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Neo Board Review MAP > Genetics > Flashcards

Genetics Flashcards

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1
Q

Genetics of Beckwith Wiedemann syndrome

A

Genomic imprinting: 11p15.5, IGF2 gene, two copies from dad leading to over expression of IGF2

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2
Q

Genetics of Simpson-Golabi-Behmel (SGB)

A

Xq26.2

Loss of function variants in GPC3 (growth modulator proteoglycan) 

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3
Q

Symptoms of Sotos syndrome

A

Triad

  • overgrowth (length >99% due to long limbs, macrocephaly, advanced bone age)
  • characteristic facial features (frontal bossing, dolichocephaly, fronto-parietal balding, early erruption of teeth, high arched palate
  • learning/intellectual disabilities, seizures

Can be confused with Marfan’s and fragile X

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4
Q

Genetics of Donahue syndrome

A

Mutation of insulin receptor gene on 16p13.2

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5
Q

Symptoms of Beckwith Wiedemann

A 
Macrosomia
Visceromegaly
Neonatal hypoglycemia
Omphalocele
Ear creases and pits
Hemihypertrophy
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6
Q

Symptoms of Simpson-Golabi-Behmel (SGB)

A 
Increased wt/lt/ht
Hypertelorism
Broad upturned nose
Macroglossia
Supernumerary nipples
Pectus excavatum
Hypotonia
Cleft lip or palate
Can be confused with BWS
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7
Q

Genetics of Sotos syndrome

A

Autosomal dominant disorder
Mutations in the NSD1 gene on 5q35
Almost all de novo mutations

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8
Q

Symptoms of Donohue syndrome

A

Fasting hypoglycemia and hyperinsulinism with postprandial hyperglycemia

IUGR
Reduced subcutaneous fat
Distended abdomen
Enlarged external genitalia and nipples
(Large and lowset ears, prominent eyes, broad nasal tip, flared nares, thick lips and gingival hyperplasia)
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9
Q

Primary skeletal dysplasia

A

Mutated genes expressed in chondro-osseous tissue

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10
Q

Secondary skeletal dysplasia

A

Abnormalities of extraosseous factors with secondary effects on the skeletal system

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11
Q

Skeletal dysostoses

A

Malformations of bones as a result of an insult during organogenesis

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12
Q

COL1A

A

Osteogenesis imperfecta type 1-4

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13
Q

FGFR3

A

Thanatophoric dysplasia and achondroplasia

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14
Q

COL2A

A

Stickler syndrome

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15
Q

EVC1/2

A

Ellis-van Creveld syndrome

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16
Q

IFT80

A

Jeune syndrome

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17
Q

Disorders associated with advanced paternal age

A 
Achondroplasia
Apert syndrome
Crouzon syndrome
Neurofibromatosis I
Osteogenesis imperfecta
Pfeiffer syndrome
Retinoblastoma
Thanatophoric dysplasia
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18
Q

Deformation

A

Altered mechanical forces (extrinsic or intrinsic) on normal tissue
Ex: fetal akinesia sequence, Positional congenital hip subluxation

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19
Q

Malformation

A

Caused by abnormal tissue formation

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20
Q

Disruption

A

Breakdown of normal tissue caused by disruption of a normal developmental process
Ex: amniotic band sequence, Teratogen exposure

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21
Q

Dysplasia

A

Abnormal organization of cellular formation into tissue as a result of dysregulation

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22
Q

Syndrome

A

Pattern of many primary malformations as a result of one etiology

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23
Q

Legius syndrome

A

Café au lait spots
Axillary/inguinal freckling
Macrocephaly
Learning disabilities

Can be confused with NF1
AD, mutation in SPRED1 gene

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24
Q

Genetic defect in cartilage hair hypoplasia

A

Chromosome 9p13

RMRP

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25
Symptoms of cartilage hair hypoplasia
Short-limbed dwarfism Hypotrichosis Hirschsprung’s Severe combined immunodeficiency
26
Disorders with cataracts
``` Galactosemia Congenital hypoparathyroidism Fabry disease Lowe Syndrome (oculocerebrorenal) Congenital rubella ```
27
Genetic defect in galactosemia
GALT | Deficiency of galactose-1-phosphate uridyltransferase
28
Defect in Fabry disease
Mutation in GLA | X-linked deficiency a-galactosidase A
29
IEM that are not autosomal recessive
OTC deficiency X-linked ALD Hunters
30
Examples of amino and organic acid acidopathies
``` PKU Tyrosinemia MSUD Nonketotic hyperglycemia Propionic acidemia Methylmalonic acidemia ```
31
Phenylalanine hydroxylase
Defective enzyme in PKU
32
Urine organic acids with elevated succinylacetone
Tyrosinemia I
33
Fumarylacetoacetate hydrolase
Deficient enzyme in tyrosinemia type I
34
Symptoms of Tyrosinemia Type I
Hepatic failure, Fanconi syndrome
35
Branched chain ketoacid dehydrogenase
Enzyme defect in maple syrup urine disease
36
Symptoms of MSUD
Poor feeding, lethargy, coma, apnea | Cerebral edema = dreaded complication
37
Which amino acids are elevated in MSUD?
Leucine Isoleucine Valine
38
Glycine cleavage system
Defect = nonketotic hyperglycemia
39
Elevated CSF/plasma glycine ratio
Diagnostic for nonketotic hyperglycemia
40
Symptoms of nonketotic hyperglycemia
Seizures, myoclonus, hiccups
41
Propionyl CoA carboxylase
Defective enzyme in propionic acidemia
42
Symptoms of propionic acidemia
``` Lethargy, coma Anion gap metabolic acidosis Hyperammonemia Neutropenia, thrombocytopenia Hyperglycemia ```
43
Diagnosis of propionic acidemia
Elevated C3 Elevated glycine Methylcitrate in urine
44
Treatment of propionic acidemia
Diet with decreased VOMITC | Carnitine
45
Treatment of nonketotic hyperglycemia
Hemodialysis | Benzoate (removes glycine)
46
Methylmalonyl CoA mutase
Enzyme deficient in methylmalonic acidemia
47
Symptoms of methylmalonic acidemia
``` Lethargy, coma Anion gap metabolic acidosis, hyperammonemia Neutropenia Thrombocytopenia Hyperglycemia ```
48
Diagnosis of methylmalonic acidemia
Elevated C3 Elevated urine methylmalonic acid Elevated plasma glycine Normal homocystine B12 deficiency can cause elevated methylmalonic acid (maternal deficiency = baby positive for MMA on NBS)
49
Examples of urea cycle disorders
Ornithine transcarbamylase deficiency Citrullinemia Argininemia
50
Encephalopathy and hyperammonemia
Urea cycle defects
51
Increased orotic acid and decreased citrulline
OTC deficiency
52
Symptoms of OTC deficiency
After 48 hours Poor feeding, grunting, lethargy, coma Affected first born males usually die or are severely impaired
53
Treatment of OTC deficiency
Stabilize until liver transplant Low protein diet Ammonia scavenging drugs - phenylbutyrate, glycerol phenylbutyrate Arginine
54
Argininosuccinate synthase 1
Enzyme defect in citrullinemia
55
Increased citrulline and decreased arginine
Citrullinemia
56
Symptoms of citrullinemia
Hyperammonemic crisis | Can have orotic acid elevations
57
Arginase
Enzyme defect in arginase deficiency (Argininemia)
58
Decreased urea and decreased ornithine
Arginase deficiency
59
Symptoms of arginase deficiency
Sometimes only spastic diplegia and delayed milestones Can see hyperammonemia Arginine levels high
60
Hyperammonemia with acidosis andelevated ketones
Organic acidemia
61
Hyperammonemia with acidosis andlow ketones
Fatty acid oxidation defect
62
Hyperammonemia with no acidosis
``` Urea cycle defects: Citrullinemia Argininemia Argininosuccinic aciduria OTC deficiency (elevated orotic acid) CPS deficiency (low orotic acid, trace citrulline) ```
63
Galactosemia associated with
E. coli sepsis/UTI, jaundice, urine reducing substances
64
Untreated galactosemia leads to…
Intellectual disability Cataracts Liver failure Death
65
Despite treatment of galactosemia patients can still have
Cognitive defects | Premature ovarian failure
66
Aldolase B
Enzyme defect in hereditary fructose intolerance
67
Neonate with liver failure due to IEM
Tyrosinemia type 1 Galactosemia Hereditary fructose intolerance
68
Alpha-L-Iduronidase
Enzyme deficiency in MPS type 1 (Hurler)
69
Symptoms of MPS type 1
``` Normal at birth Coarse facies Hepatosplenomegaly Dysostosis multiplex (ribs look like oars) Corneal clouding Intellectual disability Hydrocephalus Cardiac valvular disease ```
70
How to diagnose MPS type 1
Urine glycosaminoglycans | Enzyme activity in WBC’s or fibroblasts
71
Treatment of MPS type 1
Enzyme replacement therapy available but hard to get to brain Bone marrow transplant is better
72
Glucose-6-phosphatase
Enzyme defect in glycogen storage disease type 1A (Von Gierke)
73
Hypoglycemia when infant sleep through the night
Glycogen storage disease 1a
74
Clinical findings of glycogen storage disease 1A (Von Gierke)
``` Hepatomegaly Hypoglycemia Elevated lactate Hyperuricemia Hyperlipidemia Hypertriglyceridemia ```
75
Medication for glycogen storage disease 1a
Allopurinol | Along with avoidance of fasting
76
Alpha-1,4-glucosidase
Pompe disease
77
Symptoms of Pompe disease
Dilated cardiomyopathy FTT Macroglossia Hypotonia
78
Hypoketotic hypoglycemic crises induced by fasting or febrile illness
Early presentation of fatty acid oxidation disorders
79
Medium chain Acyl CoA dehydrogenase
Enzyme defect in MCAD deficiency
80
Symptoms of MCAD deficiency
Hypoketotic hypoglycemia Myopathy Cardiomyopathy SIDS
81
Diagnosis of MCAD deficiency
Elevated on acylcarnitine profile C6-, C8-, C10-, C10:1 species Increased C8/C10:1 ratio 80% mutations c.985A>G lysine to glutamic acid
82
Very long chain Acyl-CoA Dehydrogenase
Enzyme deficient in VLCAD deficiency
83
Symptoms of VLCAD deficiency
Three forms Early - severe with hypertrophic cardiomyopathy Milder - hypoglycemia like MCAD Episodic rhabdomyolysis
84
Elevated C14:1 on acylcarnitine profile
VLCAD deficiency
85
7-dehydrocholesterol reductase
Enzyme defect in Smith-Lemli-Opitz syndrome
86
Symptoms of SLO
``` Growth retardation Mental deficiency Cardiac defects Ambiguous genitalia in males 2,3 toe syndactyly Facial features ```
87
What are peroxisomes?
Cytoplasmic organelles | Help with metabolism of: bile acids, VLCFA (C22,C24,C26), pipecolic acid, plasmalogens
88
Peroxisome biogenesis disorders
Zellweger Neonatal adrenoleukodystrophy Infantile Refsum disease Mutations in PEX1 common Elevated C26:0, C26:1, C24/22, C26/22 ratios
89
Symptoms of Zellweger
``` High forehead Large anterior fontanelle Hypotonia Hepatomegaly Seizures Liver cysts Upslanted palpebral fissures Flat broad nasal bridge ```
90
Are most aneuploidies defects in meiosis 1 or meiosis 2?
Meiosis 1 (failure of homologues to separate, versus sister chromatids)
91
What are you looking for with a karyotype?
Aneuploidy Balanced translocations Mosaicism
92
What do you do if T21 is due to translocation?
Karyotype parents
93
Most common cause of Turner syndrome?
45XO (50%) | Isochromosome (46iXq) Only 10%
94
Is the extra genetic material in triploidy maternal or paternal?
Paternal | 2 sperm + 1 egg
95
What is triploidy associated with?
``` Large placenta 3,4 syndactyly Macrocephaly Renal anomalies Cardiac anomalies Holoprosencephaly Survival rare ```
96
What genetic test to send for dysmorphic babies with unclear diagnosis?
MicroArray
97
Symptoms of Wolf-Hirschhorn syndrome
``` Greek helmet facies High frontal hairline Prominent glabella Hypertelorism Seizures common Cleft lip/palette Micrognathia Septal cardiac defects Genital anomalies Coloboma Very low IQ ```
98
Phenylalanine crosses placenta via
Active transport | Fetal levels > maternal levels
99
Associated with Turner syndrome
``` Bicuspid aortic valve/coarctation Renal anomalies Can general hip dysplasia Melanocytic cutaneous nevi Streak ovaries Normal intelligence ```
100
Genetic causes of Prader Willi syndrome
Paternal microdeletion 15q11-q13 (70%) Maternal uniparental disomy (two copies of maternal15q11-q13) (28%) Imprinting (5%) - father passes on copy of Chr15 that he inherited from his mother (inactive) Test of choice - Methylation test
101
Rhizomelia
Upper parts of limbs short (humerus, femur) | Seen in achondroplasia
102
Genetics of tuberous sclerosis
Autosomal dominant TSC1 on 9q34.13 (Hamartin) TSC2 on 16p13.3 (Tuberin) Majority de novo
103
Genetics of myotonic dystrophy
Autosomal dominant Trinucleotide repeat (CTG) at 3’ end of the DMK gene >2000 copies severe phenotype Largest expansions from maternal transmission
104
Genetics of Cornelia de Lange
Autosomal dominant (NIPBL, RAD21, SMC3) X-linked (SMC1A, HDAC8) Most are de novo Can’t see on Microarray because it’s a single gene disorder - send gene panel
105
CHARGE Syndrome
``` Coloboma Heart defects Atresia (choanal) Retarded growth GU anomalies Ear anomalies ```
106
Genetics of CHARGE syndrome
60% mutations in CHD7 | Chromatin helicase DNA binding protein
107
What percentage of patients with Fanconi anemia meet criteria for VACTERL?
12%
108
Genetics of Fanconi anemia
Autosomal recessive Autosomal dominant (1 gene) X-linked (1 gene) Diepoxybutane (DEB) testing - looks for chromosome breakage only seen in Fanconi anemia If positive send gene panel for Fanconi anemia
109
Symptoms of Fanconi anemia
``` Short stature Microcephaly Hypoplasic thumb/radius GU anomalies Hyper/hypopigmentation Eye anomalies Bone marrow failure Predisposed to cancer ```
110
Poland anomaly
Unilateral chest wall hypoplasia Ipsilateral anomalies of upper extremity Developmental defect of subclavian Deficiency of subQ fat and axillary hair
111
Genetics of Goldenhar syndrome
Usually sporadic Can be AR and AD Associated with maternal diabetes
112
Symptoms of Goldenhar syndrome
``` Oculo-auriculo-vertebral spectrum Hypoplasia of face, jaw, cleft mouth Microtia, preauricular tags Hemivertebrae, hypoplastic vertebrae Epibulbar dermoid, microophthalmia VSD, TOF Normal intelligence ```
113
SNoW DRoP
Southern blot = DNA Northern blot = RNA Western blot = Protein
114
William D WARP, MD
``` Microdeletions Williams DiGeorge WAGR Angelman Rubenstein Taybi Prader Willi ```
115
Genetics of SMA
Biallelic deletion of SMN1 gene Chromosome 5q13 Types classified by SMN2 copy number
116
SMA type 0
Onset in utero, presents at birth 0 copies SMN1, 1 copy SMN 2 Can have congenital heart defects
117
SMA type 1
``` 60% 2 copies SMN2 Onset <6 months old Can’t sit Fasciculations, areflexia, suck/swallow difficulty Normal cognition ```
118
SMA type 2
``` 27% Onset 6-18 months 3 copies SMN2 Can sit but can’t stand Hypotonia, areflexia, progressive scoliosis, polyminimyoclonus Normal cognition ```
119
SMA type 3
``` 12% 3-4 copies SMN2 Onset after infancy Less severe weakness Can lose ability to walk Polyminimyoclonus Normal cognition ```
120
Treatments for SMA
Gene editing therapies - Nusinersen (anti-sense oligonucleotides) - all SMA types and all ages - Risdiplam (small molecules) - all SMA types >2 months of age Gene replacement with AAV9 - onasemnogene abeparvovec all SMA types <2 years of age
121
Genetics of congenital myotonic dystrophy
Autosomal dominant DMPK gene on chr 19 Genetic Anticipation Trinucleotide repeat
122
Treatment of Pompe disease
Enzyme replacement helps with heart and lung >> muscle function Critical to start therapy < six months of age
123
Three types of congenital muscular dystrophy
- Muscle weakness + abnormal brain MRI + cognitive delay - Muscle weakness + abnormal brain MRI + no cognitive delay - Muscle weakness + normal brain MRI + no cognitive delay
124
Genetics of neurofibromatosis type 1
NF1 gene on 17q11.2 | Gene for neurofibromin
125
Genetics of neurofibromatosis type 2
NF2 gene on 22q12.2 | Gene for MERLIN/schwannomin
126
Genetics of Sturge-Weber syndrome
GNAQ on 9q21.2 Gene for guanine protein-binding Q polypeptide Somatic mutation
127
Genetics of incontinentia pigmenti
X-linked dominant (lethal in males) NEMO gene for NK-kappa-B IKBGK on Xq28 for inhibitor kappa light polypeptide gene enhancer
128
Genetics of Kostmann syndrome
Autosomal recessive | HAX1 gene on 1p22.1
129
Which disorder can cause a false positive for galactosemia on the newborn screen?
G6PD
130
Genetics of pyruvate carboxylase deficiency
Autosomal recessive mitochondrial disorder
131
Which urea cycle defects have high urine orotic acid?
``` OTC deficiency Argininosuccinic acid synthetase deficiency (Citrullinemia) Argininosuccinic lyase deficiency (Argininosuccinic aciduria) Arginase deficiency (Argininemia)  ```
132
Glucocerebrosidase
Enzyme defect in Gaucher I and II diseases
133
Sphingomyelinase
Enzyme defect in Niemann-Pick A&B Cherry red spots on macula Foam cells in bone marrow
134
Hexosaminidase A
Enzyme defect in Tay-Sachs
135
Beta-galactosidase
Enzyme defect in generalized gangliosidosis infantile GM1
136
Arylsulfatase A
Enzyme defect in metachromatic leukodystrophy
137
Alpha-Galactosidase
Enzyme defect in Fabry disease
138
Beta-galactosidase
Enzyme in galactosyl-ceramide lipidosis AKA Krabbe disease
139
Acid lipase
Enzyme defect in Wolman disease
140
Deafness and thyroid resistance
Pendred syndrome
141
Genetics of Pallister-Killian mosaic syndrome (PKMS)
Mosaic tetrasomy of chromosome 12p Need to send fibroblasts for genetic testing (not blood)
142
Symptoms of Pallister-Killian mosaic syndrome (PKMS)
``` Hypotonia Cerebellar hypoplasia or atrophy Frontal bossing Low set ears Small hands and feet ```
143
Findings in pyruvate carboxylase deficiency
Hyperammonemia Ketonuria Elevated pyruvate and lactate Metabolic acidosis
144
Treatment of pyruvate carboxylase deficiency
Biotin
145
Lipidoses
Gaucher: no cherry red spots, +HSM, gaucher cells BM Neiman-Pick: cherry red spots, +HSM, foam cells BM Tay-Sachs: cherry red spots, no HSM
146
Genetics of Wolf-Hirschhorn syndrome
Partial deletion of 4p 80% paternally derived chromosome 10-15% are due to translocation (2:1 maternal:paternal)
147
Genetics of Cri du chat syndrome
Partial monosomy of chromosome 5p | 80% paternally derived
148
Symptoms of Cri du chat syndrome
``` Cat like cry due to abnormal laryngeal development Microcephaly Round face Broad nasal bridge Hypotonia Agenesis of the corpus callosum Cerebellar hypoplasia ASD, VSD, TOF Renal agenesis/horseshoe kidney ```
149
Genetics of fragile X syndrome
Trinucleotide repeat FMR1 gene located at Xq27.3 Affected individuals have >200 repeats
150
Symptoms of fragile X syndrome
``` Macrocephaly Large ears Cleft palate Hypotonia Mitral valve prolapse/aortic dilation Autism Intellectual disability Large testes ```
151
Symptoms of pyruvate dehydrogenase deficiency
``` Hypotonia Seizures Lactic acidosis Elevated alanine Microcephaly ```
152
Genetics of pyruvate dehydrogenase deficiency
Most common is X-linked dominant Can also be autosomal recessive PDHA1 gene
153
Genetics of Lowe syndrome
X-linked | OCRL gene on Xq25-26
154
Genetics of cartilage hair hypoplasia
RMRP gene on Chr 9p13 AR Amish/Finnish
155
Genetics of leukocyte adhesion deficiency
Autosomal recessive Beta-2 integrin gene mutations (ITGB2) Integrins associated with CD18
156
Genetics of Shwachman-Diamond syndrome
Autosomal recessive | SBDS gene on Chromosome 7q11
157
Thickening of Schwalbe’s ring around the cornea
Posterior embryotoxin
158
Genetics of Alagille
Autosomal dominant JAG1 on Chr 20p12 NOTCH2 on Chr 1
159
Genetics of Noonan syndrome
Autosomal dominant RASopathy - RAS/MAPK 50% mutations in PTPN11 on 12q24.1

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