Endo/Repro - Genetics - Autosomes; Sex Chromosomes; Uniparental Disomy Flashcards
What are the three categories of genetic disorder?
- Chromosomal
- Metabolic
- Syndromic
Define: mosaicism.
An individual with two genetically distinct cell lines coming from a single zygote
True/False.
Mosaicism results from a meiotic non-disjunction event occuring in the pre-zygotic phase.
False.
Mosaicism results from a mitotic non-disjunction event occuring in the post-zygotic phase.
Define: nondisjunction.
The failure of chromosomes to separate during meiosis I or mitosis (or sister chromatids during meiosis II)
What is here described?
The failure of two homologous chromosomes to separate during meiosis I, or two chromatids of a chromosome to separate in meiosis II or mitosis resulting in one daughter cell with two homologous chromosomes and the other with none.
Nondisjunction
What are three infant S/Sy that indicate you might need to check for chromosomal abnormalities?
- Growth restriction
- Structural abnormalities (especially >1)
- Developmental delay, or mental retardation
What type of genetic disorder is characterized by some mixture of the following?
- Growth restriction
- Structural abnormalities, especially more than one
- Developmental delay, or mental retardation
Chromosomal abnormalities
What are two common causes of trisomies?
- Nondisjunction (often due to advanced maternal age)
- Translocation
What is the most common form of chromosomal translocation?
14;21 Robertsonian translocation
What risk of Down syndrome does a woman’s pregnancy carry if the woman is 20?
35?
40?
49?
- 06%
- 3%
- 0%
- 1%
If a woman has given birth to a child with Down syndrome, is there a difference to future pregnancies whether the Down syndrome was caused by trisomy 21 or 14;21 Robertsonian translocation?
Yes.
If trisomy 21:
there is a 1% risk until about age 40 (then normal age risks)
If 14;21 Robertsonian translocation:
– de novo: not significantly higher
– maternal carrier: 10-15%
– paternal carrier: 3- 5%
What percentage of Down syndrome cases are due to trisomy 21?
What percentage are due to translocations?
What percentage are due to trisomy mosaicism?
95%
4%
1%
What is the genetic cause of the vast majority of cases of Down syndrome?
Trisomy 21 (95%)
What are the classical S/Sy of Down syndrome?
Mental retardation,
hypotonia, protruding tongue, short stature,
upslanting palpebral fissures, epicanthal folds,
transverse palmar crease, clinodactaly of 5th finger
What intestinal and ocular signs are often present in Down syndrome?
Intestinal: duodenal atresia
Ocular: speckled iris (Brushfield spots)
What cardiac complications often exist in patients with Down syndrome?
Atrio-ventricular canal;
VSD
True/False.
Individuals with Down syndrome are at a higher risk for Alzheimer’s disease, leukemia, hypothyroidism, and cataracts.
True.
What is the genetic cause of Edward’s syndrome?
Trisomy 18
What is the genetic cause of Patau syndrome?
Trisomy 13
How long do patients with Edward’s syndrome typically live?
< 1 year
List a few of the common S/Sy of Edward’s syndrome.
How long do these patients typically live?
Microcephaly, prominent occiput, low set ears,
clenched hands (index finger overlies 3rd finger)
< 1 year
What non-neurological organ system is often severely affected in patients with Edward’s syndrome?
>90% have congenital heart disease
How common is Down syndrome?
How common is Edward’s syndrome?
How common is Patau syndrome?
1/1000
1/10,000
1/15,000
What is the life expectancy for an individual with Down syndrome?
What is a common cause of death?
60s
congenital heart disease
What is the life expectancy for an individual with Patau syndrome?
~85% are < 1 year;
rarely, some may reach adulthood
Describe some of the visible clinical features of Patau syndrome.
Cleft lip/palate (midline usually): 70%;
abnormal ears, scalp defects;
polydactyly;
omphalocele
Describe some of the non-visible clinical features of Patau syndrome.
Holoprosencephaly, mental retardation;
congenital heart abnormalities;
single umbilical artery
What are some of the heart abnormalities associated with Patau syndrome?
VSD
PDA
ASD
Which autosomal monosomies are survivable?
None
(unless mosaic with a normal cell line)
What is it called if an individual receives an extra 23 chromosomes from one of their parents?
Triploidy
True/False.
Triploidy in humans is an example of genetic imprinting, depending on whether the error was received from the father or the mother.
True.
What is the genetic cause and effect if an individual receives an extra 23 maternal chromosomes (triploidy)?
- Digyny (triploid zygote –> haploid sperm and diploid egg)
- Small placenta, very growth-restricted fetus
What is the genetic cause and effect if an individual receives an extra 23 paternal chromosomes (triploidy)?
- Dispermy, paternal nondisjunction
- Large hydropic placenta (incomplete mole);
3,4 syndactyly, macrocephaly, deformed face, other malformations
Which is more useful in chromosomal analysis, prometaphase or metaphase analysis?
Why?
Prometaphase;
improved band resolution + detection of smaller deletions
A newborn presents with a small face, large nose, and large mouth. The patient shows poor motor tone and is making a high-pitched ‘mewling’ like that of a cat.
What is the diagnosis? What is the cause?
Cri-du-Chat syndrome;
microdeletion on chromosome 5p
Describe Cri-du-Chat syndrome.
Affected chromosome: 5p
characteristic newborn cry like a cat;
small face, large nose, large mouth;
failure to thrive, developmental delay, hypotonia
Describe the presence of fetal testis on development of the Wolffian or Mullerian ducts.
Leydig cells –> testosterone –> mesonephric (Wolffian) differentiation
Sertoli cells –> MIF –> paramesonephric (Mullerian) degeneration
What structures are formed due to the effects of fetal testosterone?
What structures are formed due to the effects of fetal dihydrotestosterone?
Epididymus, vas deferens, seminal vesicles;
penis, prostate, scrotum
Describe the effects of fetal ovaries on development of the Wolffian or Mullerian ducts.
Mesonephric (Wolffian) degenerate (due to the lack of testosterone);
paramesonephric (Mullerian) develop (due to the lack of MIF)
What adult structures develop from the paramesonephric (Mullerian) ducts?
The upper 1/3 of the vagina,
the uterus,
the Fallopian tubes
Define: Lyonization.
At ~2 weeks post-fertilization, one X chromosome in each cell of the female embryo becomes inactive
What process is defined below?
At ~2 weeks post-fertilization, one X chromosome in each cell of the female embryo becomes inactive
Lyonization
Define: gonadal dysgenesis.
Poorly developed or streak gonads due to various causes
What term describes the following:
an individual born with both ovarian and testicular tissue.
True hermaphroditism
List the genetic makeup of each of the following cases:
Kleinfelter’s syndrome
Turner’s syndrome
Trisomy X
Androgen insensitivity
47, XXY
45, XO
47, XXX
46, XY
What is male pseudohermaphroditism?
An XY male with externally ambiguous or feminine genitalia
What is female pseudohermaphroditism?
An XX female with externally ambiguous or masculine genitalia
Classic Turner’s syndrome involves complete loss of what?
An X chromosome
(45,X0)
Turner’s syndrome can also result from a loss of the X p arm or q arm. Describe the differences.
46, XX, Xp-: short stature; congenital malformations
46, XX, Xq-: gonadal dysfunction
What medication(s) can be given to treat Turner’s syndrome?
Estrogen, progesterone, growth hormone
True/False.
Turner’s syndrome leads to the following S/Sy:
cystic hygromas, short stature, cardiac and renal abnormalities, mental retardation, lack of development of secondary sexual characteristics.
False.
Turner’s syndrome leads to the following S/Sy:
cystic hygromas, short stature, cardiac and renal abnormalities, average intelligence (no mental retardation), lack of development of secondary sexual characteristics.
What is the mechanism of Kleinfelter’s syndrome?
Meiotic nondisjunction
Describe the development, puberty, and fertility of an individual with Kleinfelter’s syndrome.
Development: Normal (tall, thin); IQ slightly less than normal; behavioral problems
Puberty: Small testis; hypogonadism, gynecomastia
Reproduction: Infertile (hylanized tubules; azoospermia)
How is Kleinfelter syndrome treated?
Testosterone replacement
Describe the development and fertility of a 47, XYY male.
Development: Normal male; tall; behavioral problems
Fertility: normal
What is the cause of 47,XYY defects?
Paternal nondisjunction
Describe the development and fertility of a 47,XXX individual.
Development: Normal female; development: tall; low IQ
Reproduction: Many infertile
What is the cause of androgen insensitivity syndrome?
No androgen receptor in target cells
How do individuals with androgen insensitivity syndrome present at birth?
What is their karyotype?
As females;
46,XY
Describe the developmental effects of androgen insensitivity syndrome.
Development: Feminization; incomplete adrenarche; amenorrhea; small clitoris/labia;
lower 2/3 of the vagina; absent uterus and tubes and mesonephric structures
What is the risk of gonadal neoplasia in an individual with androgen insensitivity syndrome?
2 - 5%
What is the risk of poorly differentiated gonadal tissue in an intraabdominal environment?
Increased risk of gonadal carcinoma
What should occur if a 46,XY individual has any form of gonadal dysgenesis?
Surgical removal of gonadal tissue
What do 46,XY/45,X0 and 46,XX/45,X0 karyotypes describe?
Male and female forms of mosaic Turner’s syndrome
What karyotype is known as a ‘super male’?
What karyotype is known as a ‘super female’?
XYY
XXX
What gene determines sexual differentiation?
SRY
What is Fragile X syndrome?
What is the genetic defect?
Which parent is more likely to pass on / worsen this defect?
X-linked mental retardation;
CGG repeats in the FMR1 gene;
maternal
What are two disorders displaying anticipation?
Fragile X syndrome;
Huntington’s disease
In working up potential Fragile X syndrome, how can genetic testing be performed?
a) Southern analysis — separates trinucleotide repeat segments based on size
b) PCR — will give size of mutation (best for premutations)
Best to do both
Define: infertility.
(1) Inability to achieve conception or (2) inability to sustain a pregnancy through to live birth
What are a few chromosomal abnormalities associated with infertility?
- Turner’ syndrome
- Kleinfelter’s syndrome
- X chromosome abnormalities
- Y chromosome microdeletions
- Translocations (reciprocal and Robertsonian)
True/False.
Some genes are expressed preferentially in either the parental or maternal genotype.
True.
How is genetic imprinting regulated?
Epigenetics (extrinsic to changes in primary nucleotide sequence)
- DNA methylation
- Histone modification
- Non-coding RNAs
Define: genetic imprinting.
The differential modification of the maternal and paternal genetic contribution to the zygote
Define: uniparental disomy.
The inheritance of a pair of chromosomes from one parent with no copy of that chromosome from the other parent.
Give the term described below.
The inheritance of a pair of chromosomes from one parent with no copy of that chromosome from the other parent.
Uniparental disomy
Describe the subtype of uniparental disomy below:
Isodisomy
Two copies of the same homolog from one parent
Describe the subtype of uniparental disomy below:
Heterodisomy
One copy of each homolog from the same parent
Describe the subtype of uniparental disomy below:
Segmental UPD
A segment of a chromosome is present from the same parent
Describe trisomy rescue as a cause of uniparental disomy.
True/False.
All of the following are potential causes of uniparental disomy:
- Trisomy Rescue
- Monosomy Rescue
- Gametic Complementation
- Somatic Crossing-over
- Robertsonian Translocation
True.
70% of cases of Prader-Willi syndrome are caused by a deletion of:
25% of cases of Prader-Willi syndrome are caused by:
5% of cases of Prader-Willi syndrome are caused by:
Paternal chromosome 15 genetic material
maternal uniparental disomy of chromosome 15
imprinting center defects
What is the basic etiology of Prader-Willi syndrome?
Loss of function of a group of genes normally expressed on the paternal chromosome 15
What is the basic etiology of Angelman syndrome?
Loss of function of a group of genes normally expressed on the maternal chromosome 15
What syndrome is caused by a loss of function of a group of genes normally expressed on the maternal chromosome 15?
What syndrome is caused by a loss of function of a group of genes normally expressed on the paternal chromosome 15?
Angelman syndrome;
Prader-Willi syndrome
Describe the clinical features of Prader-Willi syndrome.
Neonatal hypotonia, intellectual impairment, short stature, small hands and feet, hypogonadism, behavior problems, obesity
Facial features: narrow bifrontal diameter, short upturned nose, triangular mouth, thin upper lip, almond-shaped eyes
Describe the clinical features of Angelman syndrome.
Severe intellectual impairment, seizures, ataxia, paroxysms of laughter, absent speech, wide mouth with protruding tongue, widely spaced teeth
70% of cases of Angelman syndrome are caused by a deletion of:
3-7% of cases of Angelman syndrome are caused by:
5-11% of cases of Angelman syndrome are caused by a mutation in what gene?
3% of cases of Angelman syndrome are caused by:
Genetic material on the maternal chromosome 15
Paternal uniparental disomy
UBE3A
Imprinting center defect
