)x2,(Y)x1

A

arr(X)x2,(Y)x1

XXY -> klinefelters found on CMA

268
Q

arr(X)x2,(Y)x1,(1-22)x3

A

arr(X)x2,(Y)x1,(1-22)x3

Triploidy seen on CMA

269
Q

arr[GRCh37]17p13.3(6160_2054122)x1

A

arr[GRCh37]17p13.3(6160_2054122)x1

CMA using genomce ref 37 showing deletion of 17p13.3

270
Q

arr[GRCh37] 8p23.3p23.1(190822_6735381)x1,8p23.1p11.21(12580131_40802481)x3

A

arr[GRCh37] 8p23.3p23.1(190822_6735381)x1,8p23.1p11.21(12580131_40802481)x3

Array using ref genome 37 whoing both a deletion and duplication on ch8

271
Q

arr[GRCh37] Yp11.32p11.2(100002_10045809)x2,20q13.3(62328478_62907526)x1

A

arr[GRCh37] Yp11.32p11.2(100002_10045809)x2,20q13.3(62328478_62907526)x1

  • CMA using ref genome 37 showing interstitial (2 breakpoints) duplication in Y and terminal deletion in ch20
272
Q

arr[GRCh37]13q11q34(19438806_115095705)x2 hmz

A

arr[GRCh37]13q11q34(19438806_115095705)x2 hmz

CMA using ref genome 37 showing homozygosity for segment of chromosome 13

273
Q

rsa(X,Y)x1,(13,18,21)x2

A

rsa(X,Y)x1,(13,18,21)x2

Region specific assay showing normal results

274
Q

seq[GRCh38] der(2)t(2;11)(p25.1;p15.2) NC_000002.12:g.pter_8247756delins[NC_000011.10:g.pter_15825272]

A

seq[GRCh38] der(2)t(2;11)(p25.1;p15.2) NC_000002.12:g.pter_8247756delins[NC_000011.10:g.pter_15825272]

Sequencing using ref genome 38 showed translocation between ch 2 and 11 with der2 sequence change in terminal P

  • Delins = deletion then insertion = sequence change
275
Q

What is the difference bewteen a parentl and nonparental gamete?

A

Parental gametes have the same combination of alleles of interest as one of the parents.

276
Q

What does syntenic genes mean?

A

Genes that reside in the same chromosome (regardless of how far apart they are)

277
Q

What conditions must be met in order to detect recombination events for linkage analyss?

A

1) A parent must be heterozygous
2) Phase of alelles must be known

278
Q

What is recombination frequency?

A

θ = frequency of recombination/total

It is between 0 (no recombination) and 0.5 (independent assortment)

θ of 0.01 = 1 centimorgan

279
Q

What is linkage disequilibirum? How is it calculated

A

Linkage disequilibrium is deveiation from predicted haplotypes based on allele frequencies

LD = freq of parental haplotypes - freq of recombinant haplotypes

If parental haplotypes are AS and as

LD = freq (AS)x Freq (as) - freq(As)xfreq(aS)

LD = 0 = alleles in linkage equilibrium

280
Q

What determines the staying power of a new disease haplotype?

A

1) # of generations
2) Frequencing of recombination (θ) between disease and haplotype
3) Selection against the phenotype

281
Q

What information do you need to perform linkage analysis in a family?

A

1) Recombination frequency (θ)
2) whether θ is significantly lower than 0.5 (expected for unliked loci)
- Result = LOD score (logarithm of the ODds)

282
Q

What is the difference between a case control, cross sectional, and cohort study?

A

Case control: individuals with disease vs individuals without disease are compared; best for super rare diseases where pop studies unlikely to find enough cases -> Odds ratio

Cross secton: Random sample of entire population analyzed for those with and without disease -> Relative risk

Cohort: Random sample of entire population followed over time to see who gets disease -> relative risk

283
Q

What is the difference between Odds Ratio and Relative Risk

A

OR is for case-control studies: Odds of a carrier developing disease vs odds of a non-carrier developing disease

OR = (a/b)/(c/d) = ad/bc

RR is for cross-sectional or cohort studies: Ratio of proportion of those with disease to carry an allele vs those without

RR = (a/(a+b))/(c/c+d)

284
Q

How does population stratification affect GWAS results?

A

Artifactual positive results since AIMs from a subpopulation with increased disease incidence will show up as associated to phenotype

285
Q

Arg506Gln Factor V

A

Factor V leiden

  • Resistance to protein C cleavage -> continued activating prothrombin (FX)
286
Q

What is Hb Kempsey?

B chain :Asp99Asn

A

β-globin allele that maintains the hemoglobin in a high oxygen affinity structure -> causes polycythemia due to decreased peripheral O2

287
Q

What is Hb A?

A

Normal adult Hemoglobin

α2β2

288
Q

What is Hb F?

A

Fetal Hemoglobin

Hb F (α2γ2), the predominant hemoglobin throughout fetal life

  • Expression decreases after birth to <10% after 3 months
289
Q

What is the LCR for B globin?

A

Locus control region -> regulatory domain upstream of B-globin gene cluster that associates w/ binding proteins for form Active Chromatin hub and regulates B-globin gene expression

  • Deleation of LCT = no B globin cluster expression
290
Q

When does B thal become clinically apparent?

A

usually after 3 months -> HbF drops off after birth.

(a-thal can have prenatal manifestations)

291
Q

What is Hb E?

B chain: Glu26Lys

A

Abnormal Hb and decrased synthesis (abnormal splicing) -> mild thalaseemia

  • most common structually abnormal Hb in the world -> common in southeast Asia
292
Q

What is Hb Hyde Park?

B chain: His92Tyr

A

Hb resistant to methemoglobin reductase -> cannot carry O2 -> cyanosis

293
Q

What is Hb Hammersmith?

B chain Phe425Ser

A

Unstable Hb -> hemolysis/low O2 affinity

294
Q

What is the strongest modifier for Sickle Cell Disease?

A

Hb F levels

  • BCL11A and MYB (transcrption factors) and the γ-globin gene contribute to HbF levels
  • BCL11A and MYB are therapeutic targets
295
Q

What are Hb Bart?

A

Hb Bart = γ4 tetramer

Seen when all 4 a-globin genes are missing -> Hydrops fetalis - gamma Hb (fetal) form tetramers

296
Q

What is Hb H?

A

β4 tetramer seen in alpha Thal when only 1 of 4 a-globin genes is present

  • moderate/severe hemolytic anemia
297
Q

a-thal + Intellectual disability

A

ATR-X syndrome

  • Alpha-that retardation syndrome
  • X linked ATRX gene encodes chromatin remodeling protein that activates α-globin genes in trans; when missing macro H2A histones accumulate and prevent transcription
298
Q

What is the modifier for B thalasemia?

A

alpha-Thal

  • Unbound a-globin is toxic, so if alpha chains are also missing phenotype is milder
299
Q

What kinds of mutations cause B-thal?

A

Anything that leads to decreased expression

1) Splicing (destroy splice site, cryptic splice site, intronic new splice site) - may be synonymous
2) Nonsense -> leads to nonsense mediated decay if >50bp upstream of final exon-exon junction
3) Frameshift.- nonfunctional product
4) PolyA tail variants -> decaps in capping

300
Q

short stature, macrocephaly, chronic otitis media, rhizomelia, metaphyseal dysplasia, small sacrosciatic notches, short broad cone-shaped proximal and middle phalanges

A

Achondroplasia

FGFR3 Gly380Arg

  • main worry is small foramen magnum -> cervical compression +central sleep apnea
301
Q

Short stature, cleft palate, hearing loss, myopia, odontoid hypoplasia

  • No pubic bone ossification
A

Spondyloepiphyseal dysplasia

Collage type II spectrum (more severe and stickler)

COLII, IX, Xi

302
Q

Normal birth -> rhizomelia, genu valgus AND varus (windswept), small irregular epiphysis, flat beaked vertebral, arthritis

A

Pseudochondroplasia

COMP (AD)

303
Q

Short stature, club foot, hithhiker thumb, cauliflower ear, short braod fingers w/ ulner deviation

A

Diastrophic dysplasia

SLC26A2 (sulfate transporter)

304
Q

Devits in distal long bones

Loose teeth early and w/ root

High urine phosphoethanolamine, pyrophosphate, and pyridoxal 5- phosphate (B6)

A

Hypophosphatasia

TNSALP - tissue nonspecific alkaline phosphatase

Adult w/ alk phos <40

  • ERT Asfotase Alfa

- avoid bisphosphonates

305
Q

Dysgerminoma

Craniosynostosis, polysyndactyly of hands and feet (mitten hands), fused cervical vertebral

A

Apert syndrome

FGFR2 (AD)

306
Q

Craniosynostosis, normal IQ/hands/feet

+ Proptosis, prognathism, beaked nose

A

Couzon syndrome

FGFR2 (AD de novo)

FGFR3 if acanthosis nigricans present

307
Q

Craniosynostosis, fused calcaneocuboid bones, borad great toes, 2/3 toe syndactyly

A

Jackson-Weiss

FGFR2, amish

  • think foot anomalies - fused calcaneocuboid bones, borad great toes, 2/3 toe syndactyly
308
Q

craniosynostosis, carpal-tarsal fushion, heaing loss

A

Muenke

FGFR3 Pro250Arg - AD w/ variable expressivity

309
Q

Craniosynostosis, broad thumbs/toes, proptosis

A

Pfeiffer

FGFR2 (95%)

FGFR1 (5%)

  • may have cloverleaf skull
310
Q

craniosynostosis, radioulnar synostosis, virilization (fetus AND pregnant mother)

A

Antley-bixler

POR (Cytochrome P450 Reductase)

311
Q

Craniosynostosis, 2/3 syndactyly, duplicated great toe, radioulnar synostosis, pointed chin

A

Saethre-Chotzen

TWIST1 (downstream transcription factor to FGFR1, 2 and 3) -> upstream of RUNX2 (cleidocranio)

312
Q

How does IFNGR2 missense variants cause mendelian susceptibility to mycobacterial disease?

A

Creates novel N-glycosylation site on interferon-gamma receptor 2 -> loss of protin function due to excess glycosylation

313
Q

What is the mechanism of disease in α1AT deficiency?

A

SERPINA1 = protease inhibitor

Novel property (aggregation) -> trapping in rough ER of hepatocytes -> Liver disease

Inability to get to lungs -> deficiency of protease activity -> lack of elastase inhibition -> COPD

314
Q

Xanthona, Arcus cornea, hypercholetersolemia, early MI

Name 3 genetic causes

A

Familial Hypercholesterolemia

LDLR = incomplete dominant.- 300 in hets, 600 in homo

ApoB100 (AR) - binds cholesterol ester (forms ligand for LDLR)

PCSK9 superactivity (AD) - targets LDLR for degradation

*PCSK 9 LOF is protective

315
Q

How does ΔF508 affect CFTR?

A

Misfolded protein cannot leave ER -> never makes it to cell surface

316
Q

Aside from CFTR, what gene can lead to high sweat chloride, lung infections, and intestinal disease?

A

SCNN1 -> epithelial Na channel

  • non-classic CF phenocopy
317
Q

How do variants in TGFβ1, IL8, and IFRD1 affect CF?

A

They modify severity of lung disease.

Increased TGFB1 expression -> more severe inflammatory response

318
Q

Which phenotype in CF correlated w/ genotype?

A

pancreatic function

319
Q

Which types of mutations in COL type 1 cause the worst disease?

A
  • missense that replace glycine residue > deletion (difficult to assemble chain)
  • COL1A1 > COL1A2 -> 2 copies of a1 chain, only 1 copy of a2 chain; thus more likely to incorporate at least one abnormal a1 chain (3/4) into assembly
  • carboxyl end glycine -> start of assembly slowed, distal end can get extra-modified post-translationally and be harder to secrete
320
Q

Name 3 genes that cause AD Alzheimer’s

A

PSEN1, PSEN2, APP

  • PSEN1 and 2 help drive cleavage of beta amyloid precursor protein into Aβ40 (non-toxic) rather than Aβ42 (aggregates)
  • APP is on chromosome 21
321
Q

homoplasmic substitution of 1178A.G in ND4 subunit of complex 1

A

Leber’s hereditary optic neuropathy

Incomplete penetrance -> affects 50% males and 10% females

322
Q

Heteroplasmic MtATP6 mutations

A

Leigh syndrome

Neurodegeneration, DD, optic atrophy, respitaroy abnormalities

323
Q

Heteroplasmic tRNAleu (3243A>G)

A

MELAS

- Diabetes, deafness

  • Myopathy, encephalopathy, lactic acidosis, stroke like episodes
  • May also cause CPEO
324
Q

Heteroplasmic tRNAlys (8344A>G)

A

MERRF

myoclonic epilepsy, RR ribers, myopathy, ataxia, SNHL, dementia

325
Q

homoplasmic mutations in 12S rRNA

A

Hearing loss induced by aminoglycosides

nonsyndromic hearing loss

326
Q

Large sporadic heteroplasmic 5mb deletion

A

Kearns-Sayre

myopathy, external ophthalmoplegia, cardiomyopathy, ptosis, RP, ataxia, diabetes

327
Q

What is the mechanism of mitochondrial depletion syndrome?

A

Reduction in number of copies of mtDNA both per mitochondria and per cell due to inability to maintain nucleotide pools/metabolize nucleotides in mitochondria

328
Q

Where is fragile X repeat expansion?

What is the mechanism of disease?

A

CGG in 5’UTR

  • transcription silencing
329
Q

Where is Frataxin repeat expansion? what is the disease mechanism?

A

GAA in intron

  • impaired transcription elongation
330
Q

Where is Huntingons repeat expansion? what is the disease mechanism?

A

CAG in exon

  • novel protein property
331
Q

Where is myotonic dystrophy type I repeat expansion? what is the disease mechanism?

What about DM2?

A

CTG in 3’ UTR of DMPK

  • novel RNA property

DM2 = CCTG in intron of ZNF9 -> also novel RNA property

332
Q

Compare mechanisms of fragile X syndrome vs FXTAS

A

Trasncription silencing: 200+ repeats -> methylation -> no FMRP protein expression

Toxic GOF: 60-200 repeat -> increased FMRP RNA transcripts -> intranuclear neuronal inclusions

333
Q

Name the following head shapes. Which one most likely syndromic?

A

Coronal most likely syndromic

334
Q

What happens to patients with GALT and PKU deficiency long term treated with diet?

A

GALT and PKU: learning disability

GALT -> ovarian faiure in females

335
Q

What is the mechanism of acter for lumacaftor? Ivacaftor?

A

Lumacaftor: Chaperone for CF: Stabalizes 3D structure of mutant ΔF508 CFTR -> normalizes trafficking

Ivacaftor: Enhances Cl transport through mutatnt CFTR

  • Use in combo for ΔF508
  • Use Ivacaftor for Gly551Asp
336
Q

Half of homocystrinura patients respond to this supplement

A

Pyridoxine (B6)

337
Q

What is danazol used to treat?

A

Hereditary Angioedema

C1 esterase inhibitor deficiency

  • Danazol increases expression of C1 Esterase inhibitor by modulating transcription
338
Q

How does decitabine help treat sickle cell disease or Beta Thal?

A

It is incorporated into DNA instead of cytidine -> inhibits methylation of the CpG island in promotor region of γ-globin -> incread HbF expression

339
Q

What is an episome?

A

Stable nuclear but non chromosomal DNA molecule

  • ie formed by AAV vector for gene therapy
  • useful in target cells that are long-lived so expression can be long term
340
Q

What makes lentivirus a good vector for gene therapy?

A

It is a retrovirus that integrate into non-dividing cells and does not show preferential integration (less likely to activate oncogene)

341
Q

What traits allow AAV to be good gene therapy vector?

A
  • can form stable episode
  • Does not elicit strong immune response (safer than adeno-derived viruses)
342
Q

When is intertional mutagenesis in gene therapy a problem?

A
  • activate proto-onco gene
  • Inactive tumor suppressor
  • Inactivate an essential gene in germline (not likely to affect enough somatic cells to affect patient, but may create germline mosaicism
343
Q

How did the first gene therapy for SCID work?

A

XL SCID - IL2RG -> γc-cytokine receptor subunit of several interleukin receptors

Retroviral vector used to infect ex-vivo bone marrow stem cells -> expressed the γc cytokine subunit cDNA

  • must monitor for leukemia due to insertional mutagenesis
344
Q

What is a malformation?

A

Intrinsic abnormality in genetic program -> abnormal phenotype

345
Q

What is a deformation?

A

extrinsic factor -> abnormal physical phenotype

346
Q

Malformation vs deformation

A

Malformation = problem w/ intrinsic developmental programming

Deformation = problem caused by extrinsic factors

347
Q

What is a disruption?

A

birth defect resulting from destruction of irreplaceable tissue

348
Q

Deformation vs disruption

A

Deformation - abnormality caused by extinsic factors physically affecting fetal development

Disruption: Destruption of irreplaceable fetal tissue

349
Q

syndrome vs sequence

A

syndrome: multiple abnormalities caused in parallel by an underlying insult

Sequence: multiple abnormalities secondary to an initial single system abnormality

350
Q

Homologous structurs vs analagous structures

A

Homolog = same function due to common ancestor

Analog = same function that evolved in parallel

351
Q

When does the inner cell mass rearrange into three germ layers?

A

Gastrulation - the most important day of your life - week 3 of embryogenesis

352
Q

What tissues arise form each germ layer?

A

Endoderm - gut cavity, airways, rep (visceral)

Mesoderm - solid organs + vasculature + MSK

Ectoderm - Nervous system and skin

353
Q

What is regulative development?

A

Removal of a part of an embryo result in compensation from other similar cells (prominent in early embryogenesis)

354
Q

When does cleavage have to occur to lead to dichorionic, monochorionic, and monoamniotic monozygotic twins?

A

Dichorionic - 4 cell stage

monochorionic - inner cell mass

monoamniotic - later

Later embryo -> conjoined

355
Q

What does CREB binding protein do?

A
  • CREBB (Rubenstein Taybi) is a transcriptional activator for GLI3 (Pallister hall and greig cephalopolysyndactyly)
  • GLI3 and PTCH1 (Gorlin) are part of SHH pathway (holoprosencephaly)
356
Q

What is an oncomir?

A

noncoding miRNA that impract gene expression and contribude to oncogenesis

357
Q

What is a proto-oncogene?

A

normal gene that when mutated to increase activity level become drive genes for cancer

activated proto-oncogene = activated oncogene

358
Q

What is a tumor suppressor gene?

A

genes in which loss of expression -> cancer

359
Q

What does the RET gene do?

A

cell surface protein w/ extracellular binding domain and cytoplasmic tyrosine kinase.

  • GOF -> MEN2A
  • LOF and GOF -> Hirshsprung
360
Q

What is the most common second hit in RB?

A

Loss of heterozygosity

  • can occur by interstitial deletion of normal RB, mitotic recombination, or monosomy 13 due to nondysjunction
361
Q

Breast, Ovarian, male breast, prostate, and pancreatic cancer

A

BRCA1 or 2 (double stranded DNA break repair)

  • risk for most cancer higher in BRCA1 except male breast and pancreas
362
Q

What is the lifetime risk of colon, endometrial, and ovarian/biliary/urinary tract ca in lynch syndrome?

A

Colon: 80%

Endometrial: 40%

Biliary/urinary/ovary: 20%

363
Q

What does imatinib do?

A

Inhibit BCR-ABL (philadelphia chromosome 9:22) tyrosine kinase activity

  • treat CML
364
Q

Which proto-oncogene is activated in burkitt lymphoma?

A

MYC (ch 8, many translocation partners)

  • Burkitt = B cell lymphoma
365
Q

Which proto-oncogene is amplified in neuroblastoma?

366
Q

What environmental agent causes a G249T mutation in TP53?

A

Aflatoxin (From peanut mold) -> causes heptaocellular carcinoma

367
Q

How does aryl hydrocarbon hydroxylase (AHH) modify smoking risk?

A

Aryl Hydrocarbon Hydroxylase (CYP1A1 gene) is induced by smoke -> increased cancer risk

  • CYP2D6 alleles are protective
368
Q

What is the probability of a random female in the population is a carrier for a lethal X-linked disorder?

A

4µ

  • Calculated from bayes
369
Q

When can amnio be performed?

A

16th - 20th week (just before halfway point)

370
Q

What are possibel causes of high AFP?

A

NTD

fetal blood contamination

Twin pregnancy

Fetal death

Ventral wall defects

Overestimated gestational age

371
Q

When can CVS be performed?

A

10-13 weeks (end of first trimester)

372
Q

Which three prenatal ultrasound findings in isolation are most likely associated with abnormal karyotype?

A

Cystic hydroma, duodenal atresia, nuchal edema

373
Q

How early can US determine fetal sex?

A

13 weeks (Start of 2nd trimester)

374
Q

When are 1st and 2nd trimester screens done?

A

12 weeks and 16 weeks

375
Q

What does extremely low levels of estriol mean in quad screen?

A

SLOS or steroid sulfatase deficiency

376
Q

Triple screen: High nuchal translucency, low PAPP-A, high B-hcg

A

Trisomy 21

high hcg = trisomy 21

377
Q

Triple screen: High nuchal translucency, low PAPP-A, low B-hcg

A

Trisomy 13 or 18

378
Q

Quad screen: Low uE3, low AFP, high hCG, high inhibin

A

Trisomy 21

high hcg = trisomy 21

379
Q

Quad screen: Low uE3, low AFP, low hCG, nl inhibin

A

Trisomy 13 or 18

380
Q

What is the first line test after prenatal US detects an anomaly?

A

CMA (not karyotyping)

  • All women having invasive testing should be given option for CMA (regardless of US findings)
381
Q

What are the 3 levels of mosiacism in amniotic fluid or CVS cell cultures?

A

1) multiple colonies from different primary cultures -> true mulsaicism
2) mosiacism involving several cells or colonies from a single primary culture -> usually pseudomosiacism, but report if unable to confirm this through other testing
3) mosiacism only in a single cell - pseudomosaicism, disregard

382
Q

What is the detection rate for fetal 10% mosiacism on CMA?

A

Unreliable when 10 cells are examing, 99% when 50 cells examined

Segmental mosiacism <20% is difficult to detect

383
Q

Compare analytical validity, clinical validity, and clinical utility?

A

analytical validity - is a rapid/economic test available

clinical validity - is the test senstitive/specific? What is PPV?

clinical utility - Is knowing the test result helpful? (affect outsomes)

384
Q

How are most metabolic diseases screening for on NBS?

A

Tandem mass spec

385
Q

What is the difference between pharmacokinetics and pharmacodynamics?

A

Pharmacokinetics - rate at which body absorbs/transports/metabolize/excretes drug

Pharmacodyamics - how body responds to drug

386
Q

What gene converst codeine to morphine (active form)

A

CYP2D6 - predicts pharmacogenomic response

387
Q

What does HLA B*5701 and HLA B*1502 predict?

A

SJS/TEN risk after drug exposure

HLA B*5701 - abacavir (5% europeans)

HLA B*1502 - carbamazepine, (10% SE Asians)

388
Q

Compare strength’s/weaknesses of cohort, cross sectional, and case control studies

A

Cohort - most accurate and complete, but expensive and time consuming (phenotype may take long time to compare, rare diseases take lots of subjects) - RR

Cross-sectional - underestimate disease prevalence (Some affected have died or are pre-symptomatic) - RR

Case-control - cannot detect population prevalence - OR

389
Q

What is the difference between Odds Ratio and Relative Risk?

A

Odds ratio = (A/B) / (C/D) = AD/CB - use in case-control studies (no population data available)

relative risk = (A/(A+B))/(C/(C+D)) - use in cohort or cross section studies (when pop data is available)

390
Q

in what situation does GINA apply?

A

Genetic info cannot be used:

  • Company of 15 or more employees cannot make employmend decision
  • Health insurance
391
Q

What is reproductive compensation

A

Prenatal diagnosis and termination means couples that are carriers for recessive conditions will have more carrier children than they otherwise would -> increase allele frequency for recessive conditions

392
Q

What should you check for before starting abacavir therapy?

A

HLB*5701 status

50% PPV for SJS/TEN

100% NPV for SJS/TEN

393
Q

HLA B*1502

HLA B*5701

HLA B*5801

What drugs do these antigens interact with?

A

HLA B*1502 - Carbamazepine

HLA B*5701 - Abacavir

HLA B*5801 - Allopurinol

  • SJS/TEN
394
Q

What does FGFR3 do?

A

Transmembrane tyrosine kinase receptor that binds fib fibroblast growth factors

RUNX2 = master downstream effector (Cleidocranial dysplasia)

395
Q

What does Tyr402His in CFH do?

What about CFB and C2?

A

RIsk for age-related macular degeneration

CFH (complement factor H) Y402H = polymorphic variant -> increase risk

CFB (complement factor B) p.L9H and C2 (complement component 2) p.E308D = protective

396
Q

When and why do patients with down syndrome get Alzheimer’s?

A

By age 40

βAPP gene is on chromosome 21

397
Q

16p11.2 microdeletion syndrome

A

Susceptibility to ID/DD/ASD

  • increase risk for obesity, epilepsy, midor dysmoprhic features
  • Reciprocal 16p11.2 duplication -> schizophrenia risk

- Low Copy Repeats = mechanism of recurrent del/dups

398
Q

What phenotypes does LOF in CDKN1C and IGF2 cause?

A

CDKN1C (Normally maternally expressed, suppresed by paternal KCNQOT1) -> represses growth -> mutations -> BWS

IGF2 (normally paternally expressed, suppressed by maternal H19) -> promote growth -> mutations -> RSS

399
Q

Which cancers are more common in BRCA2 than BRCA1?

A

male breast, pancreatic

400
Q

What does 17p12 Duplicaton cause?

A

CMT1A

  • PMP22 is in 17p12
401
Q

Name the major phenotypic features of chromodomain Helicase DNA-binding protein 7 haploinsufficiency

A

CHD7 = CHARGE

Coloboma of the iris, retina, optic disc, or optic nerve

Heart defects

Atresia of the choanae

Retardation of growth and development

Genital abnormalities

Ear anomalies

Facial palsy

Cleft lip

Tracheoesophageal fistula

402
Q

der(22)t(9;22)(q34;q11.2)

A

Philadelphia chromosome in CML

ABL = tyrosine kinase invovled in cell cycle, stress response, integrin signaling, and neural development

BCR = phophoprotein

BCR-ABL -> Constitutive activation

403
Q

Variants in what gene increase risk for Crohn’s?

A

NOD2 (aka CARD15)

  • binds to gram negative bacterial cell walls -> activated NF-κB - regulates inflammatory response in monocytes of intestinal cell wall to gut bacteria
  • Risk from baseline <0.1% to 2% in homozygotes
404
Q

chronic respiratory illness, meconeum ileus, FTT, decreased pancreatic function, azoospermia, pulmonary HTN

A

Cystic fibrosis

CFTR

405
Q

What is the mode of inheritance for hearing loss in GJB2?

A

GJB2 = connexin 26

  • LOF/frameshift -> AR (majority)
  • 35delG in Caucasians
  • 235delC in Chinese

Rare missense mutations can cause dominant hearing loss

406
Q

How does duchennes affect IQ?

A

average IQ is 1SD below mean

407
Q

What are the rates of de novo and germline mosiacism in DMD?

A

De- novo ~30%

Germline mosiacism ~15%

408
Q

Congenital hypertrophy of the retinal pigmented epithelium is associated with what gene?

A

APC - regulates transcription, cell adhesion, microtubules, cell migration, apoptosis, and proliferation

  • APC LOF -> increased free β-catenin -> inappropriate gene activation

Disease:

  • FAP (100+ polyps)
  • Gardner (polyps, osteoma, soft tissue tumors)
  • Turcot (Polyps, medulloblastoma)
409
Q

What is attenuated FAP and what gene should you look for?

A

Attenuated FAP = <100 polyps

  • If no germline APC change found, look for MYH mutations (recessive FAP2)
410
Q

Polyarthritis, tenosynovitis, arcus cornea, xanthoma, coronary artery disease

A

Familial hypercholesterolemia

LDLR, ApoB100, PCSK9 (GOF -> increased degradation of LDLR)

  • LDLR most common, incomplete dominant (2 hits = present 1st decade of life, LDL levels >600)
411
Q

Fragile X accounts for _ % of ID in boys?

412
Q

What is the fragile X premutation?

A

5’ UTR CGG repeat expansion in FMR1

59-200 repeats -> causes ovarian failure/tremor-ataxia syndrome -> can expand (especially during maternal transmission) into full

413
Q

What is correlated with abnormal genetic testing results in cases of male infertility?

A

Decreased sperm count -> increased chance of abnormal genetic test (up to 25% in azoospermia)

414
Q

What are the most common genetic causes for male infertility?

A

1) 47 XXY (Klinefelters) - Testicular atrophy/fibrosis
2) AZF insufficiency - structural abnormalities (SRY translocation, Y microdeletion, etc)
3) CBAVD (CFTR), Kallman, androgen insensitivity, congenital adrenal hypoplasia (NROB1, aka DAX1)

415
Q

Which genetic anomaly should you not do testicular sperm extration on?

A

AZFa or AZFb mutations -> zero chance of sperm recovery

416
Q

What is the most common cause of non obstruction azoospermia?

A

Klinefelter syndrome

47 XXY

  • low testosterone (Decreased Leydig cell funciton) -> low sperm count
417
Q

CFTR -> IVS8 5T + F508Del

A

5T in IVS8 affects splicing of exon 9

  • Associated with CBAVD when in trans with classic variant
418
Q

What gene should you test for in CBAVD if CFTR is normal?

A

ADGRG2

XL CBAVD

accounts for 20% of CBAVD (CFTR is most common)

419
Q

What is the only viable monosomy?

A

45X

  • risk unrelated to pat or mat age
  • 80% paternal nondysjunction
420
Q

What is the risk of a trisomy 21 fetus when mother is 35?

421
Q

Where do cfDNA come from?

A

apoptotic placental trophoblast cells

422
Q

What factors can alter cfDNA levels?

A

Gestational age (increase)

high maternal BMI (decrease - more maternal apoptosis, dilutes fetal DNA)

Anueoploidy (decrease)

Twin pregnancy (decrease)

423
Q

What is the next step after abnormal NIPT?

A

Diagnostic testing -> amnio (preferred) or CVS

424
Q

4 reasons for false positive NIPT

A

1) Vanishing twin
2) maternal sex-chromosome aneuploidy (undiagnosed mom)
3) maternal cancer
4) placental mosaicism

425
Q

What is the phenotype of confined placental mosiacism?

A

IUGR (placental unhealthy)

426
Q

Why might NIPT be false negative?

A

Mosaicism with normal placenta and abnormal fetus

427
Q

Reasons for “no-call” NIPT? What do you do next?

A
  • low fetal fraction (<4%)
  • eatly gestation
  • high maternal BMI
  • Aneuploidy
  • if no call -> get diagnostic testing because aneuoploidy may be reason
428
Q

What % of embryos is aneuploid at maternal age 38?

429
Q

When is embryo biopsied for pre-implanataion diagnosis?

A

5 days -> 5 cells taken

430
Q

Who should be offered preimplantation genetic testing?

A
  • women >35 years
  • History of multiple miscarriages or implantation failure
  • hig hrisk for single gene disorder
431
Q

What is allele dropout?

A

When one allele is preferentially amplicied in PCR such that end result falsely showed homozygosity/deletion

  • Common issue in preimplantation genetic testing due to low amount of starting DNA
432
Q

What is PGT-A?

A

Preimplantation genetic testing - Aneuploidy

AKA PGS - Preimplantation genetic Screening

  • offer to all IVF patients, standard protocol
433
Q

What is PGT-M

A

Preimplantation genetic testing - Monogenic

AKA PGD - preimplantation genetic Diagnosis

Offer to high-risk couples

  • Requires personalized test/probes
  • Allele dropout is a problem -> false positives
434
Q

What genetic changes are most common in IVF created embryos?

A
  • Chromosomal mosiacism.- may be technique/lab issues (cells damanged during processing) - do not transfer viable aneuoploidy
  • imprinting defects
435
Q

Why should PGT not be offered for mitochondrial mutations?

A

Heteroplasmy -> results at 5 cell stage does to predict phenotype because heteroplasmy levels vary with each cell division, so future levels will be different/tissue specific

436
Q

What percent of Beckwith Wiedemann Cases are caused by UPD in general? IVF?

A

BWS

General: 50% maternal imprinting defect

IVF: 90% maternal imprinting defect

437
Q

Angiofibroma + seizures

A

TSC

Tuberin and Hamartin

+ Heart/Renal/Lung neoplasms

438
Q

What do you see in ARPKD that’s not present in ADPKD?

A

LIver fibrosis

  • Hepatic (and other) cysts present in ADPKD
439
Q

Important gene in 22q11 deletion region

440
Q

periorbital edema, stellate irises, hypercalcemia, hypercalciuria

A

Williams

7q11. 23del (ELN)
- Supravalvular AS

441
Q

5p deletion vs 5q35del

A

5p del = cri du chat

5q35 = sotos (NSD1)

442
Q

Abnormal teeth, cleft lip/palate (bilateral), ectrodactyly, ankyloblepharon

443
Q

Which syndrome is adrenocortical carcinoma seen in?

A

Li Frameni

TP53

444
Q

Radial ray defect with preservation of thumb

A

Thrombocytopenia absent radius syndrome

RMB8A, 1q21.1del

445
Q

Characteristic limb anomaly in CDLS

A

ulnar hypoplasia > radial defect

NIPBL, cohesin complex (HDAC8, RAD21, SMC1A, SMC3)

446
Q

RUNX2

A

Cleidocranial dysplasia

+ supernumery teeth, open fontanelles

447
Q

Brachycephaly, medial deviation of thumbs/toes

A

Pfeiffer

FGFR2, FGFR1

448
Q

Ear tags, imperforate anus

A

Townes Brock

SALL1

+ limb anomalies

449
Q

If 2 parents with achondroplasia have children, what are expected offspring phenotypes?

A

1/3 normal

2/3 achondroplasia

  • Recessive = lethal
450
Q

Lip Pits, midline cleft

A

Van der Woude

IRF6

451
Q

What dysmorphic features are associated with diffuse gastric cancer syndrome?

A

CDH1

  • Cleft lip/palate
452
Q

Cleft L/P, flat face profile

A

Stickler

Col 2, 9, 11

+ ophtho, hearing, MSK

453
Q

What are T cell receptor excision circles? (TRECs)

A

Remnants of VDJ recombination in T cells -> used for SCID NBS

Actin = control for DNA amplification

454
Q

NBS: Low TREC

A

TREC = T cell receptor excision circle (VDJ recombination remnant)

Concern for SCID -> repeat TREC assay w/ actin control

if TREC normal or actin low -> false positive NBS

if TREC still low and actin normal -> get immune profile

455
Q

High adenosine, 2-deoxyadenosine, and deoxyadenosine triphosphate

T, B, and NK cell lymphopenia

A

SCID

ADA deficiency

+ SNHL, skeletal changes

456
Q

What gene causes XL scid?

A

IL2RG - IL2 receptor gamma

  • somatic reversion -> late onset phenotype
457
Q

What percentage of 22q11del patients will have normal FISH results?

A

5%

  • Deletion may be outside of probe coverage retion
  • Get microarray
458
Q

Frequent bacterial infections or chronic viral infections.

Small lymph nodes

Absent/small tonsils

A

Bruton’s agammaglobinemia (XL)

  • BRK gene (necessary for B cell maturation)
  • normal response to acute viral illnesses
459
Q

Micropenis, microphthalmia, renal hypoplasia

A

BMP4

  • Could be microphthalmia, aniopthalmia, or coloboma (spectrum)
460
Q

Anophthalmia, esophageal atresia, hypopituitarism, short stature

A

SOX2

  • Could be microphthalmia, aniopthalmia, or coloboma (spectrum)
461
Q

Coloboma, XY Sex reversal, skeletal dysplasia

A

SOX9

Campomyelic Dysplasia

  • Could be microphthalmia, aniopthalmia, or coloboma (spectrum)
462
Q

What teratogens can cause eye malformations?

A

Vitamin A and fetal alcohol

463
Q

Posterior embryotoxon, iris atrophy, iridogonoidysgenesis, dental hypoplasia, maxillary hypoplasia, redundant peri-umbilical skin

A

Axenfeld-Rieger Syndrome

PITX2, FOXC1 - AD

  • Posterior embryotoxon + Iris + dental + failure of involution of periumbilical skin
464
Q

Match eye findings with disease:

  1. Lisch Nodule
  2. Brushfield Spots
  3. Heterochromia
  4. Starburst Irides
A
  1. Lisch Nodule - NF1
  2. Brushfield Spots - Down Syndrome
  3. Heterochromia - Wardenburg
  4. Starburst Irides - Williams
465
Q

Which hereditary vision loss has FDA approve gene therapy?

A

RPE65 - AAV therapy

466
Q

Where are ribosomal RNA genes located in the genome?

A

p-arms of acrocentric chromosomes

467
Q

What is advanced paternal age?

A

35 (same for mothers!)

468
Q

is recombination rate higher in males or female?

A

females

  • females have more genes on X /more centimorgans (4400cM vs 2700cM)
469
Q

How many base pairs in human genome?

A

6 billion (diploid)

1 haploid set = 3 billion

470
Q

How long is the humna genome?

A

Average 3700 cM

4400 cM females

2700cM males

471
Q

What is leading strand vs lagging strand?

A

In DNA replication, leading strand is synthesized in 1 direction

Lagging strand is synthesized in pieces (Ookazaki fragments) and joined together

472
Q

Which polymerases catalyze DNA replication?

A

Leading strand = polymerase delta

Lagging strand = polymerase alpha

473
Q

Which RNA polymerase started transcription?

A

Polymerase II

474
Q

Which RNA polymerase transcribes tRNA?

A

Polymerase III

  • also 5S rRNA
475
Q

Which RNA polymerase trasncribes most rRNA?

A

Polymerase I (not 5S)

  • 5S rRNA transcribed by pol III
476
Q

Where is CAAT box? What does it do?

A

-80 to -70 upstream of gene, regulates amount of transcription

477
Q

What is TATA box?

A

-30 to -25 upstream, regulates transcription start site

478
Q

Where are enhancers located? how to to act?

A

Within 1Mb of start site (can be up or downstream)

  • Cis acting
479
Q

What are silencers? How do they act?

A

Repress transcrtiption, cis acting

- Usually up to 2000bp upstream of gene, but can be downstream or within

480
Q

What are genetic insulator?

A

DNA that blocks an enhancer when located between enhancer and gene

481
Q

What modification is seen in histones being actively transcribed?

A

Acetylation

482
Q

What modification is seen in histones being inactive?

A

methylation

483
Q

What promoter modification means inactive?

A

CpG island methylation

484
Q

What does H3K27Ac mean?

A

Histone 3, lysine 27 is acetylated -> transcription enhanced

485
Q

What does H3K27Me3 mean?

A

Histone 3, lysine 27 is tri-methylated - represses transcription

486
Q

AAUAAA

A

Poly A signal sequence -> tells endonuclease to cleage 1-15 beases downstream and RNA polymerase adds poly-A tail

487
Q

What are splice site consensus sequences?

A

Donor: GU

Acceptor: AG

Branch site -. 20-50bp upstream of aceptor -> CUPuAPy

488
Q

What are the components of spliceosome?

A

U1 - binds donor site

U2 - binds branch site

U5 - binds both donor and acceptor site

489
Q

What distinguishes an AUG as a start codon rather than a methionine in the middle of a protein?

A

Kozak sequences - GCCPuCCAUGG - signals translation initiation

490
Q

What type of mutation does CpG methyluation cause?

A

C -> T transitions due to spontaneous deaminiation of 5-methylcytosine

491
Q

What does p.Ter807LeuextTer101 mean?

A

Stop-loss variant resulting in externsion of protein another 101 amino acids

492
Q

Which SCAs are repeat expansion but not CAG in exon?

A

SCA 12 - CAG in 5’UTR

SCA 10 - intronic ATTCT

1,2,3,6,7,17 are CAG

493
Q

Where is C9ORF72 expansion located?

A

Intronic GGGGCC

494
Q

Common mechanism of UPD in PWS

A

Trisomy rescue

495
Q

Common mechanism of UPD in Angelman

A

Monosomy Rescue

  • maternal nondysjunction (no c15 in egg) -> paternal duplication -> AS
496
Q

Common mechanism of UPD in BWS

A

Post-zygotic somatic recombination

497
Q

What does dominant negative mean?

A

Mutant protein interferes w/ WT protein function

498
Q

how many PCR cycles does it take to make a million copies of DNA?

499
Q

What is the cofactor to Taq DNA polymerase in PCR?

500
Q

What is the most common single nucleotide substitution?

A

C to T

  • 2/3rds of SNPs are due to C methylation, then deamination to form T
501
Q

What method is standard to detect repeats?

A

PCR + capillary electrophoresis

502
Q

How do you calculate maternal cell contamination is a sample?

A

MCCarea/(Fetalarea + MCCarea)

503
Q

What should you do if maternal cell contamination is detected in a sample?

A

Use back up culture of resample specimen

504
Q

Large deletions account for how much DMD?

505
Q

What is a junctional fragment in DMD?

A

A fragment on multiplex PCR electorphoresis that does not match any known exon size -> means it was generated by probes up/downstream of a deletion

  • Only carriers have it
506
Q

What is MLPA used to find?

A

Use specific probe pairs that only ligate if both bind -> see specific result length

1) specific deletion
2) Copy number variant
3) methylation

507
Q

Most mutable nucleotide in human genome

A

FGFR3 1138 G>A

Gly380Arg

  • Achon
508
Q

Classic test for achondroplasia

A

RFLP analysis

  • mutations cause restriction site
  • Normal: 164bp (no digestion)
  • G>A: 55bp and 109bp
  • G>C: 57BP and 107bp
509
Q

Classic test for Sickle Cell

A

RFLP

Common mutation creates restriction site

  • Digest + southern blot
510
Q

2 tests to detect changes in DNA length

A

Southern blot or PCR + capillary electrophoresis

511
Q

What does full fragile X expansion look like on southern?

A

Smear > 5.8kb

  • Unstable
512
Q

What does methylated fragile X look like on southern?

A
  1. 2kb
    - methylated -> not digested by restriction enzyme
513
Q

What does normal active (unmethylated) fragile X look like on southern?

A

2.8kb (digested by restriction enzyme)

514
Q

What does fragile X premutation look like on southern?

A

Slightly above normal (2.8 or 5.2kb) depending on whether it is methylated (lyonized)

515
Q

What phenotype do you expect in someone with R117H in cis with 7T and a severe mutation w/ 5T?

A

Mild CF or CBAVD

  • 5T means severe allele is barely expressed while R117H with 7T = mild allele
516
Q

What % of genome is exons?

517
Q

What does treatment with bisulfite do to PCR reaction?

A

Methtylation sensitivity

Bisulfite converst unmethylated C to U

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