Genes and genetic mechanisms Flashcards
1
Q
What are the causes (percentages) of RSS?
A
11p15.5 / chr 7 regions
missing paternal or paternal variant
35-50% imprinting defect of 11p15.5
10% maternal UPD 7
rare del/dup
rare sequence CDKN1C or IGF2
2
Q
What is the most common cause of RSS?
A
imprinting defect of 11p15.5
3
Q
What are the causes (percentages) of PWS?
A
15q11.2-13 region
missing paternal or paternal variant
70% deletion
25% mat UPD
<1% imprinting defect
4
Q
What are the causes (percentages) of BWS?
A
11p15.5 region
missing maternal or maternal variant
55% imprinting defect
20% pat UPD
10% CDKN1C variant
10% del/dup
5
Q
What are the causes (percentages) of Angelman syndrome?
A
15q11.2-q13 region
missing maternal or maternal variant
70% deletion
11% UBE3A variant
5% pat UPD
4% imprinting defect
6
Q
What is the most common cause of PWS?
A
deletion of 15q11.2-13 region
7
Q
What is the most common cause of BWS?
A
imprinting defect of 11p15.5 region
8
Q
What is the most common cause of Angelman syndrome?
A
deletion of 15q11.2-13 region t
9
Q
What are normal, intermediate, premutation, and full mutation sizes for FMR1 related disorders?
A
6-44 normal
45-54 intermediate
55-200 pre
>200 full
10
Q
What type of repeat is seen in FMR1 related disorders?
A
CGG repeats
Can’t Go Golfiing
AGG repeats affect stability
11
Q
What are normal, intermediate, reduced penetrance, and full mutation sizes for Huntington’s disease?
A
10-26 normal
27-35 intermediate
36-39 reduced penetrance
>40 full penetrance
12
Q
What type of repeat is seen in Huntington’s disease?
A
CAG
Chorea And Grumpy
13
Q
What are normal, premutation, and full mutation sizes for Fredreich’s ataxia?
A
5-33 normal
34-65 premutation
66-1300 full
usually 600-1200
14
Q
What type of repeat is seen in Fredreich’s ataxia?
A
GAA
Gait AtaxiA
15
Q
What are normal, premutation, intermediate, and full mutation sizes for Myotonic dystrophy type 2?
A
<30 normal if uninterrupted
11-26 normal if interrupted
30-54 premutation
55-74 intermediate
75-11000 full
16
Q
What type of repeats in what gene cause Myotonic dystrophy type 2?
A
CCTG repeats in CNBP
Cx2- Can’t Touch Grip
17
Q
What are normal, mild, classic, and congenital mutation sizes for Myotonic dystrophy type 1?
A
35-49 normal
50-150 mild
100-1000 classic
>1000 congenital
18
Q
What type of repeats in what gene cause Myotonic dystrophy type 1?
A
CTG repeats in DMPK
Can’t Touch Grip
19
Q
What type of repeats in what gene cause SCA type 1?
A
CAG repeats (same as HD) in ATXN1
20
Q
What chromosome deletion causes Cri du Chat?
A
5p
80-90% terminal deletions
21
Q
Is cri du chat usually paternal or maternal in origin?
A
80-90% paternal
22
Q
What chromosome deletion causes Wolf hirschhorn?
A
4p
23
Q
How often is 22q deletion syndrome inherited?
A
90% de novo 10% inherited
24
Q
What deletion can cause Sotos syndrome? What population is more likely to be affected by Sotos caused by deletion vs a single gene cause?
A
5q35 deletion
Japanese
25
What gene is involved with the skin findings for William's syndrome?
ELN, also causes AD cutis laxa
26
What gene is involved with tertology or fallot in 22q deletion syndrome?
TBX1
27
What gene causes acute intermittent porphyria?
HMBS
28
What condition is associated with HMBS?
acute intermittent porphyria
29
What is the penetrance of acute intermittent porphyria?
extremely low 0.5-1%
30
What is the cause of adrenal hypoplasia congenita?
NR0B1 - XL
or Xp21 deletion
31
What condition is associated with NR0B1?
adrenal hypoplasia congenita
32
What gene causes androgen insensitivity syndrome?
AR gene- XL
33
What condition is associated with the AR gene?
androgen insensitivity syndrome
34
What is the genetic cause of McCune Albright?
somatic mutation in GNAS
35
What can somatic mutations in GNAS cause?
Mccune albright
36
What is the common HFE variant of reduced penetrance?
p.Cys282Tyr
His63Asp also common
37
What is the penetrance for male homozygote HFE p.cys282tyr?
low 28% men
(1% women)
38
What is the penetrance for men with compound heterozygote HFE mutations: Cy282Tyr and His63Asp?
extremely low 0.5-2%
39
What is the carrier frequency for the two common HFE variants in European populations?
1/3 carrier of either Cys282Tyr
or His63Asp
40
What variant in the F5 gene causes Factor V Leiden?
c.1691G>A
(AR)
41
What gene causes Hemophilia A?
F8 (XL)
42
What are genetic causes of hemophilia A?
F8 gene - XL
43-51% sequence
48% inversions of exons 1 and 22
43
What gene causes Hemophilia B?
F9 (XL)
44
What are possible genotypes for someone with beta thal trait?
B/ B0
B/ B+
45
What are possible genotypes for someone with beta thal intermedia?
B+/ B+
B+ / B0
some residual activity, no full functioning B
46
What is the possible genotype for silent carrier of alpha thal?
xHBA1 / HBA1
+
HBA2/HBA2
47
What are possible genotypes for someone with alpha thal trait?
xHBA1 / HBA1
+
xHBA2 / HBA2
or
xHBA1 / xHBA1
HBA2 / HBA2
two mutations total!
48
What is a possible genotype for someone with HbH disease?
three mutations total
xHBA1 / xHBA1
+
xHBA2 / HBA2
49
What is the genotype for someone with Hb Barts disease?
mutations in all 4
xHBA1 / xHBA1
+
xHBA2 / xHBA2
50
What mutation cause Sickle cell anemia?
HBB p.glu6Val
p.6146
51
What gene causes alpha thal ID syndrome?
ATRX (XL)
52
What condition does the ATRX gene cause?
alpha thal ID syndrome
53
What gene causes MPS1?
IDUA (AR)
Hurler/Schaie
54
What condition is associated with the IDUA gene?
Hurler MPS1
55
What gene causes MPSII?
IDS (XL)
Hunter
56
What condition is associated with the IDS gene?
MPSII Hunter
57
What gene causes MPSIII?
58
What is the most common gene associated with Zellwegger spectrum?
PEX1
59
What condition is associated with the GALT gene?
Galactosemia (AR)
60
What gene causes Galactosemia?
GALT
61
What condition is associated with the GAA gene?
Pompe disease
62
What gene causes Pompe disease?
GAA (AR)
63
What condition is associated with the ACADM gene?
MCAD
64
What gene causes MCAD?
ACADM (AR)
65
What condition is associated with the ACADVL gene?
VLCAD
66
What gene causes VLCAD?
ACADVL (AR)
67
What gene causes PKU?
PAH (AR)
68
What condition is associated with the GLA gene?
Fabry disease
69
What gene causes Fabry disease?
GLA (XL)
70
What condition is associated with the GALC gene?
Krabbe
71
What gene causes Krabbe disease?
GALC (AR)
72
What condition is associated with the GBA gene?
Gaucher
73
What gene causes Gaucher disease?
GBA (AR)
74
What condition is associated with the GCDH gene?
Glutaric acidemia type 1
75
What condition is associated with the BTD gene?
biotinidase deficiency
76
What gene causes biotinidase deficiency?
BTD (AR)
77
What condition is associated with the FGD1 gene?
Aarskogg
78
What gene causes Aarskogg syndrome?
FGD1 (XL)
79
What condition is associated with the RPS6KA3 gene?
Coffin Lowry
80
What gene causes Coffin Lowry syndrome?
RPS6KA3 (XL)
2/3 de novo
81
What condition is associated with the NIPBL gene?
Cornelia de Lange
82
What gene is the most common cause of Cornelia de Lange ?
NIPBL (AD)
80% of genetic causes
83
What gene is the most common cause of Leigh syndrome?
MT-ATP6 (m)
84
What is the most common variant causing MELAS?
MT-TL1 m.3243A>G
80%
85
What condition is associated with the MT-TL1 m.3243A>G variant?
MELAS
86
What is the most common gene associated with MERRE?
MT-TK
87
What condition is associated with the EYA1 gene?
branchiootorenal syndrome
88
What is the most common gene associated with branchiootorenal syndrome?
EYA1 (AD) - 40%
also SIX1 and SIX 5
89
What deletion syndrome is associated with aniridia?
11p13 deletion including PAX6 and WT1
90
What condition is associated with 11p13 deletions?
WAGR syndrome - WT and aniridia
91
What condition is associated with 17p13.3 deletion?
Miller dieker lissencephaly
92
What is the genetic cause of Miller Dieker lissencephaly?
17p13.3 deletion syndrome including PAFAH1B1- lissencephaly/subcortical band heteropia
YWHAE
93
What is the genetic cause of lissencephaly in Miller Dieker syndrome?
PAFAH1B1 gene (formally LIS1)
94
What condition is associated with 22q13.3 deletion?
Phelan Mcdermid, including SHANK3
95
What is the genetic cause of Phelan Mcdermid syndrome?
22q13.3 deletion syndrome
or mutations in SHANK3
96
What condition are indviduaals with Phelan Mcdermid caused by a ring chromosome also at risk for?
NF2 due to ring chromosome 22
97
What condition is associated with the CREBBP gene?
Rubinstein Taybi
98
What is the genetic cause of Rubinstein Taybi syndrome?
CREBBP (50-60%) - 20% del/dup
EP300 (10-20%)
unknown in 30%
(AD)
99
What condition is associated with the RAI1 gene?
Smith magenis
100
What is the genetic cause of Smith Magenis syndrome?
RAI1 or 17p11.2 deletion
-sequence 5-10%
-del 90-95%
101
What condition is associated with a 17p11.2 deletion?
Smith Magenis syndrome
can also include FLCN ---> BHD
102
What condition is associated with the OFD1 gene?
oro facial digital type 1
103
What is the genetic cause of oro facial digital type 1 syndrome?
OFD1 (XLD, male lethal)
Xp22.2
104
What is the de novo rate for achondroplasia?
80% de novo FGFR3
105
What condition is associated with the RUNX2 gene?
cleidocranial dysplasia
106
What is the genetic cause of cleidocranial dysplasia?
RUNX2 (AD)
sequence 70-80%, del 15%
107
What conditions are associated with the FGFR2 gene?
Apert
Beare Stevenson
Bent bone
Crouzon
Jackson Weiss
Pfeiffer >95%
108
What conditions are associated with the FGFR1 gene?
Pfieffer <5%
Jackson Weiss ??
109
What conditions are associated with the FGFR3 gene?
Achondroplasia
Hypochondroplasia
Crouzon with AN
Muenke
110
What is the genetic cause of Apert syndrome?
FGFR2
111
What is the genetic cause of Beare Stevenson syndrome?
FGFR2
112
What is the genetic cause of Bent bone dysplasia syndrome?
FGFR2
113
What is the genetic cause of Crouzon syndrome?
FGFR2
114
What is the genetic cause of Crouzon syndrome with acanthosis nigricians?
FGFR3
115
What is the genetic cause of Jackson Weiss syndrome?
FGFR2 (maybe FGFR1?)
116
What is the genetic cause of Muenke syndrome?
FGFR3
117
What is the genetic cause of Pfeiffer syndrome?
FGFR2 95%
FGFR1 5%
118
What is the genetic cause of Osteogenesis imperfecta?
COL1A1
COL1A2
119
What condition is associated with the COL1A1 gene?
OI
120
What condition is associated with the COL1A2 gene?
OI
121
What percent of TSC is due to TSC1 or TSC2 genetic causes?
26% TSC1
69% TSC2 - more severe, higher de novo
5% unknown
122
What is an XL cause of hypohidrotic ectodermal dysplasia?
EDA (XL)
123
What are the genetic causes of oculocutaneous albinism 1, 2, and 3?
TYR--> OCA1
OCA2 --> OCA2
TYRP --> OCA3
124
What genetic cause of OCA2 is most common in African populations?
OCA2 deletion of exon 7
125
What is the most common type of pathogenic variant in NF1?
severe truncating
126
What is the molecular activity of the neurofibromin protein?
neurofibromin activate RAS GTPase
- is a tumor suppressor and controls cell proliferation
127
What is distinctive of 25-50% of NF2 de novo variants?
25-50% are mosaic - may need to test other tissues
128
What types of NF2 variants lead to mild vs severe disease?
Mild: large deletions, no ID associated
Severe: nonsense and frameshift
129
What genes are associated with schwannomatosis?
LZTR1 50%
SMARCB1 60%
130
What is the genetic cause of incontinentia pigmenti syndrome?
IKBKG (XL, males often miscarry)
131
What are the most common normal and pathogenic variants in SERPINA1?
Alpha 1 antitrypsin
*M most common normal
*Z most common pathogenic
132
What is the likely genotype for a male with isolated congenital absence of the vas deferens and two CFTR variants?
1 severe LOF CFTR
+
1 non CF causing variants
OR
2 non CF causing variants
133
What is the location of the CFTR gene?
7q31.2
134
What type of CFTR variants may not be picked up on WES?
deep intronic variants
135
What is the most common CFTR variant in Northern European populations?
Phe500del
-founder variants for AJ and Amish
136
What lengths of the poly T tract for CFTR are benign or penetrant?
7 and 9 T- benign
5T variably penetrant
-decreases efficiency or intron 8 splicing
--> 50% of full length CFTR produced
137
What lengths of the poly TG tract for CFTR further decrease the amount of full protein produced?
modulate for individuals with 5 T allele
longer TG (12 or 13) + short T (5T)
--> reduction of full length CFTR to 25%
138
What is the genetic cause of BPES syndrome?
FOXL2 (AD)
139
What condition is associated with the FOXL2 gene?
BPES
140
What gene associated with Leber congenital amaurosis has a gene therapy?
RPE65
141
What type of GJB2 variants are associated with mild vs profound hearing loss?
truncating/ truncating: most likely profound
non truncating/ non truncating: most likely mild
142
In addition to AR hearing loss, what other conditions are associated with GJB2?
palmoplantar keratosis with deafness keratitis icthyosis
143
What is the GJB2 carrier rare in European populations?
2-4%
7.5% AJ c.167del%
144
What are the most common genetic causes of Hermansky Pudlak in Puerto rican popylations?
80% HPS1 duplication
20% HPS3 deletion
145
What are possible genetic causes of Pendred syndrome?
biallelic SCL26A4
OR
one SLC26A4
+
one FOXI1 or KCNJ10
146
What are the three most common mutations associated with Leber hereditary optic neuropathy ?
MT-ND1 m.3460G>A
MT-ND4 m.11778G>A (60-70% european affected)
MT-ND6 m.14484T>C (french canadian variant)
147
What mutation associated with Leber hereditary optic neuropathy has the best long term visual outcome?
MT-ND4 m.11778G>A
148
What is the penetrance of Leber hereditary optic neuropathy in males and females?
males 50%
females 10%
149
What is the genetic cause of Waardenburg syndrome type 1?
PAX3 (AD)
also caused WS3
150
What condition is associated with the PAX3 gene?
Waardenburg syndrome type 1 and 3
151
What is the genetic cause of Alagille syndrome?
JAG1 90-94%
NOTCH2 2%
50-70% de novo
152
What is the genetic cause of Brugada syndrome?
SCN5A LOF 30%
unknown 65%
rarely KCEN5- XL
153
What condition is associated with SCN5A mutations?
LOF- Brugada
GOF- LQT type 3
154
What is the genetic cause of HHT ?
ACVRL1 52%
ENG 44%
SMAD 1%
unknown 3%
155
What condition is associated with ACVRL1?
HHT
156
What is the genetic cause of Holt Oram syndrome?
TBX5 (AD)
85% de novo
157
What condition is associated with the TBX5 gene?
Holt oram
158
What are the genetic causes of Usher syndrome type 1?
MYO7A 53-70%
CDH23 10-20%
other USH genes
unknown 10-15%
159
What are the genetic causes of Usher syndrome type 2?
USH2A 55-80%
ADGRV1 6-20%
160
What condition is associated with the MYO7A gene?
Usher syndrome type 1
161
What is the genetic cause of Stickler syndrome?
COL2A1 80-90%
usually a premature stop codon
COL11A1 10-20%
AD or AR
162
Which genetic cause of Stickler syndrome is associated with more severe hearing loss?
COL11A1 mutations > COL2A1
163
What is the genetic cause of Simpson Golabi Behmel syndrome?
GPC3 - 55% sequence, 43% del
(XL)
164
What is the genetic cause of Costello syndrome?
HRAS
165
What condition is associated with germline mutations in HRAS?
Costello
166
What is the genetic cause of Noonan syndrome?
PTPN11 50% (AD)
SOS1 10-13% (AD)
LZTR1 8% (AR)
167
What additional exam should be considered in individuals with PTPN11 or KRAS associated Noonan syndrome?
physical exam to assess for spleen size and CBC every 3- 6 months until age 5 to risk for JMML/ malignancy
168
What is the genetic cause of Noonan syndrome with multiple lentigines?
PTPN11 95%
RAF1 <3%
169
What is the genetic cause of Cardiofaciocutaneous syndrome?
BRAF 75%
25% MAP2K1 and MAP2K2
170
What conditions are associated with germline mutations in BRAF? which is most common?
Noonan, NSML, *CFC*
171
What is the genetic cause of LQTS types 1, 2, 3?
Type 1: KCNQ1- LOF
Type 2: KCNH2 - LOF
Type 3: SCN5A -GOF
172
What condition is associated with mutations in KCNQ1?
LQTS1
AR Jervell Lange Nielson (also KCNE1)
173
What condition is associated with mutations in KCNH2?
LQTS2
174
What are the most common genes associated with non-syndromic HCM?
MYPBC3 50%
MYH7 33%
175
What are the most common known genes associated with non-syndromic DCM?
TTN 15-20%
LMNA 6%
176
What is the most common genetic cause of CMT?
PMP22 duplication at 17p11.2
type 1a, up to 50% of all CMT
177
What condition is associated with a 17p11.2 duplication?
CMT
178
What proportion of DMD is caused by a pathogenic deletion?
65-80%
sequence variants 20-35%
179
What are the most common genes associated with nemaline myopathies?
ACTA1 and NEB
180
What percent of the population has two copies of the SMN1 gene on one chromosome?
5-8%
-especially saharan African population
181
What condition is associated with the FH gene?
hereditary leiomyomastosis and renal cell carcinoma syndrome (AD)
fumarate deficiency (AR)
182
What is the genetic cause of HLRCC?
FH (AD)
-biallelic causes fumarate hydratase deficiency
183
What is the genetic cause of nevoid basal cell carcinoma syndrome?
PTCH1 (most)
SUFU 6%
184
What genetic cause of nevoid basal cell carcinoma syndrome is associated with an increased risk for medulloblastoma?
SUFU- 33% vs 5%
185
What are the de novo rates for MEN2A and MEN2B?
MEN2A <5%
MEN2B 50%
186
What is the most common genetic cause of MEN2B?
RET p.Met918Thr
187
What region of the APC gene is more likely to have mutations associated with attenuated FAP?
5' end
also 3' end
188
What is the result of biallelic variants in VHL?
biallelic variants
--> retention of cryptic exon 11
--> familial erythrocytosis 2 (no VHL type tumors)
189
What is the Brazilian founder mutation in TP53?
p.Arg337His
190
What is the genetic cause of XL Fanconi anemia?
FANCB
191
What is the genetic cause of CADASIL?
NOTCH3 (AD)
de novo rare
192
What are the most common genetic causes of early onset familial Alzheimer's disease?
PSEN1 20-70%
APP 10-15%
PSEN2 5% -reduced penetrance
unknown 20-40%
193
What is the genetic cause of FSHD?
pathogenic contraction at D4Z4 subtelomeric region at 4q35 on a permissive haplotype
194
Hypermethylation in what genes causes 5% of FSHD (type 2)?
SMCHD1
DNMT3B
10-30% de novo
195
What is a normal allele size in the D4Z4 region causing FSHD?
normal >=12
or any number or a non-permissive haplotype
<=9 full penetrance for FSHD
196
What is the genetic cause of Wilson disease?
ATP7B (AR)
197
What condition is associated with the ATP7B gene?
Wilson disease
198
What is the genetic cause of Menkes disease?
ATP7A (XL)
199
What condition is associated with the ATP7A gene?
Menkes disease
200
What is the genetic cause of Alport syndrome?
COL4A5 (XL) 80-85%
COL4A3 (AD or AR) 12-15%
COL4A4 (AD or AR) 5-8%
201
What genetic cause of Alport syndrome is associated with increased risk for diffuse leiomyomatosis?
large deletion at end of COL4A5 adjacent to COL4A6
202
What is the genetic cause of XL SCID?
IL2RG
203
What is the most common variant causing achondroplasia?
FGFR3 p.Gly380Arg
204
What condition is caused by somatic variants in ATK1?
Proteus syndrome
205
What somatic variant causes Proteus syndrome?
ATK1
206
What is the KIT gene associated with?
piebladism
207
On what chromosome is the VHL gene located?
3p25
208
On what chromosome is the HTT gene located?
4p
209
On what chromosome is the FGFR3 located?
4p16
210
On what chromosome is the APC gene located?
5q22
211
On what chromosome is the CF gene located?
7q31
212
On what chromosome is the FXN gene located?
9q21
213
On what chromosome is the FGFR2 gene located?
10q
214
On what chromosome is the PTEN gene located?
10q23
215
On what chromosome is the HBB gene located?
11p15
216
On what chromosome is the PTPN11 gene located?
12q24
217
On what chromosome is the PAH gene located?
12q
218
On what chromosome is the GJB2 gene located?
13q
219
On what chromosome is the BRCA2 gene located?
13q13
220
On what chromosome is the RB1 gene located?
13q14
221
On what chromosome is the FBN1 gene located?
15q21
222
On what chromosome are the HBA1 and HBA2 genes located?
16p13
223
On what chromosome is the TSC2 gene located?
16p13
224
On what chromosome is the FLCN gene located?
17p11
225
On what chromosome is the NF1 gene located?
17q11
226
On what chromosome is the TP53 gene located?
17q13
227
On what chromosome is the BRCA1 gene located?
17q21
228
On what chromosome is the DMPK gene located?
19q13
229
On what chromosome is the NF2 gene located?
22q12
