Gene 500 Flashcards
(253 cards)
1
Q
What are the 3 most common chromosomal abnormalities in recognized pregnancies?
A
1) Triploidy (100% SAB)
2) 45, X (99% SAB)
3) trisomy 16 (100% SAB)
2
Q
Large tongue, excess nuchal skin, auricular dysplasia, upslanting palpebral fissure, clinodactyly, hyperextensibility, single palmar crease, hypotonia
A
Down syndrome
47,XX,+21 (95%)
46,XX,rob(14:21) (4%)
Mosaic trisomy 21 (1%)
3
Q
What are the complications of down syndrome?
A
Hearing problems (narrow ear canals)
Vision porblems
Cataracts, OSA
CHD
hypothyroidism
Leukemia
atlantoaxial instability
dementia
4
Q
Small fingernails, short sternum, clenched hands (2 over 3, 5 over 4), micrognathia
A
Edwards Syndrome
Trisomy 18
- look for CHD, horshoe kidney, cerebllar hypoplasia, microphthalmia, central apnea
5
Q
Sloped forehard, cutis aplasia, hypoterloirsm, cleft L/P, omphalocere, polydactyly, HPE
A
Patau, Trisomy 13
- Heart, CNS, renal, general anomalies
6
Q
What are the most common karyotype findings for Turner Syndrome?
A
45,X - 50%
46, X, i(Xq) - 15%
45,X/46,XX mosiac - 15%
45X/46,X,i(Xq) - 5%
other
7
Q
Low posterior hairline, renal anomalies, cardiovascular anomalies, short stature, edema in infancy
A
Turner Syndrome
+ gonadal dysgenesis, webbed neck, widely-spaced nipples
- Lack of secondary sex characteristics/ammenorhea in puberty
- Monitor for aortic root dilation
8
Q
Hypogonadism, tall, gynecomastia, decreased muscle mass, osteopenia, low libido
A
Klinefelter
47 XXY (85%)
Mosaic 47XXY/46XY (15%)
- Increased risk for learning disabilities
9
Q
What is the phenotype for 47XYY
A
Not dysmorphic
Tall, at risk for langage delay/low verbal IQ
- ~10-15 IQ points lower than siblings
10
Q
What is 47XXX phenotype?
A
Tall, 70% have learning porblems
- no dysmorphic features
11
Q
How is gonadal sex determined?
A
SRY -> SOX9
- established around 6 weeks gestation
12
Q
When does X inactivation occur?
A
2 weeks post-fertilization
13
Q
What gene is expressed in the inactive X but not active X?
A
XIST
in Xq13
- produces large RNA molecules that coat inactive X
14
Q
Which X is usually missing in 45X?
A
paternal 75%
15
Q
Cystic hydroma, ovarian dysgenesis, low hairline, aortic root dilation
A
Turner Syndrome
Haploinsufficiency of PAR genes
- 2 Xs needed for ovarian development -> inactive X is reactivated in oogoina during meiosis (starts in fetal life)
16
Q
When are patients witt Turner Syndrome at risk for gonadoblastoma?
A
When mosaic for 45X and 46XY and external genetalia is female or ambiguous
- okay if external genetalia is male
17
Q
What does a ringed chromosome in turner syndrome mean?
A
Need to do FISH to determine if X or Y and if XIST is present
- if Y risk for gonadoblastoma
- if X and XIST is present -> PAR haploinsufficiency -> Turner
- if X and XIST is absent -> X disomy -> severe ID, OCD, dysmorhpic features, and congenital malformation
-
18
Q
Xp21 deletion syndrome
A
DMD, RP, adrenal hypoplasia, ID, glycerol kinase
19
Q
What does Xp duplication involving DAX1 do?
A
46XY females
- increased DAX1 dose can overcome sry
- w/ ID
20
Q
In X-Autosome translocations, which X is inactivated?
A
If balanced; normal X nonrandomly inactivated
If unbalanced: abnormal X is nonrandomly inactivated
21
Q
What is the reproductive consequence of X-autosome translocation?
A
Half of females infertile
All males infertile
22
Q
Which chromosomes can be involved in robertsonian translocation?
A
Acrocentrics
13, 14, 15, 21, 22
23
Q
What is the clinical consequence of balanced translocation?
A
Usually multiple miscarriages due to unbalanced offspring
- Phenotype depends on size, genes involved, monosomy vs trisomy
24
Q
What type of segregation is most common in a quadrivalent?
A
Adjacent 1 (chromosomes next to each other with different centromeres go together)
- Alternate results in normal/balanced offspring
25
What are 3 mechanisms of isochromosome formation?
Centromere misdivision - isochromosome w/ identical arms
U-type exchange in meiosis 1 (most common) - isodicentric chromosome w/ homologous arms
U-type exchange in meiosis 2 -isodicentric chromosome w/ identical arms
26
Which type of inversion involves the centromere? Which type is more likely to result in abnormal offspring?
Per**i**centric involves centromere and is more likely to result in liveborn but abnormal offspring
27
What is the significance of segmental duplications?
Seg Dup = Low copy repeats
- Non-homologous recombination -\> recurrent Del/Dup syndromes
28
Name the syndrome associated with:
5q35 deletion
7q11 deletion
15q11q13 deletion
17p11. 2 deletion or duplication
22q11. 2 deletion
5q35 deletion - Sotos
7q11 deletion - Williams
15q11q13 deletion - PWS/AS
17p11. 2 deletion or duplication - Smith magenis, HNPP/ CMT
22q11. 2 deletion - DiGeorge
29
75% of chromosome rearrangements come form which parent?
father
Exceptions:
- novo markers (associated w/ advanced maternal age)
- De novo robertsonian (90% mom)
- interstitial del/dup -\> 50/50
30
What are alpha-satellites? Why are they relevant?
Alpha-satellite is a 171bp repeated region at centromeres -\> different by 2-3% between chromosomes and **allow chromosomes to be distinguished on FISH**
## Footnote
**- Exceptions: 13 and 21, 14 and 22**
31
What are the advantages of interphase FISH?
- Fast - no need to culture cells (takes 1-2 days vs 7-14 days for karyotypes)
- better for Tandem duplications
32
What is the best FISH probe for philadelphia chromosome?
Dual fushion -\> for when both tranlsocation breakpoints are known
33
What can SNP array tell that CGH array cannot?
- UPD, loss of heterozygosity
34
Why would you follow up CMA results with FISH?
- confirm finding
- provide location of duplications
- identify balanced translocations in parents (recurrence risk)
35
According to ACOG, when should a pregnant woman be offered CMA?
- if U/S abnormal get CMA
- if U/S normal can do karyotype or CMA
- offer to women of all age groups (most findings are not AMA related)
36
What is the resoluation of:
- Karyotype
- high resolution karyotype
- CMA/FISH
- Sequencing?
- Karyotype - 5-15MB
- high resolution karyotype - 1-3MB
- CMA/FISH - 20-250KB
- Sequencing? - 1-100bp
37
What is the signfiicance of JAK2?
Driver mutations in essential thrombocytopenia and polycythemia vera
38
What is the significance of MYC ?
Burkitt lymphoma
Protooncogene on Ch8, multiple translocation partners
39
What is the significance of ALK, EGFR, and KRAS?
Amplified in lung cancer
- ALK inversion is drug target
- EGFR can betargered by Cetuximab
- KRAS is downstream of ALK and EGFR and can **negate effects of targeted therapy**
40
Which aneuploidies are more likely to be paternal origin?
45X, and XYY
41
Which aneuploidies are more likely to be MII errors?
Trisomy 18, XYY
42
Which aneuploidy is 50/50 in parent of origin?
XXY
43
Most aneuploidies originate from which parent?
Maternal M1
44
Small placenta, high B-hCG, severe growth restriction, syndactyly, multiple congenital anomalies
Digynic triploidy
45
mild growth restriction, large cytic placenta, low B-hCH, syndacytly, multiple congential anomalies
Diandreic triploidy
- Partial hydatiform mole
46
Which phase of cell cycle are cellular contents duplicated?
G1
- chromosomes duplicated in S
47
Recombination occurs in what stage of meiosis?
Porphase 1 - **Pachytene**
48
When does meiosis start?
Males: after puberty
Females: **3rd month** of gestation -\> arrest at prophase 1 -\> continue at **menstration** -\> arrest at metaphase 2 -\> complete if fertilized
49
TTAGGG repeat
Telomere cap sequence -\> critical in meiotic pairing
50
In a karyotype G banding, which bands are GC rich?
Light bands = gene rich, GC rich, more euchromatic
Dark bands = gene poor, AT rich, more heterochromatin
51
What is the difference between a polymorphism and variant?
Polymorphism is \>1% pop frequency
Variant is \< 1% pop frequency - may or may not be disease causing
52
Locus vs alleleic heterogeneity
Locus heterogeneity = **multiple genes** -\> same phenotype
Allelic heterogeneity = **multiple variants** in same gene -\> same phenotype
53
Definte autosomal dominant
phenotype seen in heterozygotes
54
Definte autosomal dominant
Phenotype only seen in homozygotes
55
What does X-Linked mean?
If recessive: No father -\> son transmission
If dominant: affected males have no affected sons but all affected daughters
56
Co dominant vs incomplete dominant
Codominant = both A and B show up (Ie ABO blood type)
Incomplete dominant = hets are intermediate to homozygotes
57
What does g.112931A\>T mean?
genomic sequence change
58
What does c.112931A\>T mean?
coding sequence change
59
What does r.112931A\>T mean?
RNA sequence change
60
What does p.112931A\>T mean?
Protein sequence change
61
What does m.112931A\>T mean?
mitochondrial DNA sequence change
62
What does n.112931A\>T mean?
noncoding RNA transcript change
63
What does c.9A\>G, p.Lys3 mean?
**synonymous** A\>G in DNA -\> Lys 3 position
- May still affect splicing
64
What does c.100+1G\>T mean?
Intronic change **1 nucleotide downstream** from nucleotide 100 in coding sequence
65
What does c.100-2A\>T
Intronic change 2 nucleotides **upstream** from nucleotide 100 in coding sequence
66
LMNA c.1824 C\>T, p.Gly608
Synonymous change in LMNA that creates **cryptic splice site**
-\> **Hutchinson-Gilford Progeria**
67
FGFR3 p.G380R
Achondroplasia
C.1138G\>A (98%) or G\>C (2%)
68
Name the stop codons
UAA
UAG
UGA
69
When does a nonsense mutation result in a truncated protein?
When stop codon is downstream of the last 50bp of penultimate oxon (50bp from the last exon junction complex)
- If stop codon is too early -\> nonsense mediated decay
- If gene has 10 exons, nonsense variant in exon 1-8 will trigger nonsense mediated decay -\> no protein -\> likely pathogenic
- If nonsense if in exon 10 or last 50bp of exon 9 then it MIGHT NOT trigger decay and may make protein -\> MIGHT have some function
70
What is the correct nomenclature?
c.locus is 1521-1523
p. Phe508del
c. 1521\_1523delCTT
- \> **not delTCT** because you **push to the right**
71
What is necessary to make a variant pathogenic?
1 very strong + 1 strong, 2 mod, or 1 mod + 2 sup
2 strong
1 strong + 3mod, 2mod +2 sup, 1mod + 4 sup
72
What evidence is necessary to classify variant at LPATH?
Very strong + mod
strong + 1-2 mod
strong + 2 sup
3 mod
2mod + 2 supporting
1 mod + 4 supporting
73
What evidence classified variant as benign?
1 stand alone strong OR 2 strong
74
What evidence classified variant as likely benign?
1 strong + 1 sup
2 supporting
75
Variant classification: allele frequency \>5% in pop database
stand-alone benign
76
Variant classification:
- allele frequency \> expected for disease
- observed in healthy individuals expected to have condition based on penetrance/age
- not damaging in in-vivo funtional studies
- no segregation
Strong Benign criteria
77
Variant Classification:
- MIssense variant in gene where mostly truncating variants cause disease
- Observed in trans with AD disease causing allele or in cis with known disease causing allel
- in-frame del/dup in repetitive region
- computations data -\> benign
- alternative molecular diagnosis found in case
- reputable source reports variant as benign
- synonymous variant not predicted to affect splicing
Supporting benign criteria
78
Variant Classification:
- Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
- De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
- funcitonal studies support damaging effect
- The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
Strong pathogenic criteria
79
Variant interpretation:
- Located in a mutational hot spot and/or critical and well-established functional domain without benign variation
- Absent in controls (AD), rare (AR)
- Detected in trans w/ pathogenic variant (AR)
- Protein length changes as result in in frame del/dup
- Novel missense in residue where missense has been seen before as disease causing
- assumed de novo
Moderate pathogenic criteria
80
Variant Classification:
- Cosegregation with disease\*
- Missense in gene w/ low missense frequency and where missense is common mechanism
- Computational -\> deleterious
- Phenotype is specific for this gene
- Reportable source interpreted this variant as pathogenic
Supporting pathogenic criteria
\* segregation can become moderate/strong depending on size of pedigree
81
How do you detect variable number tandem repeat polymorphisms (minisatellites, microsatellites)?
Multiplex PCR
- highly informative genomic variation since each locus has many possible alleles
- Used in linkage and DNA fingerprinting
82
Which SCAs are repeat exapnsion disorders?
1, 2, 3, 6, 7, 17
- CAG repeats
83
What are the 3 main types of non-random mating?
- inbreeding
- assortive mating
- negative inbreeding (small population, people actively avoid kin)
84
What does identical in state mean?
Alleles that have the same phenotypic affect
85
How can heritability be estimated?
2x Parent-offspring correlation
h2=2Ppo
or
2(monozygotic twin concordance - dizogotic twin condordance)
h2=2(Pmz-Pdz)
86
How is relative risk (λ) calculated?
Frequency in relatives/ Freuqency in general population
87
What does a high λ mean?
High relative risk ratio = more heritable
λs\>2 = significant (s= sibling)
88
What is the difference between linkage and association?
Linkage = **cosegregation** of phenotype **with chromosome region** in multiple families - best for finding **rare alleles of large effect**
Association: presence of phenotype with **specific allele in many famlities in population** -\> more frequence in cases than controls - best for findings **common alles with small effect**
89
What does linkage dysequilibrium mean?
Behavior of 2 loci violates law of independent assortment
- Excess of parental types (non-recombinants) in offspring
90
What needs to be true in order to perform linkage analysis?
One parent has to be **hetrozygous and phase** must be known
91
What is θ (recombination fraction)?
Prebability that a parent will produce a recombinant offspring (non-parental haplotype)
Recombinant haplotype/ total offspring
θ = 0 -\> complete linkage
θ = 0.5 -\> independent
θ \< 0.5 = some linkage
92
What does θ = 0.5 mean?
50% of offspring have recombinant haplotype
- Independent assortment -\> no linkage
93
what does θ = 0 mean?
No offpsring have recombinant haplotype
- complete linkage
94
Calculate θ
In generation 2 dad is heterozygote and we know phase (disease with A) -\> linkage possible
Gen 3 unaffected AD daughter = recombination
θ = 1/8 = 0.125
95
Calculate θ
Gen 2 we know dad is BE. He is heterozygous and phase of disease is E -\> linkage possible
- Gen 3 son BE unaffected is recombinant
θ = 1/4
96
Calculate θ
Phase unknown -\> cannot calculate
97
Calculate θ
Unable to tell who is recombinant in third generation because both C and D could have come from either mom or dad.
98
How do you tell if θ of \<0.5 is statistically significant?
Calculate LOD score
LOD 3 = 1000:1 odds favoring linkage
LOD 3.4 = genome wide significant linkage
99
What is the definition of association?
**Lack of independence** between 2 things
100
how can association (between phenotype and allele) and linkage (marker and phenotype) be uncoupled?
Recombination
101
Breech position, hypotonia, low birth weight, Thick saliva, hypoplastic genetalia, almond shaped eyes, small hands/feet, ID
Prader Willi
**Paternally** expressed (maternally imprinted) genes in 15q11q13 - pat deletion \> mat UPD \> methylation defects
-- hyperphagai, fair skin/hair in deletions (P gene in area)
102
Devlopmental delay, copious saliva, ataxia, happy demeanor, stereotypies, **Large amplitude slow spike waves**
Angelman
Maternally expressed (paternally imprinted) genes in 15q11q13 - UBE3A
- Mat deletion \> UBE3A mutationn \> Pat UPD \> methylation defects
103
Is the imprinted allele silent or active?
Imprinted allele is **silent**
104
How does methylation specific PCR (MS-PCR) work?
- Treat DNA w/ bisulfite to convert **unmethylated C -\> Uracil**
- Maternallly C's are methlated -\> readout C
- Paternal C's are unmetylated -\> readout U
105
What is the recurrence risk for PWS/AS?
Deletion/UPD -\> risk low (\<1/1000)
Methylation defect, chormosome rearrangements, UBE3A mutations -\> Up to 50%
106
Which ETC complex is completely encoded by nuclear genome?
Complex 2 (FAD -\> CoQ)
Succinate DH of TCA cycle
107
Why does mito genome have high mutation rate?
- Limited repair/proofreading (not part of G2 phase of cell cycle)
- no histone
- More free radicals
108
Features of most cleft lip cases
Unilateral, L sided, male patient
109
What disease can RFLP (restriction fragment length polymorphism) be useful?
Achondroplasia
Restriction enzyme + electrophoresis for a single disease causing variant at codon 380
110
What is oligonucleotide ligation assay?
PCR with specific disease allele probes to see if they are present
- good for testing for multiple disease alleles in same locus in parallel (ie CFTR)
111
What is Multiple ligant-dependent probe amplification useful for?
MLPA for changes in size -\> great for copy number variation/repeat expansions
112
What are the repeat cutoffs for DMPK?
CTG expantion in DMPK = myotonic dystrophy type 1
Repeat in 3'UTR
\<35 = normal
35-50 = premutation
50 - mild
100 - classic
2000 - congenital
113
Repeat expansion in 5'UTR of DMPK more likely to expand in which parent?
Mother
114
3 ways to find repeat expansions
MLPA, southern blot, triplet primed PCR (PCR using repeat as a proble -\> result in ladder of different lengths)
115
What is FASTQ file?
**Initial output** of next-gen sequencing - Raw data + quality scores
1) sequence identifier
2) raw read
3) optional description
4) quality value
116
What is a BAM file?
Compressed FASTQ file from NGS -\> usually the one that is **saved/transported** because it can be decompressed into FASTQ
117
What is a VCF file?
Variant Call format
- Shows points where **sample is different from reference**
118
Totipotent vs Plauripotent cells
Toti can become anything -\> zygote/blastomere
Pluri can become many, but **not extra-embryonic membranes**
119
What is the different between chimera and mosiac?
Chimera started from 2 different zygotes, mosiac started as one
120
What tissues come from endoderm
cells that line the lumen -\> GI tract, Respiratory
121
What tissues come from ectoderm?
Skin and Nervous system
122
What tissues come from mesoderm
Blood, bone, connective, solid organs
- includes mesenchyme
123
What determines digit formation in embryogenesis?
SHH concentration and duration secreted by Zone of Polarizing Activity
124
Which period of embryogenes is most critical for strucutural malformation?
3-8 weeks. After that difference tend to cause cellular level changes
125
What is a deformation?
Abnormal shape/form caused by mechanical forces
- Normally formed first -\> usually changed in 3rd trimester
- Ie Twinning, Uterine issues, low amniotic fluid
126
Disruption vs deformation
Disruption -\> destruction of normal tissue due to external factor (ie viral infections, ischemia, amniotic band)
Deformation -\> Change in shape due to external factor
127
Dysplasia
Structural defect results from abnormal cellular organization/function
- often worse with age
128
Malformation
Morphologic defect due to abnormal intrinsic programming
- Often involves multiple tissue types
129
Malformation vs dysplasia
- Both intrinsic
- **Dysplasia = ongoing** -\> worse w/ age
- Malformation = 1 time hit
130
What is a complex?
Anomalies of several structures that lie in the same body region during embryonic develoment (developmental field)
- example: OEIS complex (omphalocele, extrophy, imperforate anus, spinal defects)
131
Short stature, webbed neck, low set ears, lymphedema
Noonan (hypertelorism, downslanting PFs, pulmonia stenosis)
or
Turner (Coarctation)
132
Slender tapered fingers, cleft palate, TOF, hypotonia, tubular nose
22q11 Del
133
What are the most common causes of Beckwith Weidemann Syndrome?
1) Loss of methylation in IC2 on maternal chromosome - normally repressed CDKN1C can be expressed (50%)
2) Paternal UPD 11p15.5 - CDKNiC expressed twice (20%)
2) Gain of methylation of IC1 on maternal chromosome - growth suppressor is suppressed (5%)
3) CDKN1C mutation (5%)
134
postnata growth deficiency, persistent fetal fingertip pads, ITP, hypodonita, lateral aversion of lower eyelids
Kabuki
KMT2D, KDM6A
135
Hemihypotrophy (limb length discrepancy), 5th finger clinodactyly, prominent forehead with small jaw
Russel Silver
136
Upper seg/Lower seg ratio \<0.85
Arm span/Height ratio \> 1.05
Elongated limbs relative to body
- Commony seen in Marfan
137
Deep set eyes, downslanting PF, dolichocepahly, malar hypoplasia, micro/retrognathia, high narrow palate, striae
Marfan
FBN1
138
What are the major diagnostic features of Marfan?
- Ectopia Lentis
- Aortic root dilation/dissection
- Systemic score
- FBN1 pathogenic variant
139
What medications should be avoided by Marfan patients?
Calcium channel blockers and fluoroquinolones - worsen dilation
140
Arachnodactyly, joint laxity, pectus, pes planus, club foot, malar hypoplasia, downslanting PF, micro/retrognathia, bifid uvula
Loeys Dietz
- TGFB pathway
- **Club feet, bifid uvula, hypertelorism, arterial tortuosity, aneurysms** are not seen in Marfan
- **no** ectopia lentis
141
What is the most common connective tissue disease?
Hypermobile EDS
- Beighton score \>5
- Skeletal features or family history
- Rule out alternatives
142
Match each skin findings wtih EDS type
1) atrophic, widened scar
2) papyraceious (cigarette paper) hemosideric scar
3) thin translucent skin
4) hyperextensible skin with abnormal wound healing
5) mollusocoid pseudotumor
1) atrophic, widened scar - hypermobile
2) papyraceious (cigarette paper) hemosideric scar - classic
3) thin translucent skin - Vascular
4) hyperextensible skin with abnormal wound healing - Classic
5) mollusocoid pseudotumor - Classic
143
What type of error occurs due to advanced maternal age?
Meiosis I errors
- Meiosis I arrested at **dictyotene of prophase 1** from 5 months of embyonic development until ovulation
144
What maternal illnesses increase risk for fetal anomalies?
Diabetes, autoimmune disorders, early viral illness
145
Macrocephaly, hypertelorism, overgrowth, synophrys, palmar/plantar pits, odontogenic keratocysts, BCC, ectopic calcifications, polydactyly
Gorlin
PTCH tumor suppressor (part of SHH pathway)
- Also increased risk for medulloblastoma (**avoid radiation**), rhabdomyomas, and ovairan fibromas
146
Tiger banded hair
Trichothiodystrophy
147
What are key feaures of PTEN disorders?
Macrocephaly, Autism, Hamartomaous skin/breast, thyroid, mucusal lesions, Cancer risk
Cowden: Papillomas, Breast/Gyn/Thyroid Ca, lipoma
BRR: Penis freckline, thyroid/breast ca
148
What is the function of PTEN?
Tumor suppressor gene
- Part of PI3K, AKT, mTOR pathway
149
Most common AD ichthyosis
Filaggrin
- Incomplete Dominant
- 7.7% of europeans
- Ichthyosis, also atopic dermatitis
150
Dark, scaly, tightly adherent skin most prominent on externsor surfaces and neck
+ Corneal opacities, cryptorchidism
Maternal E3 absent
Steroid Sulfatase Deficiency
AKA: Arylsultafase C
- Abnormal cholesterol sulfate levels
-
151
Keratitis, Ichthyosis, Deafness, SCC
KID syndrome
Connexin 26 (GJB2)
- Missense variants
152
Palmar-plantar hyperketaosis, nail dystrophy, alopecia, joint hyperpigmentation
Hidrotic ectodermal dysplaia
GJB6 - connexin 30 missense variants (AD)
Ectodermal dysplasia with **normal sweating and teeth**
153
Hypotrichosis, anhidrosis, conical/pegged teetch, eczema, periorbital hyperpigmentation, absent dermal ridges
Hypohidrotic ectodermal dysplasia
EDA1 (XL), EDAR (AR)
- No Sweat - avoid fevers!
154
Split hand/feet, polysyndactyly, hypotrichosis, anodontia, hypohidrosis, pitted nails, cleft L/P, Blepharitis, Keratisis
Ectrodacylty-Ectodermal Dysplasia-Clefting syndrome
TP63 (AD)
155
ichthyosis, spastic tetraplegia, **glistening white dots in retina**, leukodystrophy
- high leukotriene B4 in urine
Sjorgren Larsson
ALDH3A2 (AR)
Fatty aldehyde dehydrogenase
156
What is the most common α1-Antitrypsin Deficiency allel?
Pi\*Z (Glu342Lys)
- Homozygotes -\>Dimerization -\> aggregate in liver (cirrhosis), insufficient in lungs (lower lobe emphysema)
157
What is the most common fatal AR disorder in whites?
Cystic Fibrosis
CFTR
1/25 carriers
158
What does ivacaftor do?
Potentiates CFTR channel
- Not useful as monotherapy for 508delF (mislocalization)
159
What does lumacaftor do?
Improved localization of mutant CFTR
- Used in combo with ivafactor for 508delF
160
Pulmonary fibrosis, albinism, granulomatous colitis, bleeding diathesis
Hermansky Pudluck
HPS1-9 (AR)
Pale Bleeding Puerto Rican
+ pulmonary fibrosis, colitis, skin ca
161
187delAG
5285insC
5946delT
999del5
156\_157insAlu
Hereditary Breast and Ovarian Ca founder mutations
187delAG (BRCA1 - Ashkenazi Jew)
5285insC (BRCA1 -Ashkenazi Jew)
5946delT (BRCA2 - Ashkenazi Jew)
999del5 (BRCA2 - Iceland)
156\_157insAlu (BRCA2 - Portuguese)
162
PALB2
High risk breast ca gene
- 50% lifetime risk
+ pancreatic, ovarian, male breast Ca
- **no melanoma** (seen in BRCA)
163
60% lifetime risk of lobular breast cancer
80% diffuse gastric cancer
CDH1
Hereditary diffuse gastric cancer
164
Breast, Renal, Follicular thyroid, uterine cancer + autism
Cowden
PTEN- Hamartoma syndrome
165
Breast, Brain, choroid plexus, adrenal, and GI cancers + sarcomas
LI Fraumeni
TP53
166
Name 3 moderate risk breast Ca genes
ATM - also pancreatic; + ataxia/telangiectasia
CHEK2 - also colon ca
NF1 - neurofibromatosis
167
Screening in Lynch Syndrome
Colonoscopy q1-2yrs - start at 20 or 5 yrs before earliest diagnosis in family
EGD q3-5 yrs - start at 40 or 5 yrs before earliest in family
168
How does APC work?
Tumor suppressor in WNT signaling pathway
169
Screening for FAP
APC gene
- Colonoscopy at age 10 (Colectomy when adenoma burden cannot be managed by polypectomy)
- EGD at 25
**- Thyroid US annually in teens**
**- AFP/U/S for hepatoblastoma q6 months until age 7**
170
Small bowel obstruction, intussusception, pigmentation around lips, hands/feet
Peutz Jagher
STK11
- **Hamartomatous polyps**
171
Non-medullary thyroid, breast, endometrial cancer
## Footnote
**Cerebelar dysplastic ganglicytoma**
Cowden
PTEN
+ Macrocephaly, ID, hamartomas
172
Management of MEN syndromes
- Prophylactic thyroidectomy
- Annual Pheo screening, and before any surgery (MEN2)
173
Ovarian Sex-cord stromal tumors, pleuropulmonary blastoma, thyroid tumors
DICER1
174
Fibrofolliculomas, lung cysts, renal cancer
Birt-Hogg-Dube
FLCN (folliculin) - AD w/ incompelte penetrance
+ angiofibromas, spontaneous pneumothorax
175
Renal cell carinoma, Leiomyomatosis (fibroids)
Fumarase deficiency
Heterozygotes: RCC + fibroids
- Homozygotes get fumaric aciduria, encephalopathy, FTT, seizures
176
What is the most common gene associated with anophthalmia?
SOX2
- Transcription factor that also interacts with PAX6 (aniridia)
- May be associated with learning disablity, CNS malformations, SNHL
177
What are the 4 major criteria for CHARGE syndrome?
All in head (Eye, nose, cranial nerve, ear)
1) Ocular coloboma
2) Choanal Atresia
3) Cranial nerve dysfunction
4) Ear changes
178
What is the difference between type 1, 2, and 3 usher syndrome?
I: Hearing loss (congenital **severe**), **Vestibular areflexia, early RP**
II: Hearing loss (congenital moderate/severe), **normal vestibular function**, RP
III: Hearing loss (**Progressive**), sporadic vestibular function, variable RP
179
How do you tell part a head shape deformity from craniosynostosis?
In deformity ears are the **same height from the back**, but different from the top
In craniosynostisis ears are different height from back and top
180
What suture is most commonly affected in nonsyndromic craniosynostosis?
Saggital: 50-60%
Coronal: 20-30%
181
craniosynostosis with toes pointing inward
Pfeiffer
182
Craniosynostosis with toes pointing outward
Saethre-Chotzen
TWIST1
183
brachycephaly, downslanting PF, proptosis, high arched palate, fused digits
Apert syndrome
FGFR2
- Brachycephaly due to bicoronal craniosynostosis
184
Cloverleaf skull, broad thumbs/toes
Pfeiffer Syndrome
FGFR2
- Cloverleaf = pansynostosis
185
Craniosynostosis with normal hands/feet
Crouzon
FGFR2
186
Craniosynostosis with fused tarsal/carpal bones
Muenke
FGFR3
Most common syndromic craniosynostosis
187
brachycephaly, hypertelorism with downslanting PF, grooved nasal tip and broad nasal root, short stature
Craniofrontonasal syndrome
EFBN1 -\> efrin
- X-Linked w/ cellular interference
- Females more affected than males
188
Which parent of origin do de novo FGFR craniosynostosis come from?
Almost exclusive paternal
189
What caues trigonocephaly?
metopic craniosynostosis
190
What does coronal synostosis look like?
Brachycephaly (bilateral)
Anterior plagiocephaly (unilateral)
191
What causes posterior plagiocephay?
Lambdoid craniosynostosis
192
What causes scaphocephaly (dolicocephaly)
Sagittal Craniosynostosis
193
Most common monogenic causes of holoprosencephaly
1) SHH
2) ZIC2
3) SIX3 and TGIF
194
What group of metabolic diseases commonly cause hearing loss?
MPS, biotinidase
195
hearing loss + RP
Usher, cockayne, Refsum
196
Hearing loss + goiter
Pendred (SLC26A4)
197
Hearing loss + Long QT
Jervell and Lange Nielen
KCNQ1, KCNE1, SCN5A
198
Hearing loss + albinism
Waardenburg (PAX3)
199
Hearing loss + renal disease
Branchial-oto-reno syndrome (EYA1)
Alport (COL4)
200
Hearing loss + skeletal findings
Stickler (COL 2, 9, 11)
Osteogenesis imperfecta (COL 1)
201
Most frequent causes of nonsyndromic genetic deafness
GJB2 (connexin 26) - AR
GJB6 (Connexin 30)
202
Genetic causes of adult onset deafness
Pendred syndrome (SLC26A4)
Aminoglycoside toxicity (mtA1555G) -12SrRNA
203
12SrRNA
mtA1555G
Aminoglycoside ototoxicity
204
All cardiac valves thickened w/ nodularity of leaflets, Coarctation of the Aorta
Trisomy 18
polyvalvular dysplasia
205
Branched pulmonary artery stenosis, supravalvular AS
Williams syndrome
7q11 del
206
Complete AV canal, TOF
Down syndrome
Trisomy 21
207
All cardiac valves thickened w/ nodularity of leaflets, Arch hypoplasia
Trisomy 13
Polyvalvar dysplasia
208
Coarctation of aorta, hypoplasic L heart, anomalous pulmonary venous return, Bicuspid AV
Turner Syndrome
209
TOF, interrupted aortic arch, truncus arteriosis, pulmonary atresia
22q11
Conotruncal defects
210
Peripheral pulmonic stenosis, coarctation of the aorta
Alagile syndrome (Jag1, Notch 2)
211
ASD, VSD, conduction abnormalities, triphalangeal thumb
Holt Oram
TBX5
- Upper limb + strucutural heart defect + conduction defect
212
Pulmonic stenosis, AV valve thickening, hypertrophic cardiomyopathy
Noonan
213
family history of **sudden death during sleep** or during fevers, nocturnal breathing, seizures, ventricular arrhythmias
Brugada syndrome
SCN5A LOF
214
KCNQ2, KCNH2, SCN5A GOF
AD - romano ward - long QT
AR - Jervell and Lange Nielsen - Long QT + SNHL
215
What is the significance of MYH7 and MYBPC3?
Account for 80% of familial hypertrophic cardiomyopathy
- part of sarcomeric contractile apparatus
216
LMNA, TTN
Familial dilated cardiomyopathy genes
217
What is the most common severe neuromuscular disease of infancy?
SMA
Carrier frequency 1/40
218
How do you distinguish types of SMA?
Type 0 - never flip/crawl
Type 1 - never sit
Type 2 - never stand
Type 3 - never walk
Type 4 - walk
219
Vaginal atresia, craniosynostosis, choanal atresia, camptodactyly, renal anomlies
- **Maternal virizliation during pregnancy**
Antley bixler
POR
220
Vaginal atresia, RP, postaxial polydactyly, obesity, DD , hypogonadism
Bardel Biedl
Ciliopathy
221
Vaginal atresia, enlarge clitoris and labia, cryptophthalmia, syndactyly, renal agenesis
Fraser syndrome
FRAS1, GRIP1, FREM2
222
Postaxial polydactyly, CHD, hydrometrocolpos
McKusick-Kaufman Syndrome
MKKS (AR)
Ciliopathy
223
Primary ovarian insufficiency + family hx tremor/ataxia
FMR1 related POI
POI = Premature ovarian failure
55-200 repeats, CGG 5' UTR
224
Primary ovarian insufficiency, low posterior hairline, short stature
Turner syndrome
45X, isoXq, mosaic
- may have delayed breast development/menarche
225
Primary ovarian insufficiency, liver disease, impaired executive function, speech apraxia
Classic Galactosemia
GALT
- especially Q188R/Q188R
226
2nd most common Ca in Lynch syndrome
Colon 80%
**Endometrial (60% lifetime risk)**
Stomach 13%
Ovarian 12%
227
Macrocephaly, pipillomatous papules, trichilemmommas
+ what is risk of GYN cancer?
Cowden
PTEN
Breast CA 50%
Thyroid Ca 10%
Endometrial Ca 10%
228
Besides GI hamartomas, what cancers are seen in Peutz-Jegher sydnrome?
STK11
- Breast Ca 54%
- Colon 39%
Pancreatic 36%
Stomach 29%
Ovarian 21%
229
What do you need to look for in adults with a pathogenic variant in Fumarate Hydratase?
Leiomyomas and Renal Cell Carcinoma
230
At what age should pubic bone be 1/2 mark between head and feet?
age 9
231
Proportiate at birgh -\> short limbs
Flat beaked vertebra
Arthritis
Small irregular epiphysis
Genu Valgus and varus
Pseudoachondroplasia
COMP (AD)
- Genu valgus and varus = windswept
- Normal at birth
232
Cauliflower ear, hitchhiker thumb, club foot, short, broad fingers w/ ulner deviation
Distrophic Dysplasia
DTDST -\> Sulfate transporter
- Deplete intracellular sulfate -\> softer cartilage/coarse collagen fibers
233
High urine phosphoethanolamine, pyrophosphate, and pyridoxal 5 phosphate
Low alk phos
Hypophosphatasia
TNSALP
- early fractures, poor heaing, osteoporosis, tooth loss, rickets
ERT: Asfotase alpha
Avoid bisphosphonates
234
What is asfotase alfa used to treat?
ERT for hypophosphatasia
TNSALP
235
meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, **juvenile cortical cataract**
NF2
Merlin
+ vestibular schwanomma, \<6 CALS
236
4 stages of incontinentia pigmenti
Blistering -\> verrucous -\> Hyperpigmented -\> hypopigmented
IKBKG/NEMO gene (XL)
- regulates NFkB
237
GAA repeat expantion
Mitochondrial iron metabolism
Friedreich's ataxia
FXN (frataxin) - AR (**only AR repeat expansion**)
Spasticity, ataxia, cardiomyopathy, deafness
238
Which SCAs are caused by CAG repeats?
What about CTG?
CAG: 1, 2, 3, 6. 7, 17
CTG: 8
239
Connective tissue dysfunction, macrocephaly, prominent ears, post pubertal macro-orchidism, DD
Fragile X
240
Hyperintense signal in cerebellum (**middle cerebellar peduncle sign**), neuropathy, ataxia, parkinsonism, tremor
Fragile X tremor-ataxia syndrome
RNA toxic GOF
241
agenesis of the corpus callosum, chorioretinal lacune, infantile spasms, upturned nose, prominent premaxilla, sparse lateral eyebrows
Aicardi Syndrome
XL -\> **Male lethal**
242
GNAQ mosiac gain of function
Sturge Weber syndrome
Quanine nucleotide binding protein (GNAQ) -\> sporadic
- Port wine stain, abnormal cerebral vasculature, seizures
243
pectoralist hypoplasia
Poland anomaly
Male \> Female
Right \> Left
244
Thrombocytopenia, absent radius
Thombocytopenia, absent radius syndrome
RMB8A
- **thumb preserved**
245
Anal atresia, thumb anomalies, ear anomalies
Towns Brock
SALL1 (AD)
246
Triphalangeal thumb, VSD, conduction defect
Hold Oram
TBX5 (AD)
Thumb can be absent, small, or triphalangeal
- Lower ext normal
247
downslanting PF, convex nasal ridge, long columella, angulated/broad thumbs/halluces
Rubenstein Taybi
CREBBP, EP300 (AD)
248
Name 2 GLI3 syndromes
Pallister Hall - AR - Polydacylty, hypothalamic hamartoma, bifid epiglottis,
Greig cephalopolysyndactyly - AD - Preaxial polydactyly, macrocephaly, hypertelorism, board nasal root
249
Central/postaxial polydactyly, hypothalamic hamartoma, bifid epiglottis, laryngeal cleft, pulmonary segmental anomalies
Pallister Hall
GLI3 - AR
250
CAG repeat in androgen receptor gene
SBMA
XL
\>38 = pathogenic
35-37 = reduced penetrance
\<34 = normal
251
What are Ataluren, Eteplirsen, Golodirsen, and Viltolarsen used for?
DMD treatment
Ataluren = stop codon read through
Golodirsen/Viltolarsen = exon 53 skipping
Eteplirsen = exon 51 skipping
- Also steroids might help
252
What are the cutoffs for symptomatic myotonic dystrophy patients?
Type 1 - CTG in 3" UTR of DMPK - **50 = mild**
Type 2 - CCTG in intron of ZNF9 - **75 = pathogenic**
253
How do nusinersen, resdiplam, and onasemnogene abeparvovec work?
SMA treatment
Nusinersen = ASO to normalize SMN2 splicing
Risdipal = small molecule (PO) that normalize SMN2 splicing
Onasemnogene abeparvovec = AA9 SMN1 repalcement
