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Flashcards in Sex chromosomes/infertility Deck (71):

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

Renal anomalies (horseshoe kidneys). Cystic hygroma. CHD (left side). ascites. Pleural effusion

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.



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)


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.


Discuss ring/marker X in females

Can be complex, del/dup regions.
Often inherited- often mosaic and the proportions can vary throughout generations.


Discuss ring X XIST+

Phenotype: TS to normal. (usually larger rings)

Subset of patients have severe phenotype.
XIST is present but isn't expressed.
XIST is present and expressed but the RNA doesn't bind


Discuss ring X XIST-

Severe phenotype. Resembles Kabuki syndrome (short stature, dev del, ID, seizures, Microcephaly).

Generally small rings (functional X disomy)


Why do some ring X XIST- have mild phenotypes

Very small ring (no euchromatin).
Prevalence of the ring.
The X chromosome the rings derived from May have under gone inactivation prior to the formation of the ring.


Whats the phenotype of a male with balanced t(X;A)

Invariably fertile due to disruption of the sex vesicle (azoospermia).

phenotypic normality in a hemizygous male implies a truly balanced rearrangement.


What phenotype is associated with delXp22.3 in males

STS: 90% have X-linked ichthyosis.

KAL1: hypogonadism, anosmia, MR.


Discuss dup X in males

Hemizygous male with functional disomy therefore more severe phenotype.

If have dup Xp of DAX1: sex reversal as have two active copies


Discuss t(X;Y)(p22.3;q11)

The classic.

46,X,der(X): female, fertile, normal intellect.

46,Y,der(X): male, infertile, possible MR.

Caused by NAHR between PRKX and PRKY


What genes lost from Xp in the classic t(X;Y)



Discuss t(X;Y)(p22.3;p11)

It's cryptic (90% have SRY on X).
Carrier is MALE. The 'XX male'.

46,XX is 46,X,der(X).

45,X is 45,der(X).

85-90% have normal genitalia (with azoospermia).
10-15% have genital ambiguity/ hypospadias/ infertility.


Whats the risk (if any) of a female t(X;A) carrier having an abnormal child

An otherwise non-viable conceptus my survive due to X-in.
Risks of having a liven born with a structural/functional aneuploidy is 20-40%


what would the phenotype of 46,X,rec(X)inv(X) be

delq/dup p: normal-tall stature and ovarian dysgenesis.

delp/dup q: short stature and possibly intact avarian function.


What is male infertility characterised by (features)

azoospermia (absence of sperm) or severe, moderate or mild oligozoospermia (low concentration of sperm).

Usually no other obvious features ie normal male.


What is the incidence of klinefelters, and what mechanism causes it


10% detected by PND. 25% detected at puberty (by karyotyping).

Non-disjunction of X at M1 in males and M2 in females


Name some features of Klinefelters

Hypogonadism. Gynaecomastia. Female pattern obesity. Tall. Long arms and legs. Reduced/absent fertility. Decreased testosterone/ endocrine function. Lower intelligence by 10 points to male siblings.


Describe clinical features of XYY

Testosterone levels are normal. Usually normal fertility. Half have LD and tall stature. Fertility can be variable because of the number of sperm with XY and poor survival of XXY to birth.


Name clinical features of XXYY

Tall, long legs, Gynecomastia. Hypogonadism. Probe to hyperactivity, aggressive behaviour.


Name features of XXXY

Hypertelorism. Flat nasal bridge. 5th finger clinodactyly. Small penis and testes. Low IQ, severely delayed speech


Name features of XXXXY

Severely affected. Microcephaly. Hypertelorism. Flat nasal bridge. Up slanting palpebral fissures. Very low IQ


Discuss t(Yq;acroP)

70% of Yq translocations. 50% are t(Y;15) next is 22.

Normal variant


Discuss t(Yq;A) non-acroP

Rare. Usually de novo.

If unbalanced: oligospermia. Hypogonadism.MR. Infertility.

If balanced: no phenotype apart from poss infertility.


Discuss Yp translocations

Yp-A is rare: risk is SRY has translocated onto A: then can have 45,X male.

Dicentric Yp-acroP: 45 chromosome count. Little genetic material lost (Yqh and part of acrop). Possibility of oligospermia.


Discuss r(Y)

Rare. 70% have 45,X cell line due to ring instability.

Features: azoospermia. Small testes and penis. Hypospadias.

Features likely due to deletion of Y material opposed to ring itself.

Most cases: male if SRY is present and intact.


Discuss i(Yq)

No SRY or RPS4Y present. All reported cases: female with sexual infantilism. Streak gonads. TS features. Short stature.


Discuss i(Yp)

Double dose of Yp no Yq!

Phen can range: normal, sterile male- ambiguous genitalia- female with testicular feminisation.

Features: ambiguous external genitalia, asymmetrical abdominal gonads, TS features, normal stature.


Discuss idic(Y)(p11)


1/3: male: small/ abnormal/ asymmetrical testes. Azoospermia. Incomplete masculinisation of external genitalia. Short stature. TS like features. Ambiguous genitalia.

2/3: female: streak gonads. Enlarged clitoris. Short stature. TS like features. **risk of gonadoblastoma about 20% requires removal.


Discuss idic(Y)(q11) or (q12)

Double dose of Yp.

1/3: males: can be normal with infertility (depend on bkpts). Small testes. Asymmetric gonads. Azoospermia. Hypospadias.

1/3: ambiguous external genitalia: hypospadias. Abnormal gonads. Inguinal/ immature testes. Gonadoblastoma.

1/3: female: streak or asymmetrical gonads. Abdominal testes. TS like features.


What percentage of infertile men have Yq deletions

13% with non-obstructive azoospermia.

5% with severe oligospermia.


Briefly discuss the AZF (azoospermia factor) region on Yq

Contains 3 regions: AZFa, b, c.

AZFb and c overlap by 1.5Mb. The deletions are defined (named) by the palindrome repeat sites the breaks are in.

AZF a and b deletions are more severe.

AZFb+c consist of : 5 large palindromic regions (P1-P5) which contain a large number of amplicons (named red1-4, green1-3, yellow1-4, etc) that are arranged both direct and inverted.
These repeats predispose the region to rearrangements by recombination.


Tell me all you know about AZFa

400-600Kb. Contains genes USP9Y and DDX3Y (LoF directly linked it infertility). Most deletions caused by recombination of 2 10Kb direct repeats.

Deletions (rare) are characterised by azoospermia and severe oligospermia.

Complete deletions of AZFa show the most severe phenotype of all these deletions: Sertoli cell only syndrome (SCOS)- bilaterally small tests and azoospermia.

Can get mut/del of USP9Y: associated with reduced spermatogenesis.


What percentage of infertile men are AZFb and AZFc deletions seen in

AZFb: 2% pts with infertility.

AZFc: 12% of non-obstructive azoospermia. 6% of severe oligozoospermia. 5% of severe oligospermia.


Tell me what you know about AZFb

6Mb region, contains 32 genes, 50% of the region is ampliconic sequence.

Deletions can be interstitial or terminal.

Breakpoints are: P5/proxP1. P5/distalP1. P4/distalP1.

All cause severe azoospermia.

Partial deletion of AZFb (P4 palindrome only) causes reduced spermocyte maturation but can be transmitted.


Tell me what you know about AZFc

3-5Mb. Contains 23 genes (7 distinct families). 100% region is ampliconic sequence. At Yq11.23.

It's the most common Y deletion: 90% (87% are isolated AZFc).

Often have sperm in testes so IVF/ICSI is possible.

AZFc only (b2/b4) has variable infertility from azoospermia and SCOS to severe or mild oligospermia.


What's the name of the 2 autosomal DAZ genes

DAZL at 3q24.3.

BOULE at 2q33


What are the 2 AZFc benign variants called

b1/b3 and b2/b3


What are the features of del(Y)(p11)

Usually female with streak gonads and TS features.

If RPS4X (Xq) and RPS4Y (Yp) are present avoid TS like features.


Define infertility

Failure of a couple to conceive within 12 months. Affects about 15% couples.


Name the 5 avenues of testing that can be taken for infertile couples with very early RM (ie no POC) or no pregnancies

1) karyotyping male and female (structural or numerical abns).
2) analysis of male for CBAVD.
3) analysis of female for POF/POI cause.
4) analysis of male and female for other causes of infertility.
5) analysis of male for Yq deletions.


Name the 3 avenues of testing that can be taken for infertile couples with RM

1) thrombophilia.
2) analysis of the POC (RCOG: karyotype of 3rd & consecutive miscarriages- 50% have chr abns).
3) parental karyotyping (about 2.5% RM couples have chr rearr).


What other genetic causes are associated with infertility, and may be considered.

Obviously other phenotypes, family history would need to be considered.

Kallman syndrome. Noonan syndrome. Androgen insensitivity syndrome. SBMA. PWS. Myotonic dystrophy. Haemachromatosis. Haemaglobinopathies.


List some non-genetic causes of infertility.

Maternal age. Polycystic ovaries. Medication. Cancer. Endocrine disorders. Stress/trauma. Anatomical anomalies. Infection.


In infertile men, what percentage have chromosomal abnormalities

90% involve a sex chromosome.

4-6% have XXY (11% azoospermia men, 0.7% Oligospermia men)


How does a structural rearrangement cause infertility

1) an autosomal rearrangement that fails to get complete synapsis results in the pachytene checkpoint to be activated causing cell death (causes infert in sperm, ooctyes- bypass this checkpoint).

2) X-Y sex vesicle: is incomplete therefore regions can pair with unpaired segments of autosomal rearrangement which in turn interferes with sex vesicle formation. Eg acroP shares sequence homology with Yqh and Xcen.