Sex chromosomes/infertility Flashcards
Describe X inactivation
It’s an mechanism to bring about equal gene expression of X-linked genes between male and females.
It’s an epigenetic process called lyonisation which results in transcriptional silencing (hypermethylation of X chromosome).
Where is the X inactivation centre XIC
Xq13 (XIST gene that’s required in initiate inactivation, not maintain it).
Describe X inactivation
X-inactivation patterns are reset at oogenesis.
In late morula/ early blastocyst stage random X inactivation occurs in each cell. This inactivation pattern is then stably inherited by each daughter cell.
XIST (cis acting RNA molecule) spreads in both directions along the X chromosome and ‘coats’ the chromatin which prevents transcription and maintains inactivation by repressing acetylation and promoting Histone modification and DNA methylation of CpG Islands causing the chromatin conformation to remain closed.
What does Tsix do
It’s a RNA that’s transcribed from the XIST antisense strand.
It’s expressed very early in the embryo (pre random X inactivation) and acts repressing XIST by regulating chromatin structure by altering Histone tail modifications and DNA methylation of the XIST promoter.
Prior to X-in both X’s weakly express XIST and Tsix. Following X-in the inactive X only expresses XIST and the active X only expresses Tsix but only for several days.
Why is Tsix only expressed for several days
Because the repression of XIST is maintained by DNA methylation.
How do you test for X-in skewing and what’s the maximum normal skew
Late replication studies. MS PCR.
Skewing considered if the ration is above 80:20.
In terms of inactivation mention some considerations with an structurally abnormal X
Inactivation patterns always results in the least imbalance (functional imbalance). Balanced t(X;A) - the intact X would be preferentially inactivated.
Unbalanced X:
46,X,der(X)t(X;A) - inactivation: derX with spreading into autosomal segment to prevent functional trisomy.
46,X,der(A)t(X;A) - inactivation of X segment of derA without spreading to autosome.
Del(X) - deleted X would be inactivated.
What do LINES do in X inactivation
Proposed to enable the interaction of XIST RNA to the X.
LINES are present on autosome a and throughout X. This may explain how inactivation can spread to the autosome segment in a t(X;A).
Possible regions that don’t get inactivated as don’t have appropriate LINE sequence.
Name the features of Turner syndrome
Prenatal: Renal anomalies (horseshoe kidneys). Cystic hygroma. CHD (left side). ascites. Pleural effusion
Postnatal:
Short stature. Short, webbed neck. Low hairline at back of neck. Broad shield-like chest with widely spaced nipples. Puffy hands and feet. Horseshoe kidneys. Cubits Valgus (wide carrying angle). Hypoplastic left heard, coarctation of the aorta. Amenorrhea (ovarian failure, streak ovaries). Mentally normal.
What’s the incidence of turners
1/2500 live births.
98% 45,X conceptuses that are identified are lost and probably represent embryos that are non-mosaic. (15% of all spontaneous abortions)
What are the turners variants and their incidences
45,X: 55%. 46,X,abnX: 25%. 46,X,i(X)(q10): 12-20%. r(X): 5%. Del(Xp): 5%
20% mosaic:
7%: 45,X/46,XX/47,XXX.
6-11%: 45,X/46,XY and 45,X/46,X,mar.
What genes and regions are implicated in turners
SHOX (Xp22.33/ Yp11.3) bone development and growth.
Loss of one copy is likely to cause short stature and skeletal anomalies.
Xp11.2-p22.1: important in ovarian failure (gonadal dysgenesis).
Discuss turners and gonadal dysfunction
Primary amenorrhea, ovarian hypo function, POI, streak ovaries, infertility (ooctyes apoptose and disappear at an accelerated rate- gone by 2yrs), failure to develop secondary sexual characteristics.
Discuss numerical mosaicism in turners
45,X/46,XX/47,XXX or 45,X/46,XY.
Have milder phenotypes, generally taller, may enter puberty spontaneously, likely to have secondary amenorrhea/ premature menopause, may be fertile.
What sex will a 45,X/46,XY phenotypically be
90% : male external genitalia with abnormal internal genitalia.
10% : ambiguous or female genitalia
Discuss structural mosaicism in turners
45,X/47,X,i(Xq10) or 45,X/46,X,r(X) or mar.
Feature fewer turner stigmata. Perhaps only short stature, gonadal dysgenesis.
Pts with mar MUST be investigated SRY as if Y material is present in a phenotypic female there’s an increased Risk of gonadoblastoma.
Treatment for turners
If have CHD must monitor this.
Growth hormone can be given for short stature.
Oestrogen replacement therapy is started at 12-13yrs to help trigger secondary sexual characteristics.
TS women who want to be pregnant may have to consider an egg donor.
What’s the phenotype of XXX
1/1000 livebirths.
Tall stature. Epicanthic folds. Hypotonia. Clinodactyly.
Seizures. Renal and genitourinary anomalies. POI.
Children have higher rates of speech and motor delay.
No difficulty getting pregnant.
Reproductive risk of XXX
Risk increases with maternal age. Risk of XXX female having abn offspring is less than 1% as ova usually have one X.
Clinical features of pentasomy X
Developmental delay and ID. Language skills are affected. Short stature. Musculoskeletal abnormalities. Small hand and feet. Clinodactyly.
Craniofacial anomalies: Microcephaly. Micrognathia. Plagiocephaly. Hypertelorism. Flat nasal bridge. Ear malformations.
Cardiovascular malformations may be present.
External genitals generally normal.
What are the critical regions of Xq associated with gonadal dysgenesis.
Xq13-q22.
Xq22-q27.
Xq22 is NOT critical.
Ovarian disorders: POF, POI (menopause by 40yrs), primary amenorrhea.
Name the three regions that escape inactivation
Regions that have genes on X and Y.
PAR 1: 2.6Mb: Xp22.3 / Yp tip (Yp11)
PAR 2: 320Kb: Xq and Yq tips (Xq28, Yq12)
Non-pseudo-autosomal XY homologous block: 3.5Mb: Xq21.3 / Yp11.2
What’s the quotable figure for abnormal phenotypes in females with a balanced t(X;A)
25%
A recessive disorder can manifest if its disrupted by breakpoints and normal X is inactivated.
Persistence of cells with inactive der(X) - functional imbalance for A and X
What are the common breakpoints of t(X;X) in females
Xp11.23 and Xq21.3.
Caused by unequal crossing over in the oocyte
What phenotype is associated with invX in females
Most inv(X) are inactivated so there’s a normal phenotype (outwardly female), may have normal fertility.
However, if breakpoint is in critical region on Xq- likelihood of gonadal dysfunction (primary amenhorrhea or POI).
Discuss females with X deletions
Usually have a turner variant.
Mosaicism with 45,X or 46, XX is common.
Phenotype depends on what genes are deleted.
Heterozygote mutations of SHOX1 are found in which disorders:
About 100% turners syndrome.
50-90% Lewi Weill Dyschrondrosteosis.
2-15% idiopathic short stature.
What type of dupX do you see and what’s the phenotype in females
Direct dup, inverted dup, isodic(X).
Minimal predicted phenotype effect due to selective inactivation.
Gain of 1-2 copies of SHOX (escapes inactivation) results install stature.
