Conditions Flashcards
1
Q
What percentage of male with Fragile X syndrome have a diagnosis of autism spectrum disorder?
A
50-70%
2
Q
What is the typical age of onset of Fragile X ataxia syndrome, and what is the molecular cause?
A
60-65 years (more common in males than females)
FX premutation: 55-200 repeats
3
Q
At what range of CGG repeats in the Fragile X region are individuals at risk for POI and FXAS?
A
Premutation, 55-200
4
Q
What are imaging and clinical signs consistent with Fragile X ataxia syndrome?
A
Imaging: MRI white matter lesions, MCP sign, brain atrophy
Clinical: tremor, gait ataxia, Parkinsonianism, memory issues, neuropathy
5
Q
What percent of cases of autism spectrum disorder have Fragile X syndrome?
A
2-3%
6
Q
What is the mean age of onset for Huntington’s disease, and what is the expected survival after diagnosis?
A
35-44 onset, median survival 15-18 years
7
Q
What are the repeat ranges for Huntington’s disease?
A
CAG repeats
normal: <26
intermediate: 27-35
reduced penetrance: 36-39
full penetrance >40
8
Q
Which symptoms of Huntington’s disease worsens with stress?
A
chorea
9
Q
What percent of HD is juvenile onset (onset <age 20)?
A
5-10%, CAG repeats usually >60
10
Q
What increases the stability of HD associated CAG repeat regions?
A
Interruption with CAA or CCG repeats
11
Q
What primary symptoms are associated with Williams syndrome, and what is the deletion region?
A
7q11.23 deletion, usually de novo
delays/ID, endocrine, growth deficiency, cardiac, connective tissue
12
Q
What is the specific cognitive profile associated with Williams syndrome?
A
strong in verbal short term language, weak in visuospatial
personality: empathetic, overfriendly, anxious with phobias/ADHD
13
Q
What endocrine anomalies are associated with Williams syndrome?
A
early puberty, hypercalcemia, hypercalciuria, hypothyroidism, diabetes mellitus
14
Q
What abnormality causes cri du chat syndrome?
A
5p deletion, usually de novo, 80-90% terminal deletions
80-90% of inherited are of paternal origin
15
Q
What abnormality causes Wolff-Hirschhorn syndrome?
A
4p deletion
16
Q
What percent of 22q deletions are inherited?
A
10% inherited, 90% de novo
except for nested deletions- 60% inherited
17
Q
What symptoms are associated with Sotos syndrome?
A
distinctive facies, learning differences, overgrowth
behavioral (autism), advanced bone age, cardiac, cranial imaging anomalies, joint laxity, maternal pre-eclampsia, scoliosis, seizures
18
Q
What gene causes Sotos syndrome and how often is this de novo?
A
NSD1, >95% de novo
In Japanese populations, 5q35 deletion is typical cause- less overgrowth, more severe learning issues
19
Q
What region is associated with Beckwith Wiedemann syndrome and what are the percentage breakdown of causes?
A
11p15.5
55% imprinting defects
-50% loss of maternal methylation at IC2
-5% gain of maternal methylation at IC1
20% paternal UPD
5-10% CDKN1C variants (40% of familial cases)
20
Q
What type of anomaly causing BWS is associated with cleft palate?
A
maternally inherited sequence variants
21
Q
What type of anomaly causing BWS is associated with the highest risk of WT?
A
UPD 11, or maternal gain of methylation at IC1
22
Q
What is the risk of neoplasia associated with BWS?
A
7.5%, concentrated in first 8 years of life
23
Q
What are surveillance recommendations for children with BWS?
A
AFP every 2-3 months first 4 years of life (for hepatoblastoma)
abd US every 3 months until age 8
annual renal US age 8- adolescence
consideration of annual urinary calcium
24
Q
What is the leading cause of morbidity/mortality for T21?
A
cardiac issues, especially in the first two years of life
25
What percentage of individuals with T21 have a CHD?
50%
26
What are the most common cardiac defects associated with T21 (%)?
40% AVSD- associated with the CRELD1 gene
32% VSD
27
Why do individuals with T21 have an increased risk of developing Alzheimer's?
50-70% develop because there is an amyloid precursor protein in region
28
What is the penetrance of acute intermittent porphyria?
05.-1%
29
What percent of 21-hydroxylase CAH is salt wasting?
75% salt wasting, 25% simple virilizing
30
What laboratory elevations are seen with 21-hydroxylase CAH?
elevated 17-OHP and elevated adrenal androgens
31
What conditions can be associated with an Xp21 deletion depending on the exact region?
DMD/BMD, NR0B1 adrenal hypoplasia congenita, GK glycerol kinase deficiency
32
What are common symptoms of McCune Albright and what is the genetic cause?
coast of Maine CALs, fibrous dysplasia, endocrine- precocious puberty, excess CH, thyroid issues
caused by early embryonic post zygotic activating mutations in GNAS
33
What is the common HFE mutation, and what percent of homozygotes are symptomatic?
p.Cys282Tyr
28% symptomatic, 1% women pre menopause
34
What causes Hemophilia A?
Factor 8 deficiency
48% of severe cases due to inversion of introns 1 and 22
35
What causes Hemophilia B?
Factor 9 deficiency
36
How does severe beta thal present in the first two years of life?
with severe anemia and hepatosplenomegaly
37
What are laboratory findings of beta thal major?
microcytic hypochromic anemia, an abnormal blood smear with nucleated RBC
reduced HbA
increased HbF
normal HbA2
decreased MCV and MCH
decreased hemoglobin
38
What ethnic groups have a higher carrier frequency for beta thal and what are they?
Mediterranean (1/20)
Middle East/SE Asia (1/7)
African (<1/8)
39
What are symptoms of Hb Bart's disease?
edema, CHF, severe anemia, hepatosplenomegaly, large placenta, death as neonate
40
What are common symptoms of alpha thal?
spleen enlargement, mild jaundice, bone changes, gallstones
41
What are laboratory findings of alpha thal major?
low MCV, low MCH, low HBA2, normal HbF
microcytic hypo chromic hemolytic anemia, moderate reticulocytosis, rarely nucleated RBC
42
What ethnic groups have a higher carrier frequency for alpha thal and what are they?
African (1/3)
Mediterranean
SE Asia (1/20)
43
What are common symptoms associated with untreated sickle cell disease?
vaso-occlusive events, chronic hemolytic anemia, acute and chronic pain, organ damage especially spleen
pain/swelling in hands and feet often first symptom
44
What is the top cause of mortality in individuals with sickle cell disease?
acute chest syndrome
45
What is the hemoglobin S allele?
HBB p.Glu6Val
46
What genes cause alpha thal, beta thal, and sickle cell?
alpha: HBA1, HBA2
beta: HBB
sickle cell: HBB p.Glu6Val homozygous
47
What are common symptoms of Bardet Biedl?
retinal rod cone dystrophy, obesity but normal birth weight, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism, renal malformations/disease
48
What are common manifestations of Meckel Gruber?
MKS genes
enlarged cystic kidneys, encephalocele, polydactyly, death before or shortly after birth
49
What are common symptoms of branchiootorenal syndrome?
ear malformations- branchial fistula and cysts, hearing loss, renal: mild hypoplasia- bilateral renal agenesis
50
What genes are associated with branchiootorenal syndrome?
EYA (40%), SIX1, SIX5
51
What are common symptoms of CHARGE syndrome?
coloboma
heart defect
choAnal atresia
retarded growth and development
genital hypoplasia
ear anomalies
cranial nerve, seizures, renal
52
What are common symptoms of Coffin Lowry syndrome?
delays, hypotonia, seizures, kyphoscoliosis, pectus, craniofacial
53
What are common symptoms of Cornelia de Lange syndrome?
facial findings, synophrys, high arched or thick eyebrows, growth restriction with prenatal onset, hypertrichosis, upper limb defects
54
What is the characteristic triad of Joubert syndrome?
molar tooth sign
hypotonia
dev delays
55
What chromosome region is associated with PAX6 related aniridia/WAGR syndrome?
11p13 deletion
56
What other anomalies can be seen in WAGR syndrome other than aniridia and WT risk?
genital anomalies
ID in 70%
57
What genes cause features of Miller Dieker deletion syndrome?
PAFAH1B1 (LIS1) - lissencephaly
YWHAE - other symptoms
58
What region causes Miller Dieker deletion syndrome?
17p13.3 deletion
59
What are characteristic features of Phelan Mcdermid syndrome?
hypotonia, severely delayed/absent speech, moderate-profound ID, large fleshy hands, dysplastic toenails, decrease perspiration
60
What are possible causes of Phelan Mcdermid syndrome?
22q13.3 deletion
SHANK3 mutations
ring chromosome 22- can include NF2 gene
61
What are the typical break points for Prader Willi syndrome?
BP1 or BP2 + BP3
8% with atypical deletion size
62
What are characteristic features of Rubinstein Taybi syndrome?
distinctive facies (low hanging columella, grimacing smile), broad thumbs, short stature, mod-severe ID
normal prenatal growth with rapid drop after birth
63
What are characteristic features of Smith Magenis syndrome?
coarse facial features, delays, cognitive, behavioral, sleep, abdominal obesity, self injurious behavior, sensory issues
64
What are possible causes of Smith Magenis syndrome?
17p11.2 deletion (90-95%)
RAI1 mutation (5-10%)
deletion can include FLCN --> BHD
65
What is the inheritance pattern of Oral-facial-digital syndrome type 1?
XLD, male lethal
66
What are characteristic features of oral-facial-digital syndrome?
tongue anomalies, clefts, hypodontia, dental, facial features, hand anomalies, polycystic kidneys, brain imaging findings
67
What is the de novo rate for achondroplasia?
80% (FGFR3)
68
What is the classic triad for cleidocranial dysplasia?
delayed closure of cranial sutures
hypoplastic or aplastic clavicles
dental anomalies
69
Which FGFR2 related syndrome has normal hands and feet?
Crouzon syndrome
Jackson Weiss- normal hands abnormal feet
70
What are the four main types of OI?
Type 1- classic non-deforming (most mild)
Type 2- perinatal lethal
Type 3- progressively deforming
Type 4- variable (moderate-mild)
71
What is the first and second leading causes of mortality for TSC?
first: CNS tumors
second: renal
72
What is the chance that a fetus with a cardiac rhabdomyoma has TSC?
75-80% risk for TSC
73
What is the inheritance pattern for hypohidrotic ectodermal dysplasia?
many genes, AR, AD
EDA- most common, XL
74
What leads to hypopigmentation in OCA?
impaired melanin synthesis
75
What percentage of individuals with NF1 have plexiform neurofibromas?
50%, mostly internal
76
What increases the likelihood that plexiform neurofibromas become malignant nerve sheath tumors?
whole gene deletion, high burden of plexiform neurofibromas
77
What is the de novo rate for NF1?
50%
78
What is the most common type of pathogenic mutation for neurofibromin?
severe truncating
79
What is the typical age of onset for NF2?
18-24 years
80
What is the de novo rate for NF2?
50%
- but 25-50% of de novo are mosaic
81
What type of NF2 mutations have more mild or more severe disease?
large deletions- more mild, no ID
nonsense and frameshift- severe
82
What percent of individuals with schwannomatosis have an affected parent?
<20%
83
What percent of sporadic cases of schwannomatosis have known cause?
40% known, 60% unknown cause (for sporadic)
84
What are the four stages of Incontinentia pigmenti?
birth- 4 months: blistering stage
several months: wart like rash
6 months- adulthood: swirling macular hyperpigmentation
adulthood:linear hypopigmentation
85
What is the de novo rate for IKBKG?
65%
86
What is the pregnancy outcome for a pregnant person who carries an IKBKG mutation?
33% affected female, 33% unaffected female, 33% unaffected male (because most affected males miscarry)
87
How can alpha 1 antitrypsin deficiency be diagnosed?
low serum concentration AAT + pathogenic variant or protein inhibitor typing
88
What is the carrier frequency for Alpha 1 antitrypsin?
2-3%
(1/43-1/50)
89
What provides a dx of cystic fibrosis?
elevated IRT on NBS, symptomatic, or fhx
+
evidence of abnormal CFTR: sweat chloride >60, biallelic variants, or nasal transmembrane potential differences
90
What cause cystic fibrosis related diabetes?
glucose metabolism is impaired due to loss of islet cells
-->absence of glucagon and insulinv
91
What can cause decreased fertility in females with CF?
pH imbalance and thickened cervical mucus
92
What is the expected CFTR genotype of a male with isolated congenital absence of the vas deferens?
severe LOF CFTR variant + non- CF causing variant
OR
two non-CF causing variants
93
Which CF variant is most widely known to be targeted by mutation specific drugs?
Phe508del
94
What is the most prevalent CFTR disease causing variant?
F508Del
(in N european, founder variant for Amish and AJ )
95
Are CFTR pathogenic variants LOF or GOF, and how does this lead to disease?
LOF of transmembrane chloride channel
without chloride, sodium does not form salt and water is not attracted
--> thickened mucus
96
How does the Poly T tract modify pathogenicity of CFTR variants?
thymidine bases in intron 8
7T and 9T benign
5T variably penetrant: decreases efficiency of intron 8 splicing
-->50% of full length CFTR produced
97
How does the Poly TG tract modify pathogenicity of CFTR variants?
11, 12, or 13 TG
longer TG tract in cis with shorter poly T - more severe
--> reduced reduction of full length protein to 25%
98
What are the four features of BPES?
blepharophimosis, ptosis, epicanthus inversus, telecanthus
99
What are the two types of BPES?
type 1: four cardinal features + POI
(proteins truncated before polyalanine tract)
type 2: four cardinal features only
100
What is the genotype/phenotype correlation with truncating variants in AR GJB2?
T/T - most likely profound hearing loss
NT/NT- most likely mild
101
What is the GJB2 carrier rate in europeans?
2-4%
(1/25-1/50)
102
What Hermansky Pudlak variants are most common in the Puerto Rican population?
80% HP is HPS1 duplication
20% HP is HPS3 deletion
103
How are Pendred syndrome and non-syndromic enlarged vestibular aqueduct diagnosed?
PS: SNHL+ characteristic temporal bone on CT + euthyroid goiter
NSEVA: same without goiter
104
What are the three variants most common with Leber hereditary optic neuropathy?
ND1 m.3460 G>A
ND4 m.11778 G>A (60-70% european)
ND6 m.14484 T>C (French Canadian, also has best long term visual outcome)
105
What is the penetrance of LHON in males and females?
50% males
10% females
106
What are three main types of Waardenburg syndrome?
Type 1: HL in 60%, distinguished by displacement of inner canthi
Type 2: multiple genes, MITF includes melanoma risk
Type 3: includes hypoplasia or contractures
107
What is the de novo rate for Alagille syndrome?
50-70%
108
What cardiac conduction anomalies are seen with Brugada syndrome?
ST segment abnormalities in leads V1-V3 on EKG
high risk for ventricular arrhythmias
109
What is the mean age of SCD for Brugada syndrome?
40
110
What percent of Brugada syndrome has an identifiable genetic cause?
~35%
111
What are the dx criteria for HHT?
3 or more of:
-epistaxis
-characteristic telangiectasias
-visceral AVMs
-FDR
112
What systems are affected in Holt Oram syndrome?
heart and hand syndrome
upper limb defects: absent thumbs-phocomelia, all with abnormal carpal bone
cong heart or cardiac conduction
113
What is the difference in hearing loss between Usher type 1 and type 2?
profound in type 1
mild-moderate low, severe-profound high in type 2
114
What are ocular findings in Stickler syndrome?
myopia, cataracts, retinal detachments
115
What are hair and skin findings in Costello syndrome?
curly or sparse hair
soft skin with deep palmar and plantar creases
papillomata
116
What is the tumor risk associated with Costello syndrome?
15% tumor risk
rhabdomyosarcoma, neuroblastoma, transitional cell carcinoma of bladder- usually seen in older adults!
117
What is a characteristic skeletal finding in Costello syndrome?
ulnar deviation
118
What percent of Noonan syndrome are affected with what types of heart disease?
CHD in 50-80%
20-50% PVS
20-30% HCM
119
What is the risk of Noonan syndrome in a normal chromosome fetus with an increased NT?
3-15%
120
What age do the characteristic skin findings of Noonan syndrome with multiple lentigines appear?
age 4-5, 1000s by puberty
121
What cardiac findings are associated with cardiofaciocutaneous syndrome?
pulmonic stenosis, valve anomalies, septal defects, HCM, rhythym defects
122
What are the hair and skin findings associated with cardiofaciocutaneous syndrome?
sparse, curly, fine or thick, wooly or brittle hair
cutaneous: xerosis, hyperkeratosis, icthyosis
123
What causes cardiac arrest in long QT?
tdp self terminating --> syncope --> cardiac arrest or SCD
124
What percent of individuals with long QT have an identified mutation?
80% identified variant
20% uknown
125
What percent of individuals with long QT pathogenic variant have symptoms?
50% with pathogenic variants have symptoms
25% with pathogenic variant have normal EKG
126
What is the risk of SCD with long QT syndrome?
6-8%
SCD is first sign in 10-15%
127
What type of long QT is characterized by muscle weakness and facial dysmorphism?
type 7- Andersen Tawil
128
What type of long QT is characterized by hand, foot, facial, and neurodevelopmental differences?
type 8- Timothy
129
What are the characteristic cardiac findings of HCM?
unexplained L ventricular hypertrophy - wall thickness >15 mm
>13 mm if fhx
increased risk for afib, SCD rare
130
What are syndromic causes of HCM?
Fabry, Fredreich's ataxia, TTR, Pompe, RASopathies
131
What percent of individuals with HCM have sarcomeric mutations?
50-60% with fhx
20-30% no fhx
132
What are characteristic cardiac findings of DCM?
L ventricular enlargement + systolic dysfunction
EF <50%
133
What are syndromic causes of DCM?
Barth, DMD/BMD, carjaval, emery dreifuss, hemochromatosis
134
How is hEDS diagnosed?
all three for clinical dx:
-joint hypermobility (Breighton score)
-syndromic features, musculoskeletal complications or fhx
-exclusion of other diagnoses
135
How is the joint hypermobility in hypermobile type and classic EDS different from vascular EDS?
in hypermobile and classic the joint hypermobility is generalized
in vascular type the joint hypermobility is small joints
136
How does ALS affected the lower and upper motor neurons?
upper: hyperreflexia, increased tone
lower: hyporeflexia, muscle atrophy
137
How does ALS typically present?
with asymmetric focal weakness of the extremities
dx feature: hyper reflexia in segments and regions of muscle atrophy without sensory involvement
138
When does CMT typically onset?
first- third decade with hand and feet involvement
139
What is the age cutoff for DMD vs BMD?
wheelchair dependence <13 for DMD
>16 for BMD
140
What are causes of mortality for DMD?
respiratory
cardiac (20%, 50% for BMD)
141
What is the typical onset for Freidreich's ataxia?
slowly progressive ataxia <25
typical onset 10-15
142
What are symptoms of Freidreich's ataxia?
dysarthria, weakness, spasticity, scoliosis, bladder dysfunction, absent lower limb reflexes, loss of position/vibration sense
2/3 HCM
30% diabetes
143
What is the onset of nemaline myopathies?
congenital onset
144
What systems are affected by myotonic dystrophy type 1?
skeletal and smooth muscle, eye, heart, endocrine, CNS
145
Is CK elevated in Myotonic dystrophy type 1?
only mildly elevated if symptomatic
146
What the SMA types?
type 0: prenatal
type 1: dx < 6 months, sit with support only
type 2: dx 6-18 months, can sit independently
type 3: dx >18 months, independent ambulation
147
What is the most common cause of death in SMA?
respiratory failure
148
What is the typical onset of ataxia telangiectasia?
progressive cerebellar ataxia at 1-4
149
What is the triad associated with septo optic dysplasia?
absent septum pellucidum
optic nerve hypoplasia
pituitary dysfunction
150
What are features commonly associated with Alagille syndrome?
paucity of bile ducts, posterior embryotoxon, liver, cardiac, kidney, facial findings
151
Are most RASopathies GOF or LOF?
GOF
152
Which RASPopathies are not GOF?
NF1 and SPRED1 are LOF
-they are negative pathway regulators, so down-regulating them up regulates
153
Which RASopathy can be characterized by papillomata and deep plantar creases?
Costello syndrome
154
Which RASopathy can be characterized by eczema, heart deefects, and coarse features?
cardiofaciocutaneous syndrome
155
What type of SCA has visual impairment?
type 7
156
Is expansion more likely in paternal or maternal transmission of SCAs?
paternal transmission more likely for expansion
157
What is the classic triad of dyskeratosis congenita?
dysplastic nails, lacy reticular pigmentation, oral leukoplakia
also with bone marrow failure, pulmonary fibrosis
158
What are common features of Treacher Collins?
craniofacial findings with malar hypoplasia, ear anomalies and hearing loss, normal intelligence, colobomas
159
What types of ocular findings are seen in Stickler syndrome?
myopia, cataracts, retinal detachments
160
What are common findings in Kabuki syndrome?
significant postnatal growth deficiency, characteristic facies, CHD in half, fetal finger pads
161
What are expected laboratory findings for Smith Lemli Opitz?
low cholesterol and high precursor
162
What are common findings in individuals with Zellwegger syndrome?
cerebro-hepato-renal
abnormal VLCFA
hypotonia, growth, facies, limb, liver, stippling of bones
often fatal in first year
163
Do carrier females of EDA1 have symptoms?
90% with dental or sweating anomalies
164
Is maternal or paternal expansion of FMR1 more likely to expand?
maternal expansion more likely
165
What percent of male or female FMR1 premutation carriers >50 have symptoms?
40-50% males
8-17% females
166
What percent of individuals with Marfan syndrome have ectopic lentis?
50-80%
167
How is Marfan syndrome dx?
FBN1 variant + aortic root enlargement OR ectopic lentis
168
What is the systemic score cutoff for Marfan syndrome?
>=7
169
What causes immunodeficiency in 22q?
thymic hypoplasia
170
What causes hypocalcemia in 22q?
hypoplasia of the parathyroid gland
171
What type of testing is most appropriate for 22q?
MLPA or CMA over FISH
172
What are typical breakpoints for 22q?
A and D, nested deletion is smaller
*TBX1 located between A and B
173
What causes polyhydramnios in 22q?
palate anomalies
174
What can cause 22q to show up on NBS?
low T cells on NBS
175
What is the appropriate next step for an individual with CF when R117H is identified?
reflux to poly T
176
What percent of individuals with CF have a F508del allele?
90%
177
What type of CFTR variants have some low vs some residual function?
those that affect folding, splicing, or transcription have low function
those that affect stability, activity, or conductance have some residual function
178
What is the next step if an individual is identified with 1 or 2 CFTR variants after an elevated IRT?
sweat test
95% with an elevated IRT and 1 variant only have a negative f/u sweat test
179
What is the next step if an individual is identified with 0 CFTR variants after an elevated IRT?
if very high IRT than still do a sweat test
180
How is cutis laxa characterized?
loose redundant skin, arterial toruosity and aneurysms, dicerticula of the colon or bladder - UTIs, pulmonary emphysema
ID if CDG disorder
181
What are acquired causes of HCM?
hypertension, aortic stenosis athletic training
182
What are triggers of LQT Type 1?
75% exercise
15% emotion
10% sleep
183
What are triggers of LQT Type 2?
63% sleep
37% emotion
184
What are triggers of LQT Type 3?
80% sleep
15% emotion
5% exercise
185
Which types of LQT are LOF or GOF?
Type 1- KCNQ1 - LOF
Type 2- KCNH2 - LOF
Type 3 - SCN5A - GOF
186
What are triggers of CPVT?
stress, syncope
187
What percent of families with HCM have identified pathogenic variants?
20-40%
188
What are common findings of myotonic dystrophy type 1?
facial weakness, balding, distal weakness, foot drop, frequent falls, sleep disturbance, premature cataracts, cardiac conduction anomalies, cognitive/apathy, endocrine- thyroid, diabetes
189
What is the characteristic triad of Emery dreifuss sydrome?
joint contractures, slowly progressive weakness, cardiac anomalies
190
What are the genetic testing recommendations for epilepsy?
genetic testing recommended for all unexplained epilepsy
panel or WES (preferred) then array
191
What percent of individuals with DMD have delayed motor milestones?
42%
192
What is the risk for DCM in carriers of DMD?
5-8%
193
How does myotonic dystrophy affect fertility?
decreased fertility in males
194
How does onset differ in myotonic dystrophy type 1 vs type 2?
type 1: variable depending on number of repeats
type 2: usually adult onset, repeat size does not correlate with onset or severity
195
What systems are affected in XL adenreoleukodystrophy?
adrenal glands and CNS
196
What percent of female carriers of XL ALD have symptoms, and at what age?
20% with spastic paraparesis in middle age or later
-adrenal function usually preserved
197
What symptom is less common in juvenile onset Huntington's?
chorea
198
What is the general population risk of Alzheimer's?
11% > 65
33% > 85
199
When is the onset of bone marrow failure in fanconi anemia?
first decade of life
200
What is the risk for AML in Fanconi anemia?
13% by age 50
201
How is chromosome breakage tested for Fanconi anemia?
cytogenetic testing of lymphocytes treated with DEB And mitomycin C
--> chromosome breakage and radial forms
202
Most causes of Fanconi anemia are AR, what are AD and XL causes?
AD: RAD51, usually de novo
FANCB: XL
203
What are laboratory findings associated with fanconi anemia?
macrocytosis, increased Hf (precedes anemia), cytopenia
204
What are prenatal and perinatal findings of Angelman?
none, normal pregnancy and birth
205
What percent of genetic causes of Angelman are picked up on DNA methylation?
80%, detected deletions, UPD, or imprinting defects
-also detected on MLPA
-FISH only detects the deletion
206
What genetic cause of Angelman syndrome has the most severe phenotype?
deletion
207
Which of the genetic causes of Angelman syndrome is sometimes mosaic?
20% imprinting defects are mosaic - may have some speech vs none
208
What cause of Angelman syndrome has a nearly 100% recurrence risk?
if father has a 15;15 Robertsonian translocation
(50% if mother has a 15;15)
209
What percent of UBE3A mutations causing Angelman are inherited?
30% (maternally inherited)
210
What are the most common breakpoints causing Angelman syndrome deletions?
50% BP2-BP3
40% BP1-BP3
211
What does CADASIL stand for?
cerebral AD arteriopathy with subcortical infarcts and leukoencephalopathy
212
How is the onset of CADASIL characterized?
mid adult onset of recurrent strokes
cognitive decline, migraines, mood, apathy
213
What is the typical duration of Alzheimer's disease before death?
8-10 years
214
What are neurological findings of a brain affected by Alzheimer's disease?
beta amyloid plaques (plaque are negative for prion disease), intraneuronal neurofibrilliary tangles including tau protien, amyloid angliopathy
215
What is the risk of Alzheimer's disease if a FDR is affected?
20-25%
216
What is a CK for an individual with FSHD?
normal to mildly elevated
217
When is the typical onset of FSHD?
teens
218
When is the onset of Wilson's disease?
childhood-40
219
What is the characteristic triad of septo-optic dysplasia?
optic nerve hypoplasia, abnormal midline structures of the brain, pituitary hypoplasia
220
What proportion of Alport syndrome is XL?
2/3
221
What is a characteristic immunostaining finding for Alport syndrome?
absence of immunostaining for collagen chains
222
What genetic causes of Alport syndrome are more likely to have earlier onset ESRD?
large rearrangements, nonsense, frameshift
223
What specific genetic cause of Alport syndrome is associated with an increased risk for diffuse leiomyomatosis?
large deletion at adjacent 5' end encompassing COL4A5 and COL4A6
224
What is the risk of ESRD by age 60 for individuals with ADPKD?
50%
225
What is a common prenatal finding for individuals with RSS?
asymmetric prenatal growth restriction
226
What percentage of individuals with RSS have an identified genetic cause?
60%
40% no identified cause
227
What are the six clinical criteria for RSS? How many are needed for a clinical dx without a genetic cause?
SGA
postnatal growth failure
* relative macrocephaly at birth *
* frontal bossing or prominent forehead *
body asymmetry
feeding difficulties
No genetic cause:
-4 criteria met including two **
-other causes ruled out
228
How does hypermethylation of the ICR1 region lead to the RSS phenotype?
hypermethylation of ICR1
--> biallelic H19 expression
--> biallelic silencing of IGF2
--> growth restriction
229
What are typical laboratory findings in SLO?
deficiency of 7 dehydro cholesterol reductase causes:
elevated 7 DHC
low serum cholestero;
