Final Flashcards
Divergence of X and Y
Four inversions, development of SRY gene (moved from q to p), Y shrinks d/t no homologous recombination
What are the PAR regions?
pseudoautosomal regions on tips of sex chromosomes
PAR1 genes
p arm- all escape inactivation in women
SHOX
PAR1 gene. missing one- short. missing two-dysplasia. Can be recombination to Y, leading to male-male transmission (inherited from mother, recombination happens, pass on to son)
when does sexual differentiation start?
around 6 weeks
CAH cause and frequency
1/12,000 live births. Most frequently due to 21-hydroxylase deficiency (21-OH) encoded by CYP21A2 gene. Enzyme deficiency leads to excess testosterone production by adrenal glands and lack of cortisol and aldosterone production. impaired synthesis of cortisol from cholesterol by the adrenal cortex
classic CAH forms
- Simple virilizing 21-OHD CAH
2. Salt-wasting 21-OHD (with/without virilization) – 75% of all individ
dexamethasone
Off label to prevent genital virilization in females. Does not impact salt-wasting. Long term effects still being studied.
AIS frequency
1/20,000 live births
AIS management
To prevent testicular malignancy, individuals with complete AIS may remove testes after puberty or have prepubertal gonadectomy accompanied by estrogen replacement therapy
5-ARD cause
Mutations in the SRD5A2 gene (on 2p23) prevent steroid 5-alpha reductase 2 from converting testosterone to DHT. DHT critical for formation of external genitalia before birth. During puberty, testes produce more testosterone, thus can develop secondary male sex characteristics (testes descends, micropenis or clitoris grows larger, deepening voice. Do not develop much facial or body hair)
Why does extra X’s still have an effect after X inactivation?
Not all genes inactivated. Abnormal dosage in embryogenesis before X inactivation. X-inactivation occurs at ~3 days post fertilization and completed by the end of first week of gestation.
Most frequent sex chromosome abnormality observed at birth in females
XXX (from maternal nondisjunction in meiosis I)
Phenotype of XXX
Very variable. Seizures, DD, subfertility
XXY phenotype
taller than average, gynecomastia, small testes in adulthood, inadequate testosterone production thus requiring testosterone supplement, slightly lower IQ. Most are infertile. Some psychological problems.
4 phenotypic categories of X-autosome translocations
- normal phenotype with or without recurrent miscarriages
- gonadal dysfunction with primary amenorrhea or
premature ovarian failure - known X-linked disorder
- congenital abnormalities and/or developmental delays
- gonadal dysfunction with primary amenorrhea or
Fragile X associated with which gene?
FMR1
Where is fragile X mutation?
5’ UTR promoter region. 6-54 CGG repeats with two AGG interruptions at positions 11 & 22.
Fragile X premutation carrier
55 to 200 CGG repeats without methylation of the FMR1 promoter
Fragile X full mutation
> 200 CGG repeats with methylation of the FMR1 promoter (methylation shuts down the gene)
Molecular test for fragile X
PCR (fast, pretty good repeat counting). Southern blot (less accurate for size, but can see expansion, can measure methylation, slow)
most common single gene cause of autism
fragile x
fragile x common presentation
2-3 y.o. boy, multiple ear infections, speech delay, global developmental delay
conditions of expression of fragile x premutation
FXPOI and FXTAS
FXPOI
Amenorrhea, elevated FSH, estrogen defeciency, subfertility (20-30% of premutation carriers). Most seen at 80-100 repeats
FXTAS
tremor, ataxia, cognitive deficits, peripheral neuropathy, anxiety. About 33% of male carriers and 5-8% of female carriers
Intermediate zone for fragile x repeats
45-54 (loss of AGG interruption leads to instability)
Fragile X expands through
mom
FMRP absence
impairs maturation and pruning of neuron synapses
Are Mendelian or chromosomal abnormalities more common?
chromosomal
Average heterozygocity upon SNP array
25-28%
What does SNP array detect that aCGH does not?
ROH, polyploidy, UPD
what can a microarray NOT tell you?
location of indels, presence of balanced rearrangements
typical resolution of karyotypes
5 Mb
typical array resolution
20-50 kb
CNVs
Stretches of DNA larger than 1000 bp. Use CMA to detect these. dels or dups undetectable by conventional sequencing analysis (opposite end of spectrum from karyotype). If sequencing is negative, del/dup by aCGH recommended
when is chromosomal microarray recommended?
ID/DD, multiple congenital anomalies, when differential includes more than one condition
indels
Insertion/deletionsless than 1000 bp. Use sequencing to detect these
on a microarray, one extra copy is numerically where?
0.5
on a microarray, one missing copy is numerically where?
-1
what is most recent genome build?
hg38 or build 38, released in December 2013
estimated SNVs in genome
10 million
what type of array has the 3 tracks?
SNP
For a DD indication, what is diagnostic yield upon karyotyping? Upon aCGH after normal karyotype? Upon microarray as first line?
5%; 10-15%; 15-20%. So can be used as first tier
when is highest prenatal microarray yield?
With abnormal US and normal karyotype
Is microarray or karyotype better on stillbirth?
microarray- 87% (karyotype- 70%)
CAH inheritance
auto rec
5-ARD inheritance
auto rec
Can females have 5-ARD?
No. They can be homozygous for the mutation, but they don’t require DHT, so are not affected.
AIS inheritance
X linked (recessive)
When does meiosis occur in females?
initiated once at 4 months gestation, remain arrested in prophase I (dictyotene), first division at ovulation, stops at metaphase II, second division at fertilization
When does meiosis occur in males?
ongoing initiation/production beginning at puberty, complete at 20(?) days. Entire process takes ~64 d.
Parts of interphase
G1, S, G2
Phases of mitosis
Prophase, prometaphase, metaphase, anaphase, telophase
With a balanced translocation, which kind of segregation in meiosis can lead to balanced or normal gametes?
Alternate
What type of inversion is most likely to lead to abnormal liveborn?
Pericentric- Unbalanced gametes likely to have one centromere and can therefore are more viable and can produce abnormal phenotypes.
Which chromosomes have known imprinting disorders?
6, 7, 11, 14, 15, 20
