20.04.15 Structural abnormalities of Y chromosome Flashcards
What are the 3 unique features of Y chromosomes
- Lack of a homologous partner for crossing over
- Functional specialisation for spermatogenesis
- High degree of sequence amplification
How is Y chromosome useful for geneaology studies
Paternally inherited portion of the nonrecombining Y chromosome retains sequential records of the accumulation of genetic diversity over time
Why is it a difficult chromosome to analyse
- High density of repeated sequences makes physical mapping and sequencing difficult
- Does not recombine during meiosis so classical linkage mapping is not possible
Why is natural selection less effective in preventing the accumulation of deleterious mutations in the Y chromsome
- The lack of recombination.
- Results in genetic erosion of Y chromosome (will eventually become redundant in function)
What are the 3 azoospermia factor regions on Yq
AZFa, AZFb, AZFc
What proportion of Y chromosome is pesudoauatosomal region (1 and 2)
5%
What gives variability to Y chromosome length
- Variation in length of Yqh region (Yq12).
- Inactive heterochromatin.
- Size doesn’t have a phenotypic consequence
What is a pericentric inversion on Y chromsome
- Inversion that moves centromeric region to the heterochromatin border.
- No apparent effect on fertility or clinical significance.
- 1:200
How are sex vesicles formed
When X and Y chromosomes synapse at PARs during meiosis.
How prevalent are Y;autosome translocations
1:2000
Phenotypic consequences of Y;autosome translocations
-Male infertility, due to spermatogenic arrest.
What is the most prevalent Yq autosome translocation
- Acrocentric p arm and Yqh.
- 70% of Y autosome translocations.
- Most commonly t(Y;15), possibly due to homology of heterochromatin blocks of 15p and Yq. Also common= t(Y;22)
- Often familial and has no clinical significance, but could predispose to structural instabilities of Y or secondary chromosomal abnormalities.
Where is Yq-autosome breakpoints usually found
- Acrocentric= p11-13
- Y= Yq12
Can translocations occur between Yq and other autosomes (other than acrocentric p arms)
- Yes but rare.
- Usually balanced so seen with oligo/azoospermia, hypogonadism
- Phenotypic abnormalities occur if there is gene disruption at break points, positional effects or unbalanced
Review of autosome Yp translocations
- Can involve SRY translocation to an autosome (usually acrocentric)
- Phenotypically male with 45 chromosomes, 45,X
- 45,X,t(Y;15) could lead to PWS if breakpoints are at 15q11-q13
What is a dicentric Yp-acrocentric translocation
- P to P arm translocation
- 45 chromosome count
- Almost no genetic material is lost from either acrocentric or Y chromosome
- may be associated with oligospermia
What is the most common X;Y translocation
-46,X/Y, der(X) t(X;Y)(p22.3;q11)
How do X;Y translocation arise
- NAHR at spermatogenesis of female carrier’s father.
- NAHR between homologous genes (94% sequence similarity) PRKX and PRKY are implicated in 30% cases
What is a risk factor for X;Y translocations
Polymorphic paracentric inversion on Yq, placing PRKY in the same orientation as PRKX
Review of female 46,X,der(X)t(X;Y)
- Typically a fertile female of normal intelligence.
- Partial monosomy of Xp
- If SHOX is deleted then patient will have Leri-Weill dyschondrosteosis (skeletal dysplasia)
- 50% risk of transmitting der(X)
- XCI tends towards der(X) but can be variable
Review of male 46,Y,der(X)t(X;Y)
- Usually son of a der(X)t(X;Y) mother
- Partial nullisomy for Xp
- Infertile. Can be cognitively normal. If breakpoint is more proximaly and involves genes like MRX, then there is mental impairment.
What translocation accounts for most 46,XX males and some 45,X males
- Cryptic Xp;Yp translocation
- Loss of distal region of X chromosome and transfer of SRY
How is a cryptic Xp;Yp translocation detected
FISH.
Phenotypic consequences of a cryptic Xp;Yp translocation
- Males are infertile
- If loss of SHOX then leads to Leri-Weill dyschondrosteosis
When are ring Y chromosomes usually seen
- With 45,X cell line (70% cases)
- Can be mosaic, e.g. 45,X/46,X,r(Y)
- Often only a small region of Yp is deleted so SRY region is left intact. i.e. phenotypically male
What are the phenotypic characteristics of males with ring y chromosomes
- Sexual infantilism, ambiguous genitalia, hypospadias, azoospermia, short stature
- varies depending on the genes deleted
What is an isochromosome
an unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other.
Review of i(Yp)
- Cannot be distinguished from a partial Yq deletion
- characteristics: ambiguous genitalia, TS abnormalities if 45,X cell line is present
- Otherwise male phenotype with microcephaly, hypogonadism, short stature.
Review of i(Yq)
- Does not contain Yp so lacks SRY and RPS4Y, there female. Have sexual infantilism.
- Features of TS such as streak gonads
Is an isodicentric Y chromosome a common abnormality
- Yes, most common Y structural abnormality.
- 91% are in mosaic form (often lost during cell division) with 45,X
- Sex-related phenotypes vary depending on percentage of 45,X cells and absence/presence of SRY gene.
Review of Idic(Yp)
- 1/3 phenotypically male, azoospermia, short stature, ambiguous genitalia, TS like features
- 2/3 phenotypically female with streak gonads, short stature and TS like features
Review of Idic(Yq)
- 1/3 phenotypically male with azoospermia, small testes, short stature TS like features
- 1/3 intersex, ambiguous genitalia, short stature gonadoblastoma
- 1/3 phenotypically females, abdominal testes, TS like features, short stature.
Common Y chromosome microdeletion
-AZFc deletion at Yq11.23
Proportion of infertility cases attributed to microdeletions at AZF regions
5-20% of azoo/oligospermia cases
How can Y microdeletions be transmitted from father to son
Via intracytoplasmic sperm injection (ICSI)
Review of AZFa microdeletion
- 0.5-4% of cases
- Patients have azoospermia and sertoli cell only syndrome (SCOS)
- Sperm retrieval for ICSI is not possible.
- Due to spermatogenic failure, caused by loss of USP9Y and DDX3Y genes.
- Arise due to recombination between repeats.
- 800kb in size
Review of AZFb microdeletion
- 1-5% of cases
- sertoli cell only syndrome (SCOS) and azoospermia.
- 6.2Mb in size
Review of AZFc microdeletion
- Most common 80% of cases
- Azoospermia or severe oligospermia.
- Includes DAZ gene
- 3.5Mb in size
- Repeats flank region
