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Board Studying > Other FAES classes and ACMG > Flashcards

Other FAES classes and ACMG Flashcards

1
Q

FGFR3 1620C>A, p.N540L

A

Hypochondroplasia

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2
Q

AR phenocopy for familial adenomatous Polyposis

A

MUTYH related polyposis syndrome

Base excision repair gene

  • Attenuated FAP phenotype
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3
Q

Colon, endometrial, small bowel, ureter/renal pelvis cancer

A

Lynch syndrome

MLH1, MSH2, MSH6, PMS2

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4
Q

How do you manage HNPCC?

A

Aspirin (may reduce ca risk)

  • Colonoscopy at 20
  • Pelvic exam/TVUS at 30
  • EGD, UA at 30
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5
Q

SMAD4, BMPR1A

A

Juvenile Polyposis Coli

Colorectal and upper GI cancers

  • 3-5 juvenile polyps
  • SMAD4 also causes HHT
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6
Q

What are homozygotes of CAG polyglutamine repeat exapnsion disorders present with?

A

Same as heterozygotes

  • mechanism is toxic GOF - homozygotes and heterozygotes have same phenotype
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7
Q

What marker is analyzed in forensic DNA analysis?

A

Short or Variable tandem repeats

  • Highly polymorphic wiht low mutation rate
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8
Q

How many STR loci are used in CODIS?

A

originally 13, now 20 as of 2017

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9
Q

What information is contained in a BAM file?

A

NGS data aligned to a referece with coverage depth

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10
Q

What are the best tests for FMR1 expansion?

A

Fragile X 5’UTR CGG

  • Triplet primed PCR, southern blot, or promoter methylation analysis
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11
Q

meconium ileus, fat/vitamin malabsorption, high LFTs, pulmonary infections

A

Cystic Fibrosis

CFTR

  • Biliary Cirrhosis = 2nd cause of death after pulm infections
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12
Q

Recurrent respiratory infections, mild intestinal disease, elevated sweat choloride, CFTR normal

A

SCNN1

Epithelial Na channel

Mild CTFR phenocopy

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13
Q

How does ivacaftor work?

A

Potentiates CFTR channel

  • For mutations that affect channel opening

( can be used in combo with lumacaftor for Phe508del)

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14
Q

What does lumacaftor do?

A

Helps get Phe508del CFTR to cell surface

-used in combo with ivacafor for Phe508del

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15
Q

What does tezacaftor do?

A

Help get mutant CFTR protein to cell surface

  • Used in combo with ivacaftor
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16
Q

What does CFTR Phe508del do to protein function?

A
  • Defect in processing -> misfolding -> stays in ER (localization problem)
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17
Q

If CFTR R117H is detected, what should you do next?

A

Look for 5T

  • Poly T tract affects splicing - 9T = 100%, 5T = 10%
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18
Q

How do you interpret R117H and 5T in CFTR?

A

If R117H and 5T in cis -> phenotype variable depending on other allele (can be severe if Phe508del)

If R117H and 5T in trans, likely CBAVD

If 5T without R117H + another CF allele -> CBAVD or mild CF

If R117H without 5T, may be CBAVD (depends on other allele)

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19
Q

What does a negative result on CFTR carrier panel mean?

A

Risk is not zero, need to calculate posterior probability

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20
Q

What if oligonucleotide ligation assay?

A

Tests for multiple common mutation in parallel using PCR products. Often used for CFTR

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21
Q

Is the imprinted allele active or silent?

A

Silent

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22
Q

Breech position, hypotonia, low birth weight, undescended testicles, narrow bifrontal diameter, downturned corners of mouth, almont PF

A

PWS

Paternally expressed (maternally imprinted) genes on 15q11q13

Pat deletion > UPD > imprinting defect

  • Hyperphagia -> obesity, tone improves, reduced salivation, small hands/feet, intellectual disability
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23
Q

Normal HC at birth -> Microcephaly by 2 years, large amplitude slow-spikes on EEG, copious saliva

A

Angelman

Mat expressed (pat imprinted) genes on 15q11q13, including UBE3A

Mat del > UBE3A > pat UPD > methylation defects

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24
Q

When is imprinting reversed?

A

Gametogenesis

  • Defect can cause functional UPD
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25
Q

What tests can detect 99% of PWS and 80% of AS?

A

methylation analysis

  • Southern blog with methylation sensitive restriction endonuclease (5-methylcytosine)
  • PCR after treatment of DNA w/ bisulfite (unmethylated C converted into U)
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26
Q

What is the recurrent risk of PWS or AS?

A

UPD or deletion - 1/1000

Methylation (imprinting center) defect - up to 50%

Rearrangement - up to 25%

UBE3A mutation - up to 50% if maternal

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27
Q

What test will detect parent of origin inUPD?

A

Trio microsatellite analysis w/ STR markers

Methylation sensitive MLPA (does not need parental data)

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28
Q

What are the imprinted chromosomes?

A

6 - transient diabetes (PLAGL1, HYMA1)

7 - RSS

11 - BWS, RSS

14 - Temple syndrome (Pat imprinted), Kagami-Ogata syndrome (Mat imprinted) - both nonspecifi skeletal

15 - PWS, AS

20 - pseudo-hypoparathyroidism

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29
Q

omphalocele, hemihyperplagia, cytomegaly of fetal adrenal cortex, renal abnormalities

A

BWS

Loss of methylation of mat IC2 (50%) -> nRNA that promotes CDKN1C is is gone -> CDKN1C is suppressed

Pat UPD11 (20%)

Gain of methylation on mat IC1 (5%) -> mat IGF2 is expressed -> increased growth

Mat CDKN1C mutation (5%) -> growth suppressor stops working

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30
Q

hemihypotrophy, DD, trancular facies, IUGR

A

RSS

50% hypomethylation in pat 11p - Pat IGF1 no longer expressed

10% maternal UPD 7

Duplication of mat 11p - mat CDKN1C expressed twice

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31
Q

CYP2D6

A

CYP2D6

Converts codine to active opiate

  • Rapid metabolizer -> avoid codine due to toxicity
  • Reduced metabolizer -> start at higher dose, if not useful try different drug
  • Poor metabolizer -> do not use as it will not work
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32
Q

CYP2C19

A

CYP2C19

Coverts clopidogrel to active form

Rapid metabolizer - use as recommended

Normal metabolizer - use as recommended

Intermediate metabolizer - use alternative

Poor metabolizer - use alternative

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33
Q

CYP2C9, VKORC1

A

CYP2C9, VKORC1

Predicts response to warfarin

  • Faster metabolizer -> need higher doses to reach therapeutic range
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34
Q

What is resoluation of microarray?

A

200kb for deletion and 500kb for duplications

  • good for microdeletion/microduplication syndromes
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35
Q

In array CGH, what is the log 2 ration of a heterogyzous deletion? Duplication?

A

Deletion = -1, Duplication = 0.6

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36
Q

What are disadvantages of SNP array vs array CGH?

A
  • SNP arrays are based on known SNPs -> cannot be customized
  • More probes needed
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37
Q

CNV characteristics:

  • Well known, recurrent
  • Published CNV w/ consistent phenotype
  • Dose senstive disease causing gene in interval
  • >3-5Mb
A

Pathogenic criteria

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38
Q

CNV charactersitics:

  • Single case report with well defined phenotype
  • CNV as compelling evidence of causing disorder relevant to clinical indication
A

Likely Pathogenic

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39
Q

CNV characteristics:

  • No genes but exceeds reportable size (3-5Mb)
  • Few genes, few CNBs reported in literature not in polymorphic region
A

Likely benign

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40
Q

CNV characteristics:

  • Few genes, dosage senstivity not established
  • No firm conclusion
A

VUS

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41
Q

What is the reportable size limit for CNVs?

A

3-5Mb

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42
Q

in a CMA, what is the lower limit of homozygosity for first-cousin relations?

A

4% homozygosity (predicted 6.25%)

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43
Q

What are strengths/weaknesses of MLPA vs exon-targeted array for exon level deletions?

A

MLPA pros:

only needs 1-2 probes per exon, robust results, more specific in region of homology

MLPA cons:

  • Allele dropout -> false positive, breakpoint determination not as precise (only 1-2 probes vs many in CMA)
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44
Q

Macrocephaly, CAL spots, axillary freckling, lipomas

A

Legius syndrome

SPRED1

-NF like but no neurofibromas

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45
Q

CAL spots, meningiomas, schwannomas, hearing loss

A

NF2

Merlin/Schwannomin

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46
Q

CAL spots, lisch nodules, neurofibromas, medulloblastoma, colon cancer

A

Constitutional mismatch repair syndrome

MSH2, MSH6, MLH1, PMS2

  • Allelic with Lynch, but homozygous
  • NF + lynch cancers (Colon, endometrial, upper GI, etc)

+ CNS and Heme cancers (GBM, medulloblastoma, NH lymphoma)

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47
Q

What is the difference between type 1 and type 2 mosiacism?

A

Type 1 = both parents normal, some cells gain mutation -> AD disease

Type 2 = one mutant allele inherited form parent, some cells get second hit -> AR disease

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48
Q

Mosaic vs Chimera

A

Mosaic starts from single fertilized egg

Chimera starts from 2 fertilized eggs -> fuse

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49
Q

linear epidermal nevi, asymmetric growth, lipoatrophy, vascular malformation, lung bullae, ovarian cystadenoma, parotid adenoma

A

Proteus

AKT1 (downstream of PI3K)

  • Cerebriform connective tissue nevus
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50
Q

Lipoatrophy, segmental overgrowth, venous anomalies, megalencephaly, capillary malformations

A

PIK3CA related overgrowth spectrum

  • Overlaps with proteus (same pathway)
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51
Q

Most common genes for CDLS

A

NIPBL (60%) - AD

SMC1A (5%) - XL

HDAC8 (2%) - XL

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52
Q

What is the pathophys of CDLS?

A

Cohesin complex part of sister chromatid exchange, dsDNA repair, maintaning genome organizaion, and distal transcription

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53
Q

Tall forehead, deep philtrum, wide neck, low posterior hairline, sparse hair (infancy) -> thick,wooly hair (childhood), macrocephaly, low set ears

A

Noonan Syndrome

PTPN11 (50%, most common), SOS1 (10%, 2nd most common), RAF1 (3rd), KRAS, HRAS

+ Pulmonic stenosis, slow growth, GU anomalies, CAL spots, bleeding diathesis

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54
Q

SHOC2 p.S2G

A

Noonan with loose anagen hair

  • Easily and painlessly pluckable, sparse, thin, slow-growing hair without sheaths
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55
Q

What gene causes Costello syndrome?

A

Noonan + papillomata

HRAS

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56
Q

What genes cause CFC syndrome?

A

Noonan + follicular hyperkeratosis, sparse/curly hair, absent eyebrows

BRAF, MEK1, MEK2

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57
Q

What cancer is associated with Noonan?

A

JMML

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58
Q

Name the mitochondrial disease associated with each phenotype:

  • Renal tubulopathy, seizures, liver failure
  • Ptosis, myopathy, ophthalmoplegia
  • ophthalmoplegia, RP, ataxia, heart block, diabetes, hypoparathyroidism
  • sideroblastic anemia, pancytopenia, exocrine pancreas failure
  • cerebellar/brainstem strokes
  • neuropathy, ataxia, RP
  • RRF, seizures, stroke like episodes, cardiomyopathy, diabetes, hearing loss, RP, ataxia
  • RRF, myoclonus, seizures, myopathy, optic atrophy, deafness, lipomas, neuropathy
  • vision loss, dystonia
A
  • Renal tubulopathy, seizures, liver failure - Alpers
  • Ptosis, myopathy, ophthalmoplegia - CPEO
  • ophthalmoplegia, RP, ataxia, heart block, diabetes, hypoparathyroidism - KSS
  • sideroblastic anemia, pancytopenia, exocrine pancreas failure - Pearson
  • cerebellar/brainstem strokes - Leigh
  • neuropathy, ataxia, RP - NARP
  • RRF, seizures, stroke like episodes, cardiomyopathy, diabetes, hearing loss, RP, ataxia - MELAS
  • RRF, myoclonus, seizures, myopathy, optic atrophy, deafness, lipomas, neuropathy - MERRF
  • vision loss, dystonia - LHON
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59
Q

where are alpha-satellite DNA located?

A

Centromeres

  • 171bp tandem repeat
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60
Q

TTAGGG sequence

A

Telomere cap - substrate for telomerase and shortens with age

  • Distal to subtelomeric repeats
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61
Q

What are characteristics of a dark band on G stain? What about R stain?

A

R = reverse G

Dark G = AT rich -> Gene sparse, early transcription, tissue specific

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62
Q

How many chiasma/chromosome is required for normal segregation?

A

At least one per chromosome arm

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63
Q

Which aneuploidy is 100% maternal M1 error?

A

Trisomy 16

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64
Q

Which aneuoploidy is ~50/50 maternal vs paternal origin?

A

XXY

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65
Q

Which aneuploidy is mostly maternal MII error?

A

Trisomy 18

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66
Q

What percent of 45,X, Tiromy 18, Trisomy 21, and 47,XXY conceptuses are liveborn?

A

45,X - 1%

Trisomy 18- 5%

Trisomy 21 -20%

47 XXY, 47 XXX, 47, XYY - 80%

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67
Q

What is the empirical risk of unbalanced offspring (adjacent segregation -> livebirth) in parent with balanced translocation?

A

10-15%

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68
Q

What should you be concerned when parent w/ robertsonian translocation has a balanced offspring?

A

UPD 14 or 15

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69
Q

What disorder is associated with marker chromsome 15? 22?

A

15 - palister killian (temporalfronto balding)

22 - cat eye

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70
Q

What causes SBMA?

A

CAG repeat expansion in AR gene

>38 = full penetrance

<34 = normal

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71
Q

What causes hemophilia B leyden?

A

Factor 9 leyden

  • Hemophilia B that resolves in puberty when androgen levels increase
  • Caused by promoter mutation at -20
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72
Q

Where is poly T tract on CFTR?

A

Exon 8

  • regulates splicing of exon 9 (skip if 5T)
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73
Q

when is a premature stop codon likely to result in truncated protein?

A

When it is within last 50bp of next to last exon, in last exon, or in single exon gene

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74
Q

What copy of SMN is telomeric?

A

SMN1

SMN2 is centromeric

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75
Q

erlotinib, getfitinib

A

EGFR targeting drugs

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76
Q

imatinib, dasatinib, nilotinib

A

BCR/ABL1 targeting drugs

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77
Q

Pantumumab, cetuximab

A

KRAS tageting drugs

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78
Q

what is the relationship between mutation rate and selection?

A

AD: u=sq

AR u=sq2

XL u=sq/3

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79
Q

1- senstivity

A

false negative rate

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80
Q

1- specificity

A

false positive rate

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81
Q

5 most common congenital anomalyes

A

1) undescended testes
2) CHD
3) Talipes
4) NTD
5) CL/P

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82
Q

normal intrinsic fetal development altered by mechnical force

A

deformation

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83
Q

normal intrinsic fetal develoment is interrupted by outside force

A

disruption

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84
Q

afternomal fetal tissue organization

A

dysplasia

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85
Q
A
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86
Q

morphological defect from abnormal intrinsic fetal development

A

malformation

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87
Q

t8:14

A

burkitt lymphoma

Activation of MYCC oncogene

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88
Q

crizotinib

A

ALK inihibitor

Used for recurrent ALK inversion in small cell lung ca

-ALK-EML4 fusion

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89
Q

vermurafinib

A

Target BRAF V600E

Melamonas

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90
Q

Erlotinib

A

target EGFR in lung ca

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91
Q

Vandetanib

A

Target RET in medullary thyroid ca

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92
Q

adrenocortical/choiroid plexus carcinoma, anaplastic rhabdomyosarcoma, hypodiploid ALL

A

TP53

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93
Q

Phenochromocytoma + paraganglioma

A

SDH

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94
Q

When do start surveillance for TP53?

A

breast MRI at 20, colonoscopy at 25

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95
Q

nail dystrophy, oral leukoplakia, reticulate skin pigmentation

A

Dyskeratosis congenita

Telomere dysfunction

+ hypoplastic bone marrow

-Very short telomeres

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96
Q

FAP management

A

Colonscopy at 10

EGD at 20

Thyroid exam

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97
Q

AR Familial polyposis

A

MUTYH

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98
Q

When do you start colonscopy for Juvenile polyposis?

A

15

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99
Q

what is the serious early complication in STK11?

A

Peutz -Jeghers

intussusception

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100
Q

CDH1

A

Hereditary diffuse gastric cancer and lobular breast cancer

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101
Q

PALB2

A

Breast and pancreatic ca

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102
Q

Olaparib

A

PARP inhibitor for BRCA tumors (especially ovarian)

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103
Q

When to start screening for BRCA?

A

Breast at 25, ovarian/prostate at 30

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104
Q

leiomyomatosis + RCC

A

fumarate hydratase

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105
Q

Chromophobe/oncycytic renal cancer

A

Birt-Hogg-Dube

FLCN - tumor suppressor gene

+ firbofolliuloma, polype, medullary thyroid, penumothorax

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106
Q

what is the probablity a women in genral population is a carrier for an XLR mutation?

A

4u

  • new u on X from mom
  • new u on X from dad
  • mom is carrier

C = u + u +1/2C -> C = 4u

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107
Q

UCD with hepatic fibrosis

A

ASL deficiency

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108
Q

which AA are N-linked CDGs attached to?

A

asparagine

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109
Q

B glucoronidase

A

Sly syndrome

MPS VII

  • Hurler like, can be very severe/hydrops
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110
Q

Premutation for Friedreich

A

GAA repeat in intron 1

34-66 = premutation

<33 is normal

>67 is pathological

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111
Q

What causes symptoms in Hartnup disease?

A

SLC6A19 - neutral AA transporter

low neural AA -> Tryptophan malabsorption -> niacin/serotonin deficiency -> Pellagra rash + ataxia

Tx : niacin

  • Neutral AA low (but not proline, Arg Lys, Orn -> which are low in renal fanconi)
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112
Q

ZNF9

A

Myotonic dystrophy type 2

CCTG

>75 = pathogenic

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113
Q

Most common congenital anomalies related to obesity in mom

A

1) NTD
2) CHD
3) CL/P

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114
Q

ectodermal dysplasia with normal teeth, short stature, eye anomalies

A

Clouston syndrome

Skin + hair + nails

GJB6 (AD)

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115
Q

ectodermal dysplasia with normal skin and teeth

A

Witkop

MSX1 (AD)

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116
Q

X linked ichthyosis

A

Steroid sulfatase

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117
Q

Blistering in or above basal layer

A

EB simplex

  • KRT5, KRT14, EXPH5
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118
Q

Blistering within basement membrane

A

Juncitonal EB

LAMB3, COL17A1

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119
Q

Blistering below basement membrane

A

Dystrophic EB

COL7A1

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120
Q

Blistering in multiple cleavage planes (within, above, and below basement membrane)

A

Kindler syndrome

Kindlin-1 (FERMT1)

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121
Q

Serpina1 Glu342Lys

A

A1AT Z allele

10% activity

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122
Q

mechanism of transient neonatal diabetes

A

overexpression of paternally expressed genes in chromosome 6

  • Paternally UPD6 or maternal hypomethylation
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123
Q

TNFRSF13B

A

CVID

  • humerol immunity issues after 2yrs (usually young adulthood)
  • Tx IVIG
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124
Q

STAT3

A

Hyper IgE syndrome

AD

  • high IgE, boils, cysts, eczema
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125
Q

IL2RG

A

XL SCID

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126
Q

XL alpha thalassemia

A

ATRX

alpha thal + ID, microcephaly, telecanthus, genital anomalies

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127
Q

Gonads in androgen insensitivy

A

XL- AR gene

  • Female external genetalia, male gonads
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128
Q

XL salt wasting, hypoglycemia, and low BP

A

NROB1

XL congenital adrenal hypoplasia

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129
Q

asfotase alfa

A

Hypophosphatasia

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130
Q

high deoxypyridinoline/pyridinoline ratio in urine (HPLC)

A

EDS6 - kyphoscoliotic

PLOD1 -> deficient lysyl hydroxylase 1 activity

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131
Q

forrowed skin, droopy face, doughy skin without hyperelasticity

A

Cutis laxa

ATP6VOA1, EFEMP2, FBLN4, FBLN5

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132
Q

ABCC6

A

pseudoxanthoma elasticum

Skin papules, retinal streaks/hemorrhages, GI bleed, angina

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133
Q

cerebro-oto-renal syndrome

A

Lowe syndrome

OCRL -> part of PI pathway

  • cataracts/glaucoma, CNS, renal fanconi
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134
Q

High uric acid, gout, renal failure

A

AD tubulointestinal kidney disease

  • Uromodulin, Renin
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135
Q

CYP2C9

A

Warfarin metabolism

136
Q

CYP2D6

A

CoDeine, hearth (Beta blockers, antiarrhythmics), antidepressants, antipsychotics

137
Q

CYP2C19

A

Clopidogrel

138
Q

Thiopurine S methyltransferase

A

involved in inactivation of 6-mercaptopurine and 6-thioguanine

low activity -> need to lower dose of drug

139
Q

HLAB*5701

A

hypersensitivty to abacavir

140
Q

malignant hyperthermia + hypokalemic periodic paralysis

141
Q

SDHD

A

Paraganlioma

  • paternally imprinted on Ch11

SDHD -> D for DAD

142
Q

Medulloblastoma

Jaw cysts

Ovarian fibroma

A

Gorlin

PTCH1

143
Q

cancer syndrome with insulinoma/gastrinoma

144
Q

tumor in alport syndrome

145
Q

short stature, azoospermia, diabetes, sun sensitivty

A

Bloom

RECQ2 helicase

146
Q

recurrent chronic ulcers, early hair graying, sarcomas, osteoporosis, atherosclerosis

A

RECQ helicases

  • early manifestations of adult diseases
  • includes bloom syndrome and others
147
Q

papillommas, trichilemommas, acral keratoses

148
Q

How to distinguish diamond blackfan from other marrow failure syndromes (like fanconi)

A
  • no solid tumors
149
Q

Is the template strand sense or antisense?

A

antisense

RNA looks the same as the template strand, but is transcribed using the sense strand, which is complementary to the template

150
Q

Polyglutamine repeat SCAS

A

1,2,3,6,7,17

  • 12 is 5’UTR
151
Q

what is the dinucleotide for splice donor and acceptor site?

A

donor - GT

acceptor - AG

152
Q

Mechanism that removes thymine dimers and large chemical adducts

A

Nucleotide excision repair

defective in XP

153
Q

Mechanism for removal of double stranded breaks by homologous recombination or non-homologous end-joining

A

Postreplication repair

Nijmegen breakage (NBS)

Bloom (BLM)

BRCA1/2

154
Q

Steps to preparing karyotype

A

1) add phytohemagglutinin (stimulate T lymphocyte division)
2) culture (3 days)
3) add colchicene (prevent spnidle formation -> arrest in metaphase)
4) hypotonic saling (lysis)
5) Spread/mount
6) Trypsin/Giemsa (digest proteins + stain)

155
Q

Lineage of expansion in CAG repeats

A

Noncoding tends to be maternal (DM1, Fragile X)

Coding tends to be paternal (HDD, SCA)

156
Q

pThr312Ile in ABL

A

Resistance to Gleevac -> abnormal binding site in CML with 9:22 translocation

157
Q

XL lethal condition germiline mosiacism risk

A

1/3rd -> if mom has one affected male child, her risk of being carrier is 2/3rd

158
Q

NPC gene function

A

Intracellular cholesterol trafficking

  • accumulation of unesterified cholesterol
159
Q

gene for RCDP type 1

A

PEX7

low plasmalogen and high phytanic acid

160
Q

MPS + ichthyosis

A

Multiple Sulfatase deficiency

AR formylglycine enzyme deficinecy -> post translation l modification of cys in all sulfatases

161
Q

crizotinib

A

ALK-EML4 inversion in lung ca

162
Q

BRAF V600E

A

melanoma

Treat with vermurafinib

163
Q

EML4-ALK inversion

A

NSCLC

Treat with Crizotinib

164
Q

EGFR missense in lung cancer

A

Treat with erlotinib

165
Q

RET missense in Medullary Thyroid Ca

A

Treat with Vandetanib

166
Q

Olaparib

A

BRCA1/2 germline Ca

167
Q

GATA1

A

Somatic mutation in down syndrome -> acute megakaryocytic leukemia risk

168
Q

atypical teratoid/malignant rhabdoid tumor

A

SMARCB1 (Also schwannomatosis)

169
Q

Oncogenes that cause familial cancer syndromes

A

RET - MEN2

HRAS - Costello

KRAS - CFC

ALK - neuroblastoma

EGFR - lung ca

170
Q

AML, Head/neck cancer

Leukoplakia, nail dystrophy, reticulate skin lesions

A

Dyskeratosis congenita

Telomere shortening diosrders

171
Q

miRNA processing disorder

A

DICER1

AD w/ incompelte penetrance

  • > processes pre-microRNA to microRNA
  • pleuropulmonary blastoma + goiter, CNS rhabdo, pinealblastoma, etc
172
Q

downstream oncogene in APC

A

Beta Catenin (CTNNB1)

  • > activating variant = sporadic polyp
  • > germline APC LOF (Tumor suppressor) -> activates Beta Catenin
173
Q

Promotor 1B mutations in APC

A

Gastric adenocarcnoma and proximal polyposis

  • no colorectal or duodenal polyps
174
Q

What is the function of MUTYH

A

base excision repair

AR polyps

175
Q

Risk of colon Ca in juvenile polyposis

A

~50%, avg age 43

SMAD4 > BMPR1A

  • colonoscopy at 15
176
Q

Benign ovarian sex-cord tumors, Sertoli-cell testicular tumors

A

STK11

  • Peutz Jeghers

+ pigmented spots on buccal mucosa

  • GI + breast ca

+ Intussiception risk

177
Q

GREM1

A

Upstream promotor duplication -> mixed polyposis syndrome

  • Need to do CNV testing in panel
178
Q

Laterality of colon ca in HNPCC

A

Right side > Left

~70% lifetime risk for CRC and endometrial Ca

179
Q

Most common genes for HNPCC

A

MSH2 and MLH1 = 90% of amsterdam criteria

MSH6 more rare

PMS2 rare with multiple psudogenes

EPCAM deletion -> epigeneic silencing of MSH2

180
Q

What does BRAF V600E or MLH1 methylation in colon cancer mean?

A

More likely sporadic

181
Q

Management of HNPCC

A

Colonoscpy at 20-25 for MSH2 and MLH1

182
Q

Ultra mutated colon cancer

A

POLE or POLD1

183
Q

Biallelic Lynch mutations cause ___

A

Constitutional mismatch repair deficiency

CAL spots + axillar freckling (NF like)

+ Cancer risk

184
Q

PTEN diagnosis

A

Macrocephaly

Mucocutaneous lesions

Cerebellar dysplasic gangliocytoma

Thyroid Ca

Breast Ca

185
Q

Tumor profile in BRCA1

A

Homologous recombination deficient

186
Q

What are the 3 high risk Breast Ca genes?

A

BRCA1, BRCA2, PALB2 (binds BRCA2)

187
Q

c.185delAG

A

A. Jew founder variant in BRCA1

188
Q

c. 5382insC

A

A. Jew founder variant in BRCA1

189
Q

c.6174delT

A

A. Jew founder variant in BRCA2

190
Q

Most common moderate risk Breast Ca genes

A

CHEK2, ATM

191
Q

RAD51C

A

Ovariant Ca risk gene (not breast)

192
Q

Hypodiploid ALL with TP53 mutation

A

high likelihood (48%) of germline TP53 (LFS)

193
Q

Cancers in ATM

A

Moderate risk for breast, colon, pancreatic

+ high AFP

194
Q

Telomere shortening

A

Dyskeratosis Congenita

1) Leukoplakia
2) nail hypoplasia
3) reticular skin lesions

195
Q

senstivity to ionizing radiation

A

Ataxia Telangiectasia (+ high AFP)

Nijmegen breakage

196
Q

What gene can cause both coffin-siris syndrome, familial schwannomatosis, or atypical rhabdoid tumors?

197
Q

c.985A>G, p.Lys329Glu

A

Common mutation in MCAD (50-90% of cases)

198
Q

Where are alpha satelites found?

A

171bp repeats clustered around centromeres

199
Q

Stage of prophase 1 where homologs pair and synaptonemal complexes form

200
Q

Stage of prophase 1 where crossing over happens

201
Q

Stage of prophase 1 where homologues start to separate but remain attached at chiasmata

A

Diplotene

  • This is where female meiosis arrests
202
Q

Empirical risk of liveborn offsprnine with adjacent 1 unbalanced chromosomes when parents have balanced translocation

A

10-15%

(theoretical 25%)

203
Q

Empirical risk of trisomy 21 in offspring of parent w/ robersonian translocation

A

female carrier 15%

male carrier 2%

204
Q

When does X-inactivation occur?

A

2 weeks after fertilization

205
Q

Qualities of G band dark regions

A

G dark = high AT, rich in LINE repeats

Less GC = less promoters -> sparse genes, late replicating; tissue specific genes

206
Q

resolution of FISH

A

100Kb

(karyotype = 5MB, CMA = 10kb)

207
Q

Mechanism of non-recurrent CNVs

A

Non-homologous end-joining

Fork stalling and template switching

208
Q

malignancy with 5q-

A

Myelodysplatic syndrome

209
Q

HgB Glu26Lys

A

HbE - mild anemia when homozygous

210
Q

HgB Glu6Val

211
Q

HgB Glu6Lys

A

HbC -> can cause sickle cell when compound het w/ HbS

212
Q

HTT: 30 repeats

A

27-35 = intermediate/mutable allele

Normal phenotype, but at risk for expansion

213
Q

most common congenital anomalies

A

1) Undescended testes
2) heart defect
3) Talipes
4) NTD
5) CL/P

214
Q

What probability an unaffected daughter of a normal parents is a carrier for an XLR allele?

A

2u (1 per each X inherited)

215
Q

What is the probability a woman in general population is a carrier for an XLR allele?

A

4u

C = u + u + 1/2C (change of de novo from each parent + change of inheriting if a parent was a carrier)

216
Q

relationship between selection and mutation rate in AR disease

A

q= (u/s)1/2

fitness = 1-s

each generation q2 –> q2(1-s) (sq2 is lost)

Thus u = sq2

217
Q

relationship between selection and mutation rate in AD disease

A

u = sp

Each generaiton 2pq –> 2pq (1-s)

Assuming q ~ 1, 2ps alleles are lost each generation

2u = 2sp, u=sp

218
Q

N-acetyltransferase 2

A

Pharmacogenomics

Breakdown of insoniazid and hydralazine

Variants -> increased toxicity

219
Q

SLCO1B1*5

A

Pharmacogenomics

Statin induced myopathy

220
Q

SLC22A

A

Pharmacogenomics

Metformin toxicity

221
Q

CACNA1S

A

Malignant hyperthermia risk and hypokalemic periodic paralysis

222
Q

What charge does DNA have?

A

negative

Gel runs cathode (-) to anode (+)

223
Q

What is the advantage of an invader/FRET assay?

A

Can detect SNPs in unamplified DNA

  • invader oligo contained specific allele
  • If both invader and probe bind then probe will be cleaved -> Fluorescence
224
Q

Best techniques to detect large expansions

A

Southern blot

Triplet primed PCR

225
Q

What is the function of NF2?

A

Cytoskeletal protein

226
Q

Selumetinib

A

FDA approved MEK inhibitor for plexiform neurofibroma in children > age 2

227
Q

GAA repeat cutoffs for FA

A

<33 normal

>66 pathological

34-65 = premutation

228
Q

Non muscle manifestations of FSHD

A

Retinal vasculopathy

SNHL

229
Q

DNAJC12

A

Chaperone for hydroxylases

high Phe on NBS

+ dystonia/nystagmus (TH)

230
Q

Most common reason for low C0 on NBS

A

maternal carnitine deficiency

231
Q

Most common mutation in MCAD

A

Lys304Glu

>90% of cases

232
Q

NBS analyte for 3MCC

233
Q

globotriaosylceramide

A

GB3

Fabry biomarker

234
Q

Ace, TRAP, Chito

A

Gaucher Biomarkers

235
Q

If GALC activity is low on NBS what is the reflex test?

A

psychosine levels

if high reflex to 30kb deletion (45% cases)

Otherwise do sequencing and del/dup

236
Q

Where does cfDNA for NIPT come from?

237
Q

Main reasons for false positive NIPT

A

Alternative sources of non-germline maternal DNA

  • Placental mosiacism
  • Vanishing Twin
  • Maternal cancer
238
Q

Clinical consequences of confined placental mosaicism

A

IUGR

UPD (trisomy rescue)

239
Q

Reasosn for “no call” NIPT

A

Low fetal fraction

  • too early in gestational age
  • maternal BMI
  • small placenta in trisomy 13, 18, or triploidy
  • Down syndrome NOT part of this
240
Q

prenatal US: AV canal and absent nasal bone

A

Trisomy 21

241
Q

Prenatal US: Clenched hands

A

Trisomy 18

242
Q

Prenatal US: MIdline cleft, polydactyly

A

Trisomy 13

243
Q

Prenatal US: Cystic hygroma, HLHS

244
Q

What is the mechanism of BWS seen in IVF babies

A

Loss of methylation on maternal 11p.15

245
Q

Most frequent imprinted disorder in IVF

A

Russel Silver Syndrome

  • maternal methylation defect

(male imprinting happens near birth, female imprinting happens around meiosis II)

246
Q

When should CVS happen?

A

10-13 weeks

Limb reduciton defects seen when done at 8 weeks

247
Q

Common fetal anomalies seen in maternal obesity

A

1) NTD
2) Cardiac
3) CL/P

248
Q

white forelock, patchy hypopigmentation

A

Piebaldism

KIT, SNAI2 (AD)

249
Q

KIT, SNAI2

A

Piebaldism

250
Q

LYST

A

Chediak Higaski

hypopigmentation, decreased visual acuity, HSM, neuropathy, anemia, infections, ID

251
Q

Hypopigmentation, poor eye fixation, silver-gray hair, DD

A

Griscelli syndrome

MYO5A, RAB27A, MLPH

252
Q

Hyperhidrosis, hypodonia, absent/thin hair, dysrophic nails, smooth tongue

A

Odonto-Onycho-Dermal dysplasia

WNT10A

  • Ectodermal dysplasia with hyperhidrosis and smooth tongue
253
Q

Small/absent teeth, thin nails

A

Witkop syndrome

MSX1 (AD)

Ectodermal dysplasia with normal skin/hair

254
Q

Ectodermal Dysplasia with normal teeth

A

Clouston syndrome (Hydrotic ectodermal dysplasia)

GJB6 (AD)

+ short stature and eye anomalies

255
Q

Common mutation in IKBKG

A

Incontinential Pigmenti

65% due to deletions in exon 4-10

256
Q

KRT5, KRT15

A

Epidermolysis Bullosa Simplex

Splitting above basal layer

EXPH5, KRT5/14, TGM4

257
Q

LAMB3, COL17A1

A

Epidermolysis Bollosa Junctional

Splitting within BM

LAMB3 (70%), COL17A1, LAMC2, LAMA3

258
Q

COL7A1

A

Dystrophci epidermolysis Bullosa

Splitting below BM (AD or AR)

259
Q

FERMT1

A

Kindler sydnrome

Kindlin-1

Epidermolysis Bullosa with multiple cleavage planes

260
Q

UGT1A1 deficiency

A

Bilirubin conjugation defect -> unconjugated hyperbili

LOF -> Crigler-Najjar

Promoter mutation -> Gilbert (benign)

261
Q

Orange Tonsils

A

Tangier Disease

ABCA1

Low HDL

262
Q

15q11-q13 duplication

263
Q

Paternally transmitted GNAS mutation

A

Albright hereditary osteodystrophy (ID and subcutaneous calcification)

264
Q

Maternally transmitted GNAS mutation

A

Pseudohypoparathyroidism

265
Q

R506Q

A

Factor V Leiden

AKA R534Q

266
Q

maternal meiosis I -> what kind of UPD?

A

Heterodisomy

267
Q

Paternal meiosis II error -> what kind of UPD

268
Q

pat UPD 6

A

Transient neonatal diabetes

  • Duplication of PLAGL/ HYM1
269
Q

Mat UPD 7

A

RSS (10%)

GRB10, MEST

270
Q

Chromosomes involved in mat UPD disorders

A

7, 11, 14, 15, 20

271
Q

Chromosomes involved in pat UPD disorders

A

6, 11, 14, 15, 20

272
Q

mat UPD 14

A

Temple

MEG, RTL1

Hyperextensible joints, scoliosis, DD, hypotonia, hypogonadism, obesity, small hands/feet

273
Q

pat UPD 14

A

Kagami-Ogata

MEG, RTL1

Omphalocele, coat hanger sign (narrow ribs), DD

274
Q

Paternal UPD 20

A

Pseudohypoparathyroidism

GNAS

  • maternally inherited GNAS LOF -> Pseudohypoparathyroidism
275
Q

Risk of RSS in IVF

A

12% (9x RR)

276
Q

Risk of BWS in IVF

A

6% (4.5x RR)

277
Q

Prevalence of POF and FXTAS in premutation carriers?

A

CGG repeats 56-199

20% of women have POF

20-40% have FXTAS

278
Q

Nasal polyps, pneumothorax, meconium ileus, rectal prolapse, diabetes

A

Manifestations of CF

279
Q

Mode of inheritance for Bruton’s agammaglobinemia

280
Q

stat3

A

Hyper IgE (Jobs) syndrome

Boils, chiari, arterial toruosity, eosinophilia

281
Q

CD40LG mutatons

A

XL Hyper igM syndrome

Low IgA and E, high IgM

Tx: Allogenic SC Transplant

282
Q

IL2RG

283
Q

high testosterone, dihydrotestosterone, LH

46XY w/ female external genetalia

A

Androgen insensitivty

AR - XL

284
Q

Combined 17-a hydroxylase and 21-hydroxylase deficiency

A

Antley Bixler

Cyp450oxidooreductase deficiency (POR)

285
Q

Female virilization + salt wasting

A

CAH

CYP21A1

286
Q

ABCC8, GK, GLUD1

A

Familial hyperinsulinism

  • hypoglyemia with low ketones
287
Q

Management of Kallman syndrome

A

GnRH deficency

In males give testosterone and hCG

In females give protestins

288
Q

AVPR2, AQP2

A

Hereditary nephrogenic diabetes insipidus

  • inability to concentrate urine
289
Q

FGFR3 Arg248Cys, Tyr373Cys, Lys650Glu

A

Thanatophoric dysplasia

Type 1- bowed femurs

Type 2- cloverleaf

290
Q

4 types of OI due to COL1A1/2

A

1) Classic non-deforming
2) perinatal lethal
3) progressive deforming
4) variable with normal sclera

291
Q

TRPPC2

A

XL Spondyloepiphyseal dysplasia tarda

  • normal until 6-8yo -> progressive skeletal dysplasia + joint/back pain
292
Q

Main causes of multiple epiphyseal dysplasia

A

COMP, COL9A, MATN2

293
Q

Skeletal dysplasia. anemia, immunodeficiency, fine silky hair

A

Cartilage Hair Hypoplsia

AR - RMRP

294
Q

high deoxypyridinoline/pyridinoline ratio in urine

A

PLOD1 - kyphoscoliotic EDS

295
Q

FBLN4, ATP6VOA2, EFEMP2

A

Cutix Laxa

Doughy skin

296
Q

ABCC6

A

Pseudoxanthoma elasticum

  • Lax skin w/ yellow papule, angiod retina streaks, macular degeneration, cardiac calcifications
297
Q

What percent of marfan is de novo?

298
Q

What is the difference between LDS type 1 and LDS type 2?

A

Type 2 has no craniofaicial findings

299
Q

SMAD2, SMAD3

A

LDS

SMAD2/3 , TGFB2/3, TGFBR1/2

300
Q

PKHD1, DZIP1L

A

ARPKD

  • neonatal echogenic kidneys, dialted bio ducts, pulmonary hypoplasia
301
Q

MUC1, REN, UMOD

A

AD tubulointestinal kidney disease

+ hyperuricemia and gout

Renal failure in 40’s

302
Q

First tier evaluation for autism

A

Fragile X (males)

CMA

303
Q

Second tier evaluation for autism per ACMG

A

MECP2 sequencing in all females

MECP2 duplication in males

PTEN is HC >2.5 SD

MRI if other indicators

304
Q

c. 665 C->T, p.Ala222Val
c. 1286A->C, p.Glu429Ala

A

Thermolabile MTHFR

305
Q

Best time for NTD screening

A

16-18 weeks

  • high AFP -> NTD or ventral wall defects
306
Q

What are measured in first trimester screen?

A

PAPPA, hCG, nuchal translucency

307
Q

How do you determine prenatal lethality when there is concern for skeletal dysplasia?

A

Chest to abdominal circumference ratio <0.6

Femur lengh to abdominal circumference ratio <0.16

308
Q

First line genetic workup for short stature and mild features

A

CMA

  • Get karyotype for Turner if female
309
Q

Isolated short stature + madelung deformity

A

SHOX (Turner)

310
Q

Differences between SMN1 and SMN2

A

SMN1 is telomeric; common mutation is deletion of exon 7

SMN2 is centromeric, 5bp silent mutations -> abnormal splicing

311
Q

PALB2

A

High risk breast cancer (binds to BRCA2)

low ovarian ca risk

312
Q

Breast Ca Screening in NF1

A

annual mammo starting at 30

313
Q

most sensitive and specific test for pheo in NF1

A

Plasma free metanephrines

If equivocal follow up with 24 hour urine study

314
Q

What groups of NF1 patients should be screened for renal-vascular hypertension as first line?

A

Hypertensive patients under 30, have abdominal bruits, and/or are pregnant

315
Q

When do you test fathers for prenatal carrier status?

A

Before 14 weeks - if mother is positive

After 14 weeks - test mom and dad concurrently

316
Q

Who should be considered for ashkenazi jew carrier screening?

A

One grandparent is jewish

317
Q

What % of SMA is de novo

A

2%

5% of people have 2 copies in cis

318
Q

fracture of long bongs on fetal US

A

Hypophosphatasia

NF

OI

319
Q

Poor mineralization of calvarium in prenatal US

A

Achondrogenesis

Cleidocranial dysplasia (RUNX2)

hypophophatasia

OI

320
Q

When can achondroplasia be definitely found on prenatal US

321
Q

Cancer screening in patients hemihyperplasia

A

Abdominal US for wilms tumor ever 3 months until age 8

AFP measurement every 3 months until age 4 (hepatoblastoma)

322
Q

Which mechanism of BWS confers highest risk for wilm’s

A

Hypermethylation of maternal IC1 or UPD

323
Q

recurrence risk for ASD

A

If 1 affected sibling -> 5-10%

If 2 or more -> 30%

324
Q

selumetinib

A

treatement for NF1 -> MPNST and Plexiform NF

325
Q

Most common dilated CM genes

326
Q

Most common genes for HCM

A

MYH7, MYBPC3

327
Q

How many generations does it take for allele frequency of AR disease with fitness 0 to half?

A

X where allele frequency = 1/X

328
Q

adrenocrotical carcinoma

329
Q

Hepatoblastoma

A

BWS or APC

330
Q

What % of patients with omphalocele have BWS

331
Q

neuroblastoma, bladder cancer, rhabdomyosarcoma

+ CHD, low set ears

A

costello

HRAS

332
Q

Thrombocytopenia (small platelets), eczema, Immune deficiency

A

Wiskott aldrich

XL - WAS

333
Q

hypoplastic 5th nail

A

Coffin siris

  • ARIDB1
334
Q

t(8:21), inversion 16, t(9:11)

335
Q

Palmar Pits

A

Gorlin

PTCH

336
Q

pre-auricular tags and pits

A

Branchio Oto Renal

EYA, SIX5

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