Other FAES classes and ACMG Flashcards
(336 cards)
1
Q
FGFR3 1620C>A, p.N540L
A
Hypochondroplasia
2
Q
AR phenocopy for familial adenomatous Polyposis
A
MUTYH related polyposis syndrome
Base excision repair gene
- Attenuated FAP phenotype
3
Q
Colon, endometrial, small bowel, ureter/renal pelvis cancer
A
Lynch syndrome
MLH1, MSH2, MSH6, PMS2
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
5
Q
SMAD4, BMPR1A
A
Juvenile Polyposis Coli
Colorectal and upper GI cancers
- 3-5 juvenile polyps
- SMAD4 also causes HHT
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
7
Q
What marker is analyzed in forensic DNA analysis?
A
Short or Variable tandem repeats
- Highly polymorphic wiht low mutation rate
8
Q
How many STR loci are used in CODIS?
A
originally 13, now 20 as of 2017
9
Q
What information is contained in a BAM file?
A
NGS data aligned to a referece with coverage depth
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
11
Q
meconium ileus, fat/vitamin malabsorption, high LFTs, pulmonary infections
A
Cystic Fibrosis
CFTR
- Biliary Cirrhosis = 2nd cause of death after pulm infections
12
Q
Recurrent respiratory infections, mild intestinal disease, elevated sweat choloride, CFTR normal
A
SCNN1
Epithelial Na channel
Mild CTFR phenocopy
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)
14
Q
What does lumacaftor do?
A
Helps get Phe508del CFTR to cell surface
-used in combo with ivacafor for Phe508del
15
Q
What does tezacaftor do?
A
Help get mutant CFTR protein to cell surface
- Used in combo with ivacaftor
16
Q
What does CFTR Phe508del do to protein function?
A
- Defect in processing -> misfolding -> stays in ER (localization problem)
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%
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)
19
Q
What does a negative result on CFTR carrier panel mean?
A
Risk is not zero, need to calculate posterior probability
20
Q
What if oligonucleotide ligation assay?
A
Tests for multiple common mutation in parallel using PCR products. Often used for CFTR
21
Q
Is the imprinted allele active or silent?
A
Silent
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
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
24
Q
When is imprinting reversed?
A
Gametogenesis
- Defect can cause functional UPD
25
What tests can detect 99% of PWS and 80% of AS?
methylation analysis
- Southern blog with methylation sensitive restriction endonuclease (5-methylcytosine)
- PCR after treatment of DNA w/ bisulfite (unmethylated C converted into U)
26
What is the recurrent risk of PWS or AS?
UPD or deletion - 1/1000
Methylation (imprinting center) defect - up to 50%
Rearrangement - up to 25%
UBE3A mutation - up to 50% if maternal
27
What test will detect parent of origin inUPD?
Trio microsatellite analysis w/ STR markers
Methylation sensitive MLPA (does not need parental data)
28
What are the imprinted chromosomes?
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
29
omphalocele, hemihyperplagia, **cytomegaly of fetal adrenal cortex**, renal abnormalities
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
30
hemihypotrophy, DD, trancular facies, IUGR
RSS
50% hypomethylation in pat 11p - Pat IGF1 no longer expressed
10% maternal UPD 7
Duplication of mat 11p - mat CDKN1C expressed twice
31
CYP2D6
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
32
CYP2C19
CYP2C19
Coverts clopidogrel to active form
Rapid metabolizer - use as recommended
Normal metabolizer - use as recommended
Intermediate metabolizer - use alternative
Poor metabolizer - use alternative
33
CYP2C9, VKORC1
CYP2C9, VKORC1
Predicts response to warfarin
- Faster metabolizer -\> need higher doses to reach therapeutic range
34
What is resoluation of microarray?
200kb for deletion and 500kb for duplications
- good for microdeletion/microduplication syndromes
35
In array CGH, what is the log 2 ration of a heterogyzous deletion? Duplication?
Deletion = -1, Duplication = 0.6
36
What are disadvantages of SNP array vs array CGH?
- SNP arrays are based on known SNPs -\> cannot be customized
- More probes needed
37
CNV characteristics:
- Well known, recurrent
- Published CNV w/ consistent phenotype
- Dose senstive disease causing gene in interval
- \>3-5Mb
Pathogenic criteria
38
CNV charactersitics:
- Single case report with well defined phenotype
- CNV as compelling evidence of causing disorder relevant to clinical indication
Likely Pathogenic
39
CNV characteristics:
- No genes but exceeds reportable size (3-5Mb)
- Few genes, few CNBs reported in literature not in polymorphic region
Likely benign
40
CNV characteristics:
- Few genes, dosage senstivity not established
- No firm conclusion
VUS
41
What is the reportable size limit for CNVs?
3-5Mb
42
in a CMA, what is the lower limit of homozygosity for first-cousin relations?
4% homozygosity (predicted 6.25%)
43
What are strengths/weaknesses of MLPA vs exon-targeted array for exon level deletions?
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)
44
Macrocephaly, CAL spots, axillary freckling, lipomas
Legius syndrome
SPRED1
-NF like but no neurofibromas
45
CAL spots, meningiomas, schwannomas, hearing loss
NF2
Merlin/Schwannomin
46
CAL spots, lisch nodules, neurofibromas, medulloblastoma, colon cancer
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)
47
What is the difference between type 1 and type 2 mosiacism?
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
48
Mosaic vs Chimera
Mosaic starts from single fertilized egg
Chimera starts from 2 fertilized eggs -\> fuse
49
linear epidermal nevi, asymmetric growth, lipoatrophy, vascular malformation, lung bullae, ovarian cystadenoma, parotid adenoma
Proteus
AKT1 (downstream of PI3K)
- Cerebriform connective tissue nevus
50
Lipoatrophy, segmental overgrowth, venous anomalies, megalencephaly, capillary malformations
PIK3CA related overgrowth spectrum
- Overlaps with proteus (same pathway)
51
Most common genes for CDLS
NIPBL (60%) - AD
SMC1A (5%) - XL
HDAC8 (2%) - XL
52
What is the pathophys of CDLS?
Cohesin complex part of sister chromatid exchange, dsDNA repair, maintaning genome organizaion, and distal transcription
53
Tall forehead, deep philtrum, wide neck, low posterior hairline, sparse hair (infancy) -\> thick,wooly hair (childhood), macrocephaly, low set ears
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
54
SHOC2 p.S2G
Noonan with loose anagen hair
- Easily and painlessly pluckable, sparse, thin, slow-growing hair without sheaths
55
What gene causes Costello syndrome?
Noonan + papillomata
HRAS
56
What genes cause CFC syndrome?
Noonan + follicular hyperkeratosis, sparse/curly hair, absent eyebrows
BRAF, MEK1, MEK2
57
What cancer is associated with Noonan?
JMML
58
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
- 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
59
where are alpha-satellite DNA located?
Centromeres
- 171bp tandem repeat
60
TTAGGG sequence
Telomere cap - substrate for telomerase and shortens with age
- Distal to subtelomeric repeats
61
What are characteristics of a dark band on G stain? What about R stain?
R = reverse G
Dark G = AT rich -\> Gene sparse, early transcription, tissue specific
62
How many chiasma/chromosome is required for normal segregation?
At least **one per chromosome arm**
63
Which aneuploidy is 100% maternal M1 error?
Trisomy 16
64
Which aneuoploidy is ~50/50 maternal vs paternal origin?
XXY
65
Which aneuploidy is mostly maternal MII error?
Trisomy 18
66
What percent of 45,X, Tiromy 18, Trisomy 21, and 47,XXY conceptuses are liveborn?
45,X - 1%
Trisomy 18- 5%
Trisomy 21 -20%
47 XXY, 47 XXX, 47, XYY - 80%
67
What is the empirical risk of unbalanced offspring (adjacent segregation -\> livebirth) in parent with balanced translocation?
10-15%
68
What should you be concerned when parent w/ robertsonian translocation has a balanced offspring?
UPD 14 or 15
69
What disorder is associated with marker chromsome 15? 22?
15 - palister killian (temporalfronto balding)
22 - cat eye
70
What causes SBMA?
CAG repeat expansion in AR gene
\>38 = full penetrance
\<34 = normal
71
What causes hemophilia B leyden?
Factor 9 leyden
- Hemophilia B that resolves in puberty when androgen levels increase
- Caused by **promoter mutation at -20**
72
Where is poly T tract on CFTR?
Exon 8
- regulates splicing of exon 9 (skip if 5T)
73
when is a premature stop codon likely to result in truncated protein?
When it is within last 50bp of next to last exon, in last exon, or in single exon gene
74
What copy of SMN is telomeric?
SMN1
SMN2 is centromeric
75
erlotinib, getfitinib
EGFR targeting drugs
76
imatinib, dasatinib, nilotinib
BCR/ABL1 targeting drugs
77
Pantumumab, cetuximab
KRAS tageting drugs
78
what is the relationship between mutation rate and selection?
AD: u=sq
AR u=sq2
XL u=sq/3
79
1- senstivity
false negative rate
80
1- specificity
false positive rate
81
5 most common congenital anomalyes
1) undescended testes
2) CHD
3) Talipes
4) NTD
5) CL/P
82
normal intrinsic fetal development altered by mechnical force
deformation
83
normal intrinsic fetal develoment is interrupted by outside force
disruption
84
afternomal fetal tissue organization
dysplasia
85
86
morphological defect from abnormal intrinsic fetal development
malformation
87
t8:14
burkitt lymphoma
Activation of MYCC oncogene
88
crizotinib
ALK inihibitor
Used for recurrent ALK inversion in small cell lung ca
-ALK-EML4 fusion
89
vermurafinib
Target BRAF V600E
Melamonas
90
Erlotinib
target EGFR in lung ca
91
Vandetanib
Target RET in medullary thyroid ca
92
adrenocortical/choiroid plexus carcinoma, anaplastic rhabdomyosarcoma, hypodiploid ALL
TP53
93
Phenochromocytoma + paraganglioma
SDH
94
When do start surveillance for TP53?
breast MRI at 20, colonoscopy at 25
95
nail dystrophy, oral leukoplakia, reticulate skin pigmentation
Dyskeratosis congenita
Telomere dysfunction
+ hypoplastic bone marrow
-Very short telomeres
96
FAP management
Colonscopy at 10
EGD at 20
Thyroid exam
97
AR Familial polyposis
MUTYH
98
When do you start colonscopy for Juvenile polyposis?
15
99
what is the serious early complication in STK11?
Peutz -Jeghers
intussusception
100
CDH1
Hereditary diffuse gastric cancer and lobular breast cancer
101
PALB2
Breast and pancreatic ca
102
Olaparib
PARP inhibitor for BRCA tumors (especially ovarian)
103
When to start screening for BRCA?
Breast at 25, ovarian/prostate at 30
104
leiomyomatosis + RCC
fumarate hydratase
105
Chromophobe/oncycytic renal cancer
Birt-Hogg-Dube
FLCN - tumor suppressor gene
+ firbofolliuloma, polype, medullary thyroid, **penumothorax**
106
what is the probablity a women in genral population is a carrier for an XLR mutation?
4u
- new u on X from mom
- new u on X from dad
- mom is carrier
C = u + u +1/2C -\> C = 4u
107
UCD with hepatic fibrosis
ASL deficiency
108
which AA are N-linked CDGs attached to?
asparagine
109
B glucoronidase
Sly syndrome
MPS VII
- Hurler like, can be very severe/hydrops
110
Premutation for Friedreich
GAA repeat in intron 1
34-66 = premutation
\<33 is normal
\>67 is pathological
111
What causes symptoms in Hartnup disease?
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)
112
ZNF9
Myotonic dystrophy type 2
CCTG
\>75 = pathogenic
113
Most common congenital anomalies related to obesity in mom
1) NTD
2) CHD
3) CL/P
114
ectodermal dysplasia with normal teeth, short stature, eye anomalies
Clouston syndrome
Skin + hair + nails
GJB6 (AD)
115
ectodermal dysplasia with normal skin and teeth
Witkop
MSX1 (AD)
116
X linked ichthyosis
Steroid sulfatase
117
Blistering in or above basal layer
EB simplex
- KRT5, KRT14, EXPH5
118
Blistering within basement membrane
Juncitonal EB
LAMB3, COL17A1
119
Blistering below basement membrane
Dystrophic EB
COL7A1
120
Blistering in multiple cleavage planes (within, above, and below basement membrane)
Kindler syndrome
Kindlin-1 (FERMT1)
121
Serpina1 Glu342Lys
A1AT Z allele
10% activity
122
mechanism of transient neonatal diabetes
**overexpression of paternally expressed genes** in chromosome 6
- Paternally UPD6 or maternal hypomethylation
123
TNFRSF13B
CVID
- humerol immunity issues after 2yrs (usually young adulthood)
- Tx IVIG
124
STAT3
Hyper IgE syndrome
AD
- high IgE, boils, cysts, eczema
125
IL2RG
XL SCID
126
XL alpha thalassemia
ATRX
alpha thal + ID, microcephaly, telecanthus, genital anomalies
127
Gonads in androgen insensitivy
XL- AR gene
- Female external genetalia, male gonads
128
XL salt wasting, hypoglycemia, and low BP
NROB1
XL congenital adrenal hypoplasia
129
asfotase alfa
Hypophosphatasia
130
high deoxypyridinoline/pyridinoline ratio in urine (HPLC)
EDS6 - kyphoscoliotic
PLOD1 -\> deficient lysyl hydroxylase 1 activity
131
forrowed skin, droopy face, doughy skin **without hyperelasticity**
Cutis laxa
ATP6VOA1, EFEMP2, FBLN4, FBLN5
132
ABCC6
pseudoxanthoma elasticum
Skin papules, retinal streaks/hemorrhages, GI bleed, angina
133
cerebro-oto-renal syndrome
Lowe syndrome
OCRL -\> part of PI pathway
- cataracts/glaucoma, CNS, renal fanconi
134
High uric acid, gout, renal failure
AD tubulointestinal kidney disease
- Uromodulin, Renin
135
CYP2C9
Warfarin metabolism
136
CYP2D6
CoDeine, hearth (Beta blockers, antiarrhythmics), antidepressants, antipsychotics
137
CYP2C19
Clopidogrel
138
Thiopurine S methyltransferase
involved in inactivation of 6-mercaptopurine and 6-thioguanine
low activity -\> need to lower dose of drug
139
HLAB\*5701
hypersensitivty to abacavir
140
malignant hyperthermia + hypokalemic periodic paralysis
CACNA1S
141
SDHD
Paraganlioma
- paternally imprinted on Ch11
SDHD -\> D for DAD
142
Medulloblastoma
Jaw cysts
Ovarian fibroma
Gorlin
PTCH1
143
cancer syndrome with insulinoma/gastrinoma
MEN1
144
tumor in alport syndrome
Leiomyoma
145
short stature, azoospermia, diabetes, sun sensitivty
Bloom
RECQ2 helicase
146
recurrent chronic ulcers, early hair graying, sarcomas, osteoporosis, atherosclerosis
RECQ helicases
- early manifestations of adult diseases
- includes bloom syndrome and others
147
papillommas, trichilemommas, acral keratoses
PTEN
148
How to distinguish diamond blackfan from other marrow failure syndromes (like fanconi)
- no solid tumors
149
Is the template strand sense or antisense?
antisense
RNA looks the same as the template strand, but is transcribed using the sense strand, which is complementary to the template
150
Polyglutamine repeat SCAS
1,2,3,6,7,17
- 12 is 5'UTR
151
what is the dinucleotide for splice donor and acceptor site?
donor - GT
acceptor - AG
152
Mechanism that removes thymine dimers and large chemical adducts
Nucleotide excision repair
defective in XP
153
Mechanism for removal of double stranded breaks by homologous recombination or non-homologous end-joining
Postreplication repair
Nijmegen breakage (NBS)
Bloom (BLM)
BRCA1/2
154
Steps to preparing karyotype
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
Lineage of expansion in CAG repeats
Noncoding tends to be maternal (DM1, Fragile X)
Coding tends to be paternal (HDD, SCA)
156
pThr312Ile in ABL
Resistance to Gleevac -\> abnormal binding site in CML with 9:22 translocation
157
XL lethal condition germiline mosiacism risk
1/3rd -\> if mom has one affected male child, her risk of being carrier is 2/3rd
158
NPC gene function
Intracellular cholesterol trafficking
- accumulation of unesterified cholesterol
159
gene for RCDP type 1
PEX7
low plasmalogen and high phytanic acid
160
MPS + ichthyosis
Multiple Sulfatase deficiency
AR formylglycine enzyme deficinecy -\> post translation l modification of cys in all sulfatases
161
crizotinib
ALK-EML4 inversion in lung ca
162
BRAF V600E
melanoma
Treat with vermurafinib
163
EML4-ALK inversion
NSCLC
Treat with Crizotinib
164
EGFR missense in lung cancer
Treat with erlotinib
165
RET missense in Medullary Thyroid Ca
Treat with Vandetanib
166
Olaparib
BRCA1/2 germline Ca
167
GATA1
Somatic mutation in down syndrome -\> acute megakaryocytic leukemia risk
168
atypical teratoid/malignant rhabdoid tumor
SMARCB1 (Also schwannomatosis)
169
Oncogenes that cause familial cancer syndromes
RET - MEN2
HRAS - Costello
KRAS - CFC
ALK - neuroblastoma
EGFR - lung ca
170
AML, Head/neck cancer
Leukoplakia, nail dystrophy, reticulate skin lesions
Dyskeratosis congenita
Telomere shortening diosrders
171
miRNA processing disorder
DICER1
AD w/ incompelte penetrance
- \> processes pre-microRNA to microRNA
- pleuropulmonary blastoma + goiter, CNS rhabdo, pinealblastoma, etc
172
downstream oncogene in APC
Beta Catenin (CTNNB1)
- \> activating variant = sporadic polyp
- \> germline APC LOF (Tumor suppressor) -\> activates Beta Catenin
173
Promotor 1B mutations in APC
Gastric adenocarcnoma and proximal polyposis
- no colorectal or duodenal polyps
174
What is the function of MUTYH
base excision repair
AR polyps
175
Risk of colon Ca in juvenile polyposis
~50%, avg age 43
SMAD4 \> BMPR1A
- colonoscopy at 15
176
Benign ovarian sex-cord tumors, Sertoli-cell testicular tumors
STK11
- Peutz Jeghers
+ pigmented spots on buccal mucosa
- GI + breast ca
+ Intussiception risk
177
GREM1
Upstream promotor duplication -\> mixed polyposis syndrome
- Need to do CNV testing in panel
178
Laterality of colon ca in HNPCC
Right side \> Left
~70% lifetime risk for CRC and endometrial Ca
179
Most common genes for HNPCC
MSH2 and MLH1 = 90% of amsterdam criteria
MSH6 more rare
PMS2 rare with multiple psudogenes
EPCAM deletion -\> epigeneic silencing of MSH2
180
What does BRAF V600E or MLH1 methylation in colon cancer mean?
More likely sporadic
181
Management of HNPCC
Colonoscpy at 20-25 for MSH2 and MLH1
182
Ultra mutated colon cancer
POLE or POLD1
183
Biallelic Lynch mutations cause \_\_\_
Constitutional mismatch repair deficiency
CAL spots + axillar freckling (NF like)
+ Cancer risk
184
PTEN diagnosis
Macrocephaly
Mucocutaneous lesions
Cerebellar dysplasic gangliocytoma
Thyroid Ca
Breast Ca
185
Tumor profile in BRCA1
Homologous recombination deficient
186
What are the 3 high risk Breast Ca genes?
BRCA1, BRCA2, PALB2 (binds BRCA2)
187
c.185delAG
A. Jew founder variant in BRCA1
188
c. 5382insC
A. Jew founder variant in BRCA1
189
c.6174delT
A. Jew founder variant in BRCA2
190
Most common moderate risk Breast Ca genes
CHEK2, ATM
191
RAD51C
Ovariant Ca risk gene (not breast)
192
Hypodiploid ALL with TP53 mutation
high likelihood (48%) of germline TP53 (LFS)
193
Cancers in ATM
Moderate risk for breast, colon, pancreatic
+ high AFP
194
Telomere shortening
Dyskeratosis Congenita
1) Leukoplakia
2) nail hypoplasia
3) reticular skin lesions
195
senstivity to ionizing radiation
Ataxia Telangiectasia (+ high AFP)
Nijmegen breakage
196
What gene can cause both coffin-siris syndrome, familial schwannomatosis, or atypical rhabdoid tumors?
SMARCB1
197
c.985A\>G, p.Lys329Glu
Common mutation in MCAD (50-90% of cases)
198
Where are alpha satelites found?
171bp repeats clustered around centromeres
199
Stage of prophase 1 where homologs pair and synaptonemal complexes form
Zygotene
200
Stage of prophase 1 where crossing over happens
Pachytene
201
Stage of prophase 1 where homologues start to separate but remain attached at chiasmata
Diplotene
- This is where female meiosis arrests
202
Empirical risk of liveborn offsprnine with adjacent 1 unbalanced chromosomes when parents have balanced translocation
10-15%
| (theoretical 25%)
203
Empirical risk of trisomy 21 in offspring of parent w/ robersonian translocation
female carrier 15%
male carrier 2%
204
When does X-inactivation occur?
2 weeks after fertilization
205
Qualities of G band dark regions
G dark = high AT, rich in LINE repeats
Less GC = less promoters -\> sparse genes, late replicating; tissue specific genes
206
resolution of FISH
100Kb
| (karyotype = 5MB, CMA = 10kb)
207
Mechanism of non-recurrent CNVs
Non-homologous end-joining
Fork stalling and template switching
208
malignancy with 5q-
Myelodysplatic syndrome
209
HgB Glu26Lys
HbE - mild anemia when homozygous
210
HgB Glu6Val
HbS
211
HgB Glu6Lys
HbC -\> can cause sickle cell when compound het w/ HbS
212
HTT: 30 repeats
27-35 = intermediate/mutable allele
Normal phenotype, but at risk for expansion
213
most common congenital anomalies
1) Undescended testes
2) heart defect
3) Talipes
4) NTD
5) CL/P
214
What probability an unaffected daughter of a normal parents is a carrier for an XLR allele?
2u (1 per each X inherited)
215
What is the probability a woman in general population is a carrier for an XLR allele?
**4u**
C = u + u + 1/2C (change of de novo from each parent + change of inheriting if a parent was a carrier)
216
relationship between selection and mutation rate in AR disease
q= (u/s)1/2
fitness = 1-s
each generation q2 --\> q2(1-s) (sq2 is lost)
Thus u = sq2
217
relationship between selection and mutation rate in AD disease
u = sp
Each generaiton 2pq --\> 2pq (1-s)
Assuming q ~ 1, 2ps alleles are lost each generation
2u = 2sp, u=sp
218
N-acetyltransferase 2
Pharmacogenomics
Breakdown of insoniazid and hydralazine
Variants -\> increased toxicity
219
SLCO1B1\*5
Pharmacogenomics
Statin induced myopathy
220
SLC22A
Pharmacogenomics
Metformin toxicity
221
CACNA1S
Malignant hyperthermia risk and hypokalemic periodic paralysis
222
What charge does DNA have?
negative
Gel runs cathode (-) to anode (+)
223
What is the advantage of an invader/FRET assay?
Can detect SNPs in unamplified DNA
- invader oligo contained specific allele
- If both invader and probe bind then probe will be cleaved -\> Fluorescence
224
Best techniques to detect large expansions
Southern blot
Triplet primed PCR
225
What is the function of NF2?
Cytoskeletal protein
226
Selumetinib
FDA approved MEK inhibitor for plexiform neurofibroma in **children \> age 2**
227
GAA repeat cutoffs for FA
\<33 normal
\>66 pathological
34-65 = premutation
228
Non muscle manifestations of FSHD
Retinal vasculopathy
SNHL
229
DNAJC12
Chaperone for hydroxylases
high Phe on NBS
+ dystonia/nystagmus (TH)
230
Most common reason for low C0 on NBS
maternal carnitine deficiency
231
Most common mutation in MCAD
Lys304Glu
\>90% of cases
232
NBS analyte for 3MCC
C5-OH
233
globotriaosylceramide
GB3
Fabry biomarker
234
Ace, TRAP, Chito
Gaucher Biomarkers
235
If GALC activity is low on NBS what is the reflex test?
psychosine levels
if high reflex to 30kb deletion (45% cases)
Otherwise do sequencing and del/dup
236
Where does cfDNA for NIPT come from?
placenta
237
Main reasons for false positive NIPT
Alternative sources of non-germline maternal DNA
- Placental mosiacism
- Vanishing Twin
- Maternal cancer
238
Clinical consequences of confined placental mosaicism
IUGR
UPD (trisomy rescue)
239
Reasosn for "no call" NIPT
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
prenatal US: AV canal and absent nasal bone
Trisomy 21
241
Prenatal US: Clenched hands
Trisomy 18
242
Prenatal US: MIdline cleft, polydactyly
Trisomy 13
243
Prenatal US: Cystic hygroma, HLHS
45X
244
What is the mechanism of BWS seen in IVF babies
Loss of methylation on maternal 11p.15
245
Most frequent imprinted disorder in IVF
Russel Silver Syndrome
- maternal methylation defect
(male imprinting happens near birth, female imprinting happens around meiosis II)
246
When should CVS happen?
10-13 weeks
Limb reduciton defects seen when done at 8 weeks
247
Common fetal anomalies seen in maternal obesity
1) NTD
2) Cardiac
3) CL/P
248
white forelock, patchy hypopigmentation
Piebaldism
KIT, SNAI2 (AD)
249
KIT, SNAI2
Piebaldism
250
LYST
Chediak Higaski
hypopigmentation, decreased visual acuity, HSM, **neuropathy**, anemia, infections, **ID**
251
Hypopigmentation, poor eye fixation, silver-gray hair, DD
Griscelli syndrome
MYO5A, RAB27A, MLPH
252
Hyperhidrosis, hypodonia, absent/thin hair, dysrophic nails, smooth tongue
Odonto-Onycho-Dermal dysplasia
WNT10A
- Ectodermal dysplasia with **hyperhidrosis and smooth tongue**
253
Small/absent teeth, thin nails
Witkop syndrome
MSX1 (AD)
Ectodermal dysplasia with normal skin/hair
254
Ectodermal Dysplasia with normal teeth
Clouston syndrome (Hydrotic ectodermal dysplasia)
GJB6 (AD)
+ short stature and eye anomalies
255
Common mutation in IKBKG
Incontinential Pigmenti
65% due to deletions in exon 4-10
256
KRT5, KRT15
Epidermolysis Bullosa Simplex
Splitting above basal layer
EXPH5, KRT5/14, TGM4
257
LAMB3, COL17A1
Epidermolysis Bollosa Junctional
Splitting within BM
LAMB3 (70%), COL17A1, LAMC2, LAMA3
258
COL7A1
Dystrophci epidermolysis Bullosa
Splitting below BM (AD or AR)
259
FERMT1
Kindler sydnrome
Kindlin-1
Epidermolysis Bullosa with multiple cleavage planes
260
UGT1A1 deficiency
Bilirubin conjugation defect -\> unconjugated hyperbili
LOF -\> Crigler-Najjar
Promoter mutation -\> Gilbert (benign)
261
Orange Tonsils
Tangier Disease
ABCA1
Low HDL
262
15q11-q13 duplication
ASD
263
Paternally transmitted GNAS mutation
Albright hereditary osteodystrophy (ID and subcutaneous calcification)
264
Maternally transmitted GNAS mutation
Pseudohypoparathyroidism
265
R506Q
Factor V Leiden
AKA R534Q
266
maternal meiosis I -\> what kind of UPD?
Heterodisomy
267
Paternal meiosis II error -\> what kind of UPD
Isodisomy
268
pat UPD 6
Transient neonatal diabetes
- Duplication of PLAGL/ HYM1
269
Mat UPD 7
RSS (10%)
GRB10, MEST
270
Chromosomes involved in mat UPD disorders
7, 11, 14, 15, 20
271
Chromosomes involved in pat UPD disorders
6, 11, 14, 15, 20
272
mat UPD 14
Temple
MEG, RTL1
Hyperextensible joints, scoliosis, DD, hypotonia, hypogonadism, obesity, small hands/feet
273
pat UPD 14
Kagami-Ogata
MEG, RTL1
Omphalocele, coat hanger sign (narrow ribs), DD
274
Paternal UPD 20
Pseudohypoparathyroidism
GNAS
- maternally inherited GNAS LOF -\> Pseudohypoparathyroidism
275
Risk of RSS in IVF
12% (9x RR)
276
Risk of BWS in IVF
6% (4.5x RR)
277
Prevalence of POF and FXTAS in premutation carriers?
CGG repeats 56-199
20% of women have POF
20-40% have FXTAS
278
Nasal polyps, pneumothorax, meconium ileus, rectal prolapse, diabetes
Manifestations of CF
279
Mode of inheritance for Bruton's agammaglobinemia
XL
BTK
280
stat3
Hyper IgE (Jobs) syndrome
Boils, chiari, arterial toruosity, eosinophilia
281
CD40LG mutatons
XL Hyper igM syndrome
Low IgA and E, high IgM
Tx: Allogenic SC Transplant
282
IL2RG
XL- SCID
283
high testosterone, dihydrotestosterone, LH
46XY w/ female external genetalia
Androgen insensitivty
AR - XL
284
Combined 17-a hydroxylase and 21-hydroxylase deficiency
Antley Bixler
Cyp450oxidooreductase deficiency (POR)
285
Female virilization + salt wasting
CAH
CYP21A1
286
ABCC8, GK, GLUD1
Familial hyperinsulinism
- hypoglyemia with low ketones
287
Management of Kallman syndrome
GnRH deficency
In males give testosterone and hCG
In females give protestins
288
AVPR2, AQP2
Hereditary nephrogenic diabetes insipidus
- inability to concentrate urine
289
FGFR3 Arg248Cys, Tyr373Cys, Lys650Glu
Thanatophoric dysplasia
Type 1- bowed femurs
Type 2- cloverleaf
290
4 types of OI due to COL1A1/2
1) Classic **non-deforming**
2) perinatal **lethal**
3) progressive **deforming**
4) variable with **normal sclera**
291
TRPPC2
XL Spondyloepiphyseal dysplasia tarda
- normal until 6-8yo -\> progressive skeletal dysplasia + joint/back pain
292
Main causes of multiple epiphyseal dysplasia
COMP, COL9A, MATN2
293
Skeletal dysplasia. anemia, immunodeficiency, fine silky hair
Cartilage Hair Hypoplsia
AR - RMRP
294
high deoxypyridinoline/pyridinoline ratio in urine
PLOD1 - kyphoscoliotic EDS
295
FBLN4, ATP6VOA2, EFEMP2
Cutix Laxa
Doughy skin
296
ABCC6
Pseudoxanthoma elasticum
- Lax skin w/ yellow papule, angiod retina streaks, macular degeneration, cardiac calcifications
297
What percent of marfan is de novo?
25%
298
What is the difference between LDS type 1 and LDS type 2?
Type 2 has no craniofaicial findings
299
SMAD2, SMAD3
LDS
SMAD2/3 , TGFB2/3, TGFBR1/2
300
PKHD1, DZIP1L
ARPKD
- neonatal echogenic kidneys, dialted bio ducts, pulmonary hypoplasia
301
MUC1, REN, UMOD
AD tubulointestinal kidney disease
+ hyperuricemia and gout
Renal failure in 40's
302
First tier evaluation for autism
Fragile X (males)
CMA
303
Second tier evaluation for autism per ACMG
MECP2 sequencing in all females
MECP2 duplication in males
PTEN is HC \>2.5 SD
MRI if other indicators
304
c. 665 C-\>T, p.Ala222Val
c. 1286A-\>C, p.Glu429Ala
Thermolabile MTHFR
305
Best time for NTD screening
16-18 weeks
- high AFP -\> NTD or ventral wall defects
306
What are measured in first trimester screen?
PAPPA, hCG, nuchal translucency
307
How do you determine prenatal lethality when there is concern for skeletal dysplasia?
Chest to abdominal circumference ratio \<0.6
Femur lengh to abdominal circumference ratio \<0.16
308
First line genetic workup for short stature and mild features
CMA
- Get karyotype for Turner if female
309
Isolated short stature + madelung deformity
SHOX (Turner)
310
Differences between SMN1 and SMN2
SMN1 is telomeric; common mutation is deletion of exon 7
SMN2 is centromeric, 5bp silent mutations -\> abnormal splicing
311
PALB2
High risk breast cancer (binds to BRCA2)
low ovarian ca risk
312
Breast Ca Screening in NF1
annual mammo starting at 30
313
most sensitive and specific test for pheo in NF1
Plasma free metanephrines
If equivocal follow up with 24 hour urine study
314
What groups of NF1 patients should be screened for renal-vascular hypertension as first line?
Hypertensive patients under 30, have abdominal bruits, and/or are pregnant
315
When do you test fathers for prenatal carrier status?
Before 14 weeks - if mother is positive
After 14 weeks - test mom and dad concurrently
316
Who should be considered for ashkenazi jew carrier screening?
One grandparent is jewish
317
What % of SMA is de novo
2%
5% of people have 2 copies in cis
318
fracture of long bongs on fetal US
Hypophosphatasia
NF
OI
319
Poor mineralization of calvarium in prenatal US
Achondrogenesis
Cleidocranial dysplasia (RUNX2)
hypophophatasia
OI
320
When can achondroplasia be definitely found on prenatal US
24 weeks
321
Cancer screening in patients hemihyperplasia
Abdominal US for wilms tumor ever 3 months until age 8
AFP measurement every 3 months until age 4 (hepatoblastoma)
322
Which mechanism of BWS confers highest risk for wilm's
Hypermethylation of maternal IC1 or UPD
323
recurrence risk for ASD
If 1 affected sibling -\> 5-10%
If 2 or more -\> 30%
324
selumetinib
treatement for NF1 -\> MPNST and Plexiform NF
325
Most common dilated CM genes
TTN
LMNA
326
Most common genes for HCM
MYH7, MYBPC3
327
How many generations does it take for allele frequency of AR disease with fitness 0 to half?
X where allele frequency = 1/X
328
adrenocrotical carcinoma
TP53
329
Hepatoblastoma
BWS or APC
330
What % of patients with omphalocele have BWS
20%
331
neuroblastoma, bladder cancer, rhabdomyosarcoma
+ CHD, low set ears
costello
HRAS
332
Thrombocytopenia (small platelets), eczema, Immune deficiency
Wiskott aldrich
XL - WAS
333
hypoplastic 5th nail
Coffin siris
- ARIDB1
334
t(8:21), inversion 16, t(9:11)
AML
335
Palmar Pits
Gorlin
PTCH
336
pre-auricular tags and pits
Branchio Oto Renal
EYA, SIX5
