Genetics (Part III) Flashcards
What is euploid?
any exact multiple of the haploid number of chromosomes (23)
What is aneuploidy?
if an error occurs in meiosis or mitosis and a cell acquires a chromosome complement that is not the exact multiple of 23
what are the 2 usual causes of aneuploidy?
nondisjunction and anaphase lag
what happens during nondisjunction?
during gametogenesis, the gametes formed either have an extra chromosome or one less chromosome
what happens during anaphase lag?
one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus; the result is one normal cell with monosomy
what is mosaicism?
mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement
what are ring chromosomes?
when a break occurs at both ends of a chromosome with fusion of the damaged ends
what is an example of a ring chromosome?
46 XY,r(14)
what is inversion of chromosomes?
rearrangement that involves 2 breaks within a single chromosome with reincorporation of that inverted intervening segment
what are the two different types of inversion of chromosomes can you have?
pericentric and paracentric
what is pericentric inversion?
when the breaks are on opposite sides of the centromere
what is paracentric inversion?
inversion involving only one arm of the chromosome
what are isochromosomes?
when one arm of a chromosome is lost, the remaining arm is duplicated–> results in a chromosome that contains 2 short arms only or 2 long arms only
What is translocation?
when a segment of one chromosome is transferred to another chromosome
What are the two different types of translocations?
balanced reciprocal and robertsonian/centric fusion
what are robertsonian translocations?
translocation between 2 acrocentric chromosomes
where do the breaks in the chromosomes typically occur with robertsonian translocations?
closer to the centromeres of each chromosome
what is the result of a robertsonian translocation?
transfer of segments–> 1 very large chromosome and 1 extremely small one; the small one typically is lost
what is the association with robertsonian translocations and trisomy 21?
approximately 3-4% of trisomy 21 cases are caused by robertsonian translocation, in which the q arm of chromosome 21 is translocated onto another chromosome
what is the result of the robertsonian translocation of chromosome 21?
the fetus has 46 chromosomes but 3 copies of the long arm of chromosome 21
What are the typical features of trisomy 21 patients?
typical facies with epicanthal folds and slanted palpebral fissures; single palmer crease
what is the most common chromosomal disorder?
down syndrome
what is the most common cause of trisomy 21?
meiotic nondisjunction; parents have a normal karyotype
in 4% of cases with down syndrome, robertsonian translocations occurred. What is found with these cells?
the genetic material normally found on long arms of two pairs of chromosomes is distributed among only 3 chromosomes
What is the main associated risk with trisomy 21 patients?
40% of trisomy 21 patients have congenital heart disease
what is the most common congenital heart disease seen with trisomy 21 patients?
atrioventricular septal defects (AVSD)
what follows AVSD in the line of congenital heart disease associated with trisomy 21?
VSD, then ASD, then tetralogy of fallot
What is responsible for the majority of the deaths in infancy and early childhood in patients with trisomy 21?
the cardiac abnormalities
What are trisomy 21 patients at increased risk of developing?
acute leukemia
trisomy 21 patients have a 20x increased risk of developing what leukemia?
acute B lymphoblastic leukemia
trisomy 21 patients have a 500x increased risk of developing what leukemia?
acute myeloid leukemia (usually acute megakaryoblastic leukemia)
what leukemia is very uncommon and almost always associated with trisomy 21?
megakaryoblastic leukemia
virtually all patients with trisomy 21 who are >40 years old will develop what?
neuropathologic changes characteristic of Alzheimer disease
abnormal immune responses predispose trisomy 21 patients to serious infections particularly of what organs?
the lungs and to thyroid autoimmunity
progress in unraveling the molecular basis of down syndrome has been quite slow due to what?
1) down syndrome results from gene dosage imbalance rather than the action of a few genes 2) majority of the protein coding genes of chromosome 21 are overexpressed 3) the genes overexpressed in down syndrome are directly involved in regulation of mitochondrial function 4) chromosome 21 has the highest density of noncoding RNAs
how can we perform an non-invasive screening test for prenatal diagnosis of trisomy 21?
because 5-10% of the total cell free DNA in maternal blood is from the fetus and we can test by polymorphic genetic markers
what is one of the main protein coding genes of chromosome 21 that is overexpressed in down syndrome?
amyloid-beta precursor protein (APP)
what is the significance of amyloid-beta precursor protein aggregates?
aggregation of amyloid beta proteins is critical in the development of Alzheimer disease
What is trisomy 13?
Patau syndrome
what is trisomy 18?
Edwards syndrome
What is unique to patau syndrome?
microcephaly, cleft lip and palate, small eyes
which trisomies have rocker bottom feet?
Edwards syndrome and Patau syndrome
which trisomy has over lapping fingers?
Edwards syndrome
which trisomy has polydactyly?
Patau syndrome
which trisomies have umbilical hernias?
down syndrome and patau syndrome
which trisomy has renal defects?
patau syndrome
which trisomy has renal malformations such as horseshoe kidney?
edwards syndrome
what do all of the trisomies have in common?
all have problems with congenital heart defects and all have intellectual disabilities
why is chromosome 22q.11.2 deletion syndrome usually missed?
because there are variable clinical features
what are some of the features you might see in chromosome 22q.11.2 deletion syndrome?
congenital heart defects, abnormalities of the palate, facial dysmorphism, developmental delay, and variable degrees of T-cell immunodeficiency and hypocalcemia; there is also a high risk of psychotic illnesses
patients with DiGeorge syndrome have what symptoms?
thymic hypoplasia with resultant T cell immunodeficiency, parathyroid hypoplasia, which leads to hypocalcemia, cardiac malformations, and mild facial anomalies
what are the clinical features of velocardiofacial syndrome?
facial dysmorphism, cleft palate, cardiovascular anomalies, and learning disabilities
what syndromes are associated with chromosome 22q.11.2 deletion syndrome?
DiGeorge syndrome and Velocardiofacial syndrome
what are the facial abnormalities seen in Velocardiofacial syndrome?
long face, narrow palpebral fissures, puffy lids, over-folded helix, nose is pear-shaped
Imbalances (excess or loss) of sex chromosomes are much better tolerated than are similar imbalances of autosomes. Why?
1) lyonization of all but one X chromosome 2) the modest amount of genetic material carried by the Y chromosome
what is the lyon hypothesis?
only one of the X chromosome is genetically active
when does inactivation of either the maternal or paternal X occur?
on or about day 5.5 of embryonic life
what happens to the inactive X?
it is compacted to make a small dense structure called a Barr body
when are sex chromosome disorders usually diagnosed?
first recognized at puberty
in general, sex chromosome disorders cause what?
subtle chronic problems relating to sexual development and fertility
what is Klinefelter syndrome?
male hypogonadism that occurs when there are two or more X chromosome and one or more Y chromosomes
what is the classic karyotype of Klinefelter syndrome?
47, XXY
What is the most common cause of hypogonadism in males?
Klinefelter syndrome
what do patients with Klinefelter syndrome have an increased risk of developing?
Type 2 DM and metabolic syndrome; increased risk of breast cancer; extragonadal germ cell tumors (mostly mediastinal teratomas); and SLE
what could result from the hormone imbalance seen in Klinefelter syndrome?
osteoporosis
Klinefelter syndrome is an important genetic cause of what?
reduced spermatogenesis and male infertility
what are the main clinical features seen in Klinefelter syndrome?
gynecomastia, osteoporosis, lack of secondary male characteristics
What is the most common sex chromosome abnormality in females?
Turner syndrome
What is turner syndrome?
complete or partial monosomy of the X chromosome characterized by hypogonadism in phenotypic females
What is the main karyotype seen in turner syndrome?
45, X
What are the 3 types of karyotypic abnormalities seen in Turner Syndrome?
missing the entire X chromosome, partial monosomy of X chromosome, mosaic patients have 45, X cell population plus >1 karyotypically normal cells
What are Turner syndrome patients with a Y chromosome sequence at an increased risk for?
increased risk for developing gonadoblastoma
What is cystic hygroma seen in Turner syndrome?
infant with edema–> swelling of the nape of the neck due to lymph stasis
what happens to patients with cystic hygroma?
as the infants develop, the swellings subside but leave bilateral neck webbing and persistent looseness of skin on the back of the neck
What are patients with turner syndrome at risk of also having?
congenital heart disease
what are the congenital cardiac abnormalities seen in patients with turner syndrome?
left-sided cardiovascular abnormalities–> especially preductal coarctation of the aorta and a bicuspid aortic valve
what is the most important cause of increased mortality in children with turner syndrome?
cardiovascular abnormalities
what are the clinical presentations of Turner syndrome?
shortness of stature, webbing of the neck, cardiovascular malformations, amenorrhea, lack of secondary sex characteristics and fibrotic ovaries
what is the most important cause of primary amenorrhea?
Turner syndrome
how are the ovaries described in patients with turner syndrome?
streak ovaries
what do around 50% of patients with Turner syndrome eventually develop?
autoantibodies that react with the thyroid gland–> leads to hypothyroidism
what are some minor problems that can arise from Turner syndrome?
glucose intolerance, obesity, NASH, and insulin resistance
what is a true hermaphrodite?
presence of both ovarian and testicular tissue
what is pseudohermaphrodite?
a disagreement between the phenotypic and gonadal sex
what is a female pseudohermaphrodite?
they have ovaries but male external genitalia
what is a male pseudohermaphrodite?
they have testicular tissue but female type genitalia
What are the four categories of single-gene disorders with non-classic inheritance?
diseases caused by trinucleotide-repeat mutations; disorders caused by mutations in mitochondrial genes; disorders associated with genomic imprinting; disorders associated with gonadal mosaicism
What are two examples of trinucleotide repeat disorders?
fragile x syndrome and huntington disease
what is the gene associated with fragile X syndrome?
FMRI
what is the repeat associated with fragile x syndrome?
CGG
what is the gene associated with huntington disease?
HTT
what is the chromosome associated with huntington disease?
chromosome 4
what is the normal CGG repeat for the FMRI gene?
6-55
what is the number of trinucleotide repeats associated with fragile x syndrome?
55-200 (pre disease) and and expand to 4000 during oogenesis
what is the normal number of CAG in on the HTT gene ?
6-35
what is the number of CAG associated with Huntington disease?
36-121
what type of defect is associated with expansion of trinucleotide repeats?
neurodegenerative disorders
what does the expansion of trinucleotide-repeats depend strongly on?
on the sex of the transmitting parent
when do fragile x syndrome repeats occur?
during oogenesis
when do huntington disease repeats occur?
during spermatogenesis
what is the mechanism associated with fragile x syndrome?
loss of function of the affected gene (repeats are in non-coding region)
what is the mechanism associated with Huntington disease?
toxic gain of function (expansions occur in coding region)
what is the mechanism associated with fragile x tremor ataxia syndrome?
toxic gain of function mediated by mRNA (non coding parts of gene affected)
What is a morphologic hallmark of the diseases caused by trinucleotide-repeat mutations?
accumulation of aggregated mutant proteins in large intracellular inclusions
What happens when we increase the number of copies of trinucleotide repeats in huntington’s disease?
we get an earlier age of onset
what is the mechanism associated with Friedreich ataxia?
loss of protein function
what is the trinucleotide repeat associated with Friedreich ataxia?
GAA
what is the second most common genetic cause of intellectual disability?
fragile x syndrome
what happens when the trinucleotide repeats in the FMR1 gene exceed 230?
the DNA of the entire 5’ region of the gene becomes abnormally methylated leading to a loss of function of the FMR protein
what neuro symptoms do affect males with fragile x syndrome have?
intellectual disability, epilepsy, aggressive behavior, autism, anxiety, or hyperactivity
what is the phenotype of fragile x syndrome?
long face with a large mandible, large everted ears, large testicles (macro-orchidism), hyperextensible joints, high arched palate, and mitral valve prolapse
what is the most distinctive feature of fragile x syndrome?
macro orchidism
what are some patterns of transmission seen in fragile x syndrome that are not typically associated with other x-linked recessive disorders?
carrier males, affected females, anticipation
for fragile x, when can premutations be converted to mutations by triplet-repeat amplification?
during the process of oogenesis (NOT SPERMATOGENESIS)
what is anticipation of fragile x syndrome?
clinical features of fragile x syndrome worsen with each successive generation
CGG premutations in the FMR1 gene can cause two disorders that are phenotypically different from FXS. What are they and what is their mechanism?
fragile x-associated primary ovarian failure and fragile-x associated tremor/ataxia; toxic gain of function
what is fragile x-associated primary ovarian failure?
20% of females carrying the premutation (carrier females) have premature ovarian failure (before the age of 40)
what are the symptoms of affected women with fragile x-associated primary ovarian failure?
menstrual irregularities and decreased fertility; develop menopause approximately 5 years earlier
what is fragile x-associated tremor/ataxia?
50% of premutation-carrying males (transmitting males) exhibit a progressive neurodegenerative syndrome starting in their 6th decade
how is fragile x-associated tremor/ataxia characterized?
intention tremors and cerebellar ataxia and may progress to parkinsonism
how does a Huntington brain compare to a normal brain?
the HD patient will have a flattening of the ventricle rather than the head of the caudate and globus pallidus projecting out into the lateral ventricle; the HD patient will have global atrophy
what does mitochondrial DNA primarily encode? and what is the effect of this on mutations in mitochondrial genes?
enzymes in oxidative phosphorylation; mutations primarily effect CNS, skeletal muscle, cardiac muscle, liver, and kidneys
what is heteroplasmy?
tissues and individuals harbor both wild-type and mutant mitochondrial DNA
what is the threshold effect when talking about mutations in mitochondrial genes?
minimum number of mutant mitochondrial DNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease
what is the prototypical mitochondrial disorder?
Leber hereditary optic neuropathy (LHON)
what is the effect of Leber hereditary optic neuropathy?
it is a neurodegenerative disease that manifests as a progressive bilateral loss of central vision
when is visual impairment first noted in patients with LHON?
between ages 15-35
besides the bilateral loss of central vision, what has also been observed in LHON patients?
cardiac conduction defects and minor neurologic manifestations
what occurs during genomic imprinting?
imprinting selectively inactivates either the maternal or paternal allele
what does maternal imprinting refer to?
transcriptional silencing of the maternal allele
what does paternal imprinting refer to?
transcriptional silencing of the paternal allele
where and when does imprinting occur?
it occurs in the ovum or the sperm before fertilization
What are the 3 mechanisms of genomic imprinting?
1) deletions 2) uniparental disomy 3) defective imprinting
what occurs during deletions during genomic imprinting?
a gene or a set of genes on the maternal chromosome 15q12 is imprinted (silenced)
what is uniparental disomy?
inheritance of both chromosomes of a pair from one parent
what is prader-willi syndrome characterized by?
intellectual disability, short stature, hypotonia, profound hyperphagia, obesity, small hands/feet, and hypogonadism
what causes prader-willi syndrome?
deletion of band q12 in the long arm of chromosome 15 (del(15)(q11.2q13)) on the paternal chromosome
what is Angelman syndrome characterized by?
intellectual disability, ataxic gait, seizures, and inappropriate laughter
what causes Angelman syndrome?
deletion of q12 in the long arm of chromosome 15 on the maternal chromosome
