20.04.13 Genetic causes of Infertility Flashcards
WHO definition of infertility
Failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse
What proportion of couples will conceive within 1 year
- > 80%
- Half of the remaining 20% will conceive in 2nd year (cumulative pregnancy rate >90%)
What proportion of couples have unexplained infertility
25-30%
Non-genetic causes of infertility
- Side effect of medication (chemotherapy)
- Lifestyle (smoking, obesity, stress)
- Maternal age
- Infection (mumps)
- Ovulation disorders (polycystic ovary syndrome, thyroid problems, POI)
- Endometriosis
- Injury (to testicles)
- Low sperm count/motility
4 main types of male infertility
- Spermatogenic quantitative defects
- Ductal obstruction or dysfunction
- Hypothalamic-pituitary axis disturbances
- Spermatogenic qualitative defects
What proportion of male infertility is genetic
15% (25% in men with azoospermia)
What is azoospermia
Absent sperm in ejaculate
What is oligozoospermia
Reduced sperm count (<15x10^6/mL)
What is asthenozoospermia
Reduced sperm motility (<40% motility)
What is teratozoospermia
Morphologically abnormal sperm
Examples of sex chromosome abnormalities causing infertility
- 47XXY Klinefelter syndrome
- 45,X/46,XY mosaicism
- 46,XX male DSD
- Y isochromosome
- X autosome translocation
- Y autosome translocation
Review of Klinefelter syndrome
- in 4-6% of infertility cases (most frequent)
- 1 in 600 in general population, 1 in 7 in nonobstructive azoospermia
- 15% are mosaic 47,XXY/46,XY and have residual spermatogenesis.
- Patients also have low sperm count, hypogonadism, gynecomastia, increased levels of gonadotrophins and low testosterone.
- Pregnancy can be achieved by testosterone treatment, sperm extraction and PGD (preimplantation genetic diagnosis)
45,X/46,XY mosaicism
- most or all of the Y chromosome is lost in one of the newly created cells. The 46,XY cells will continue to multiply at the same time as the 45,X cells multiply.
- 90% normal male externally
- 10% have abnormal, ambiguous or female genitalia.
- Could be due to malformation (isodicentricism) of the Y chromosomes, deletions of Y chromosome or translocations of Y chromosome segments
Review of 46,XX male DSD
- 1 in 20,000 males
- Due to presence of Yp material on one X chromosome, asymptomatic XX/XXY mosaicism or inappropriate gene activity
- 75% have SRY gene present (exchange during paternal meiosis I, t(Xp;Yp). 10% have some genital ambiguity.
- 25% are SRY absent. Ambiguous genitalia. Likely due to inappropriate activation of testis-determining cascade
Review of Y isochromosome
- Seen in mosaic and non-mosaic form with a 45,X
- Phenotypically variable (depending on extent of 45,X cell line), from males with infertility to females with Turner syndrome features.
X autosome translocations
-leads to spermatogenic arrest, leading to azoospermia/infertility
Y autosome translocations
- Phenotypically normal males with infertility due to disruption of sex vesicles.
- 70% of translocations involve Yqh with short arms of acrocentrics (most often 15 and 20), not associated with infertility
Are spermatogenic cells more vulnerable to pachytene checkpoint
- yes
- Oocytes tend to bypass the checkpoint, leading to chromosome imbalance.
What activates the pachytene checkpoint
Failure to complete synapsis, usually due to chromosomal abnormalities. Leads to cell death
What is a bivalent
A pair of chromosomes in a tetrad, held together by at least 1 crossover (during pachynema stage of meiotic prophase 1)
How many times more do infertile men have autosomal translocations
4-10x
How many times more do infertile men have Robertsonian translocations
9x
Review of Y chromosome microdeletions
-1 in 4000 men, 2-10% of azoospermic or oligospermic men
How do Y chromosomal microdeletions arise
Homolgous recombination between azoospermic factor (AZF) regions.
What is the most frequent Y chromosomal deletion
- AZFc (b2/b4)
- Removes 3.5Mb, including 12 genes.
- 80% of deletions
- Variable clinical phenotype, often residual spermatogenesis
Which y chromosome genes are deleted in azoospermia
DAZ genes
Review of DAZ genes
- Y chromosome
- 4 copies
- Encode proteins with RNA recognition motifs (RRMs), which are involved in the regulation of RNA translation and control meiosis.
- Control germ cell development
- Multiple copies of DAZ which can compensate for deletions.
Proportion of CAVD, CUAVD, CBAVD caused by CFTR pathogenic variants
80% cases
Clinical characteristics of CBAVD
- Agenesis of seminal vesicles.
- Reduced volume, acidic pH, absence of spermatozoa in semen.
How can pregnancy be achieved in CBAVD patients
-Sperm retrieval and ICSI (intracytoplasmic sperm injection)
What is the most common CF mutation combination in CBAVD
- One severe variant with 5 T allele.
- poly T in intron 8 influences splicing efficiency of exon 9
- TG polymorphism upstream of PolyT also affects efficiency of exon 9 inclusion in final transcripts.
- 5 T is not fully penetrant for CBAVD, TG length modifies effect of 5T (5T13TG most effect on splicing)
Main types of female infertility
- Turner syndrome
- Swyer syndrome
- FXPOI (FMR1)
- 46,XX gonadal dysgenesis
- CF
Review of Turner syndrome
- 45,X
- 1 in 2500 liveborn females (10% miscarriages)
- Short stature, delayed puberty, ovarian dysgenesis, hypergonadotrophic hypogonadism, infertility, congenital heart defects.
- Prenatally, cystic hygroma, nuchal thickening.
- Frequently mosaic (55% cases)
- Parental nondisjunction accounts for 70% liveborn cases
What proportion of Turners syndrome cases have Y chromosome material
- 6-11%
- Carries the risk of gonadoblastoma
Review of Swyer syndrome
- 46,XY females
- 1 in 80,000
- Female external genitalia, normal uterus and fallopian tubes, but streak gonads. Infertility, pubertal failure.
- risk of gonadoblastoma
- 15% caused by pathogenic on SRY on Y chromosome
- XY complete gonadal dysgenesis
Review of FXPOI
- FMR1 triplet repeat expansion- CGG in first untranslated exon
- 20% of premutation carriers have POI
- FMR1 RNA toxicity may affect oogenesis
What is the size range for FMR1 premutation alleles
59-200 repeats (may expand to a full mutation in one generation)
Review of 46,XX gonadal dysgenesis
- Hypergonadotrophic hypogonadism (impaired response of the gonads to gonadotrophins)
- Ranges from primary amenorrhea, lack of pubertal development to POF
- Mutations in FSHR, BMP15, NR5A1
Why may females with CF have infertility
- Thicker cervical mucus makes it harder for sperm to penetrate cervix
- Poor nutrition can lead to irregular ovulation
- 20% have fertility issues
Other genetic causes of infertility
- Noonan syndrome (PTPN11, SOS1, RAF1, KRAS, HRAS)
- CAH (Congenital adrenal hyperplasia due to 21-hydroxylase deficiency). CYP21A2 mutations (AR).
- PWS. 80-90% have cryptorchidism (failure of testes to descend to scrotum)
- Androgen insensitivity syndrome. Mutations in AR gene.
- DM1. CTG repeat in 3’UTR of DMPK. 80% Males have testicular atrophy.
Genetic testing strategy
- A specific clincal phenotype may suggest targeted testing. e.g. CYP21A2 where biochemical tests are indicative, or CFTR for CBAVD.
- Less specific phenotypes are investigated by karyotyping and molecular testing. e.g. Y chromosome microdeletion of FMR1 in females with POF.
- A large proportion will not receive a genetic diagnosis.
