Genetics Flashcards
(145 cards)
1
Q
Most common cause of inherited intelectual disability and autism
A
Fragile X syndrome
2
Q
Clinical findings in FXS
A
- Post-pubertal
- Macroorchidism
- Long face with large jaws
- Large everted ears
- Autism
- MVP
3
Q
Gene affected in FXS and where is it
A
FMR1 in the long arm of the X chromosome
4
Q
Trinucleotide repeat in FXS
A
CGG (“Chin giant gonads”)
5
Q
When in cell division can trinucleotide repeats expand in FXS
A
Oocyte meiosis
6
Q
How many repeats are needed for a full mutation in FXS
A
More tan 200
7
Q
Genetic consequence of CGG trinucleotide repeat in FXS
A
Hypermethylation
8
Q
Missing gene in Turner syndrome resulting in short stature
A
SHOX gene
9
Q
Classic presentation in neurofibromatosis type 1
A
- Café-au-lait spots
- Lisch nodules (iris hamartomas)
- Cutaneous neurofibromas
- Pheochromocytomas
- Optic gliomas
*Can also present with bony abnormalitis such as congenital pseudoarthrosis
10
Q
Inheritance pattern of neurofribromatosis type 1
A
Autosomal dominant
11
Q
Affected gene on neurofibromatosis type 1
A
NF1 gene on chromosome 17
12
Q
Define codominance
A
Both alleles contribute to the phenotype of the heterozygote
*eg, blood groups
13
Q
Define variable expressivity
A
Patients with the same genotype have varying phenotypes
*eg, 2 pts with NF1 may have varying disease severity
14
Q
Define incomplete penetrance
A
Not all individuals with a mutant genotype show the mutant phenotype
*eg, BRCA1 gene mutations do not always result in breast or ovarian cancer
15
Q
Define pleiotropy
A
When one gene contributes to multiple phenotypic effects
*eg, untreated PKU manifests with light skin, intellectual disability, and musty body odor
16
Q
Define anticipation
A
Increased severity or earlier onset of disease in succeeding generations
*eg, trinucleotide repeat diseases
17
Q
Define loss of heterozygosity
A
If a patient inherits or develops a mutation in a tumor supressor gene, the complementary allele must be deleted/mutated before cancer develops
*eg, retinoblastoma and the “2-hit hypothesis”, Lynch syndrome (HNPCC), Li-Fraumeni syndrome
18
Q
Define a dominant negative mutation
A
When a heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
*eg, mutation of a transcription factor in its allosteric site (nonfunctional mutant can still bind DNA, preventing wild-type transcription factor from binding)
19
Q
Define linkage disequilibrium
A
Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance
*Measured in a population
20
Q
Define mosaicism
A
Presence of genetically distinct cell lines in the same individual
21
Q
Define somatic mosaicism
A
When the mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs
22
Q
Define gonadsl mosaicism
A
When the mutation appears only in egg or sperm cells
23
Q
Pathogenesis of McCune-Albright syndrome
A
Mutation affecting G-protein signaling
24
Q
Signs and symptoms of McCune-Albright syndrome
A
Triad:
- Café-au-lait spots with ragged edges (follow lines of Blashko)
- Polyostotic fibrous dysplasia
- At least 1 endocrinopathy (eg, precocious puberty)
*Survivable in patients with mosaicism
25
Define locus heterogeneity
Mutations in different loci can produce a similar phenotype (eg, albinism)
26
Allelix heterogeneity
Different mutations in the same locus produce the same phenotype (eg, beta thalassemia)
27
Define heteroplasmy
Presence of both normal and mutated mtDNA, resulting in variable expression of a mitochondrial disease
28
Define uniparental disomy
Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent
29
Type of uniparental disomy that reflects an error in meiosis 1
Heterodisomy
30
Type of uniparental disomy that reflects an error in meiosis 2
Isodisomy
31
What is the Hardy-Weinberg equilibrium formula
p2 + 2pq + q2 and p
32
What is the Hardy-Weinberg equilibrium formula
p2 + 2pq + q2 and p + q = 1
* P2 is the frequency of homozygosity for allele A
* Q2 is the frequency if homozygosity for allele a
* 2PQ is the frequency of heterozygosity
33
Affected chromosome in Prader-Willi and Angelman syndromes
Chromosome 15
34
Pathogenesis of Prader-Willi syndrome
Gene from mother is imprinted while the paternal gene is deleted/mutated
35
Signs and symptoms of Prader-Willi syndrome
* Hyperphagia
* Obesity
* Intellectual disability
* Hypogonadism
* Hypotonia
36
Percentage of cases of Prader-Willi syndrome due to maternal uniparental disomy
25%
37
Pathogenesis of Angelman syndrome
Paternal gene is normally imprinted, and maternal gene is deleted/mutated
38
Signs and symptoms of Angelman syndrome
* Inappropite laughter
* Seizures
* Ataxia
* Severe intellectual disability
39
Percentage of cases of Angelman syndrome that are due to paternal uniparental disomy
5%
40
Mode of inheritance of hypophosphatemic rickets
X-linked dominant
41
Pathogenesis of hypophosphatemic rickets
Increased phosphate wasting at proximal tubule
42
Characteristic histopathologic finding seen in mitochondrial myopathies
Ragged red fibers
43
Signs and symptoms common to mitochondrial myopathies
* Myopathy
* Lactic acidosis
* CNS disease
44
Mode of inheritance of cystic fibrosis
Autosomal recessive
45
Defective gene in cystic fibrosis
CFTR on chromosome 7
46
Most common mutation in cystic fibrosis
Deletion of Phe508 leads to misfolding of the protein and its retention in the RER
47
Normal function of the CFTR (abnormal protein in cystic fibrosis)
It is an ATP-gated Cl- channel that secretes Cl- in lungs and GI tract and reabsorbs Cl- in sweat glands
48
Pathogenesis of cystic fibrosis
Retained CFTR causes decreased Cl- and water secretion, leading to increased intracelular Cl- and compensatory increased Na reabsorption - This causes increased water reabsorption and abnormally thick mucus
49
Laboratory diagnosis of cystic fibrosis
Increased Cl- concentration (more tan 60 mEq/l) in sweat
50
Cystic fibrosis increases susceptibility to which bacterial infection
Pseudomonas aeruginosa
51
Cystic fibrosis increases resistance to which bacterial infection
Salmonella typhi
52
Complications that are usually seen in cystic fibrosis
* Recurrent pulmonary infections, chronic sinusitis, and bronchiectasis
* Pancreatic insufficiency
* Infertility in men (abscence of vas deferens) and subfertility in women (thick cervical mucus)
* Nasal polyps
* Clubbing of the nails
53
Type of mutation commonly seen in Duchenne muscular dystrophy
Frameshift mutation (and nonsense)
*This leads to a truncated or absent dystrophin protein
54
Mutated protein in Duchenne muscular dystrophy
Dystrophin
*Largest protein-coding human gene, increases chance of spontaneous mutations
55
Mode of inheritance of Duchenne muscular dystrophy
X-linked
56
Signs and symptoms of Duchenne muscular dystrophy
* Weakness of pelvic girdle muscles (progresses superiorly)
* Onset before 5 years of age
* Pseudohypertrophy of calf muscles (fibrofatty replacement)
* Waddling gait (duck-like walk, trunk sways side to side with wide base of support)
* Dilated cardiomyopathy (common cause of death)
57
Normal function of dystrophin
Anchors the actin cytoskeleton of muscle fibers to the transmembrane proteins alpha and beta dystroglycan, which are connected to the extracelular matrix
58
Laboratory findings seen in Duchenne muscular dystrophy
Increased CK and aldolase
*Loss of dystrophin results in myonecrosis
59
Type of mutation commonly seen in Becker muscular dystrophy
Non-frameshift deletions
60
Mutated protein in Becker muscular dystrophy
Dystrophin
61
Age of onset of Becker muscular dystrophy
Adolescence or early adulthood
62
Muscular dystrophy caused by a CTG trinucleotide repeat
Myotonic type 1 muscular dystrophy
63
Affected gene in myotonic type 1 muscular dystrophy
DMPK gene
*Abnormal expression of myotonin protein kinase
64
Signs and symptoms of myotonic type 1 muscular tystrophy
* Myotonia
* Muscle wasting
* Cataracts
* Testicular atrophy
* Frontal balding
* Arrhythmia
-- CTG: Cataracts, Toupee, Gonadalar atrophy
65
Define the Gower sign
Patient uses upper extremities to help stand up
*Classically seen in Duchenne muscular dystrophy
66
Trinucleotide repeat expansion disease in which there is increased number of repeats in an exon, coding for glutamine
Huntington disease
67
Most important gastrointestinal associations in Down syndrome
Duodenal atresia and Hirschprung disease
68
Most important cardiovascular association in Down syndrome
Endocardial cushion defects (atrioventricular septal defect)
69
Ophthalmologic sign associated with Down syndrome
Brushfeld spots (White/gray discolorations in the periphery of the iris)
70
Neurologic disease associated with Down syndrome
Early onset Alzheimer disease
*Chromosome 21 codes for amyloid precursor protein
71
Common hematologic malignancies associated with Down syndrome
ALL and AML (M7)
72
Most common etiology of Down syndrome
Meiotic nondisjunction in meiosis 1 (95% of cases)
73
Percentage of cases of Down syndrome that are the result of an unbalanced Robertsonian translocation
4%
74
Most common chromosomes involved in a Robertsonian translocation leading to Down syndrome
14 and 21
75
Diagnostic second trimester quad screen for Down syndrome
* Low alpha fetoprotein
* Low estriol
* High beta hCG
* High inhibin A
76
Classical ultrasound characteristic seen in Down syndrome
High nucal translucency and hypoplastic nasal bone
77
Signs and symptomes of Edwards syndrome
"PRINCE Edward"
* Prominent occiput
* Rocker-bottom feet
* Intellectual disability
* Nondisjunction
* Clenched fists (with overlapping fingers)
* low-set Ears
78
Gastrointestinal abnormalities associated with Edwards syndrome
* Meckel's diverticulum
| * Malrotation
79
Renal abnormalities associated with Edwards syndrome
Horseshoe kidney
80
Diagnostic quad screen for Edwards syndrome
Prince Edward is DOWN
* Low alpha fetoprotein
* Low beta hCG
* Low estriol
* Low (or normal) inhibin A
81
Trisomy of which chromosome is seen in Edwards syndrome
18
82
Trisomy of which chromosome is seen in Patau syndrome
13
83
Signs and symptoms of Patau syndrome
* Severe intelectual disability
* Rocker-bottom feet
* Microphthalmia
* Microcephaly
* Cleft lip/palate
* HOLOPROSENCEPHALY
* Polydactyly
* Cutis aplasia
84
Type of chromosome involved in Robertsonian translocations
Acrocentric chromosome (chromosomes with centromeres near their ends)
85
Chromosomal abnormality seen in Williams syndrome
Microdeletion of the long arm of chromosome 7 (elastin gene)
86
Signs and symptoms of Williams syndrome
* Elfin facies
* Intellectual disability
* Hypercalcemia (increased sensitivity to vitamin D)
* Well-developed verbal skills
* Extreme friendliness with strangers
* Cardiovascular problems
87
Signs and symptoms of 22q11 deletion
"CATCH-22"
* Cleft palate
* Abnormal facies
* Thymic aplasia leading to T cell deficiency
* Cardiac defects (most important is tetrallogy of Fallot)
* Hypocalcemia
88
Syndromes associated to 22q11 deletion
1. DiGeorge syndrome: thymic, parathyroid, and cardiac defects
2. Velocardiofacial syndrome: palate, facial, and cardiac defects
89
Aberrant development of which branchial pouches is associated with 22q11 deletion syndromes
3rd and 4th
90
Characteristics of autosomal dominant inheritance
* Disease observed in every generation
* Males and females affected equally
* Affected genes often structural genes
* Often pleiotropic and variably expressive
91
Characteristics of autosomal recessive inheritance
* Disease skips generations
* Males and females affected equally
* Often due to enzyme deficiencies
* Increased risk in consanguíneos families
92
Characteristics of X-linked recessive inheritance
* Males more than females
* Skipped generations are commonly seen
* Male-to-male transmission never seen
93
Characteristics of X-linked dominant inheritance
* Male-to-male transmission never seen
* Heterozygous females are affected
* Does not skip generations
94
Characteristics of mitocondrial inheritance
* Disease transmitted only from affected females
* Both males and females affected
* No offspring of the affected male affected
95
Leading known cause of intelectual disability and pregnancy loss
Chromosome abnormalities
96
Definition of karyotype
Display of 23 pairs of human chromosomes in typical somatic cells
97
Chromosomal abnormality that results from fertilization of an ovum by 2 sperm cells
Triploidy
98
Definition of a reciprocal translocation
Genetic material exchanged between non-homologous chromosomes
99
Consequences of reciprocal translocation during gametogenesis
* No clinical consequences for carrier
| * Reproduction by carrier may cause partial trisomies or monosomies
100
Consequences of reciprocal translocation in somatic cells
May lead to cancer if there is alteration of oncogenes or tumor supressor genes
101
Name the types of chromosomal inversions
* Paracentric (include the centromere)
| * Pericentric (doesn't include the centromere)
102
Consequences of chromosomal inversions
Carriers usually unaffected but offspring may have small partial trisomy
103
Chromosome structural abnormalities that result in Turner syndrome
* Loss of ring X chromosome
| * Isochromosome of long arm of X chromosome
104
What is an isochromosome
When a chromosome has 2 copies of one arm but no copy of the other
105
Mode of inheritance of achondroplasia
Autosomal dominant
106
Affected gene in familial adenomatous polyposis
APC gene on chromosome 5q21
107
Apart from adenocarcinoma of the colon, a mutation in the APC gene increases the risk for developing what other type of cancer
Adenocarcinoma of the duodenum and ampulla of Vater
108
Mode of inheritance of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
Autosomal dominant disorder
109
Signs and symptoms of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
* Blanching skin lesions (telangiectasias of skin and mucosas)
* Recurrent epistaxis
* Skin discolorations
* AVM
* GI bleeding
* Hematuria
* Possible iron deficiency anemia
110
Mode of inheritance of hereditary spherocytosis
Autosomal dominant
111
Pathogenesis of hereditary spherocytosis
Defect in proteins ankyrin, spectrin, band 3, and protein 4.2 (all part of the cell membrane), leading to a spherical shape of the erythrocytes, which are removed from the bloodstream by splenic macrophages
112
Signs and symptoms of hereditary spherocytosis
* Splenomegaly
* Hemolytic anemia
* Jaundice
* Pigmented gallstones
* Increased MCHC
113
Hereditary spherocytosis treatment
Splenectomy
114
Mode of inheritance of Huntington's disease
Autosomal dominant
115
Affected gene in Huntington's disease
HD gene in chromosome 4
116
Affected protein in Huntington's disease
Huntingtin
117
Trinucleotide repeat expansion seen in Huntington's disease
CAG
118
Pathogenesis of Huntington's disease
Degeneration of GABAergic neurons in the caudate nucleus leads to removal of inhibitory input in extrapiramidal circuit, resulting in chorea
119
Signs and symptoms of Huntington's disease
* Chorea
* Onset between ages 20 and 40
* Personality changes
* Dementia
120
Mode of inheritance of multiple endocrine neoplasia (MEN) syndromes
Autosomal dominant
121
Affected gene in multiple endocrine neoplasia (MEN) 1
MEN1 in chromosome 11, it is a tumor supresor gene
122
Affected protein in multiple endocrine neoplasia (MEN) 1
Menin
123
Multiple endocrine neoplasia (MEN) 1 associated tumors
* Pituitary (prolactinomas or GH)
* Pancreatic endocrine tumors (gastrinomas are the most common)
* Parathyroid adenomas (most common presentation)
124
Affected gene in multiple endocrine neoplasia (MEN) 2A and 2B
RET gene, which codes for a receptor tyrosine kinase in cells of neural crest origin (proto-oncogene)
125
Multiple endocrine neoplasia (MEN) 2A associated tumors
* Parathyroid hiperplasia or adenoma
* Pheochromocytoma
* Medullary thyroid carcinoma
126
Multiple endocrine neoplasia (MEN) 2B associated tumors
* Phecochromocytoma
* Medullary carcinoma of the thyroid
* Mucocutaneous neuromas
- Patients have a marfanoid habitus
127
Mode of inheritance of neurofibromatosis type 2
Autosomal dominant
128
Affected gene in neurofibromatosis type 2
NF2 in chromosome 22 (tumor suppressor gene)
129
Signs and symptoms of neurofibromatosis type 2
* Bilateral acoustic neuromas
* Neurofibromas
* Café-au-lait spots
* Increased risk for meningiomas and ependymomas
130
Mode of inheritance of tuberous sclerosis
Autosomal dominant
131
Affected gene in tuberous sclerosis
TSC1/TSC2 mutation on chromosome 16
132
Signs and symptoms of tuberous sclerosis
"HAMARTOMAS"
* Hamartomas in CNS, skin, and lungs
* Angiofibromas (butterfly pattern in face)
* Mitral regurgitation
* Ash-leaf spots
* Rhabdomyomas (cardiac)
* (Tuberous sclerosis)
* dÓminant
* Mental retardation
* Angiomyolipomas (renal)
* Seizures
* Shagreen patches
133
Apart from hamartomas, tuberous sclerosis predisposes the patient to what other type of CNS and ungueal tumor
Subependymal giant cell astrocytoma and ungual fibroma
134
Mode of inheritance of von Hippel Lindau syndrome
Autosomal dominant
135
Affected gene in von Hippel Lindau syndrome
VHL gene on chromosome 3p
*Tumor suppressor gene whose main action is to tag proteins with ubiquitin for degradation (eg, hipoxia-inducible factor)
136
Signs and symptoms of von Hippel Lindau syndrome
"HARP"
* Hemangioblastomas in retina, brain stem, cerebellum, spine
* Angiomatosis (cavernous hemangiomas) in skin, mucosa, and organs
* Renal cell carcinomas (bilateral)
* Pheochromocytomas
137
Mode of inheritance of Friedrich ataxia
Autosomal recessive
138
Affected gene in Friedrich ataxia
Frataxin gene, develops a GAA trinucleotide repeat on chromosome 9
139
Signs and symptoms of Friedrich ataxia
* Gait ataxia (pes cavus, hammer toes)
* Dysarthria
* Hand clumsiness
* Loss of sense of position
* Impaired vibratory sensation
* Arreflexia in all 4 limbs
* Diabetes mellitus
* Hypertrophic cardiomyopathy
140
Pathogenesis of Friedrich ataxia
Frataxin is essential for mitochondrial iron regulation, in its absence, mitochondrial iron builds up, leading to free radical damage and mitochondrial dysfunction
141
Only trinucleotide repeat expansion disease that appears in exons and actually codes for an aminoacid
Huntington's disease, CAG codes for glutamine
142
Sequence of events in disjunction during meiosis 1
1. Homologue chromosomes pair with each other at metaphase plate
2. During anaphase 1, homologues disjoin
3. At the end of meiosis 1, each daughter cell has 1 homolog
143
Sequence of events in disjunction during meiosis 2
1. During metaphase 2, each chromosome aligns individually at the metaphase plate
2. In anaphase 2, sister chromatids migrate to opposite poles
3. At the end of meiosis 2, each daughter cell has 1 chromatid
144
Normal function of the NF1 gene product
Inhibit p21/RAS oncoprotein
145
Most common trisomy among miscarriages
Trisomy 16
