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Path 19.04 > 20.04.13 Genetic causes of Infertility > Flashcards

20.04.13 Genetic causes of Infertility Flashcards

1
Q

WHO definition of infertility

A

Failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse

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2
Q

What proportion of couples will conceive within 1 year

A
  • > 80%

- Half of the remaining 20% will conceive in 2nd year (cumulative pregnancy rate >90%)

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3
Q

What proportion of couples have unexplained infertility

A

25-30%

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4
Q

Non-genetic causes of infertility

A
  • 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
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5
Q

4 main types of male infertility

A
  • Spermatogenic quantitative defects
  • Ductal obstruction or dysfunction
  • Hypothalamic-pituitary axis disturbances
  • Spermatogenic qualitative defects
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6
Q

What proportion of male infertility is genetic

A

15% (25% in men with azoospermia)

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7
Q

What is azoospermia

A

Absent sperm in ejaculate

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8
Q

What is oligozoospermia

A

Reduced sperm count (<15x10^6/mL)

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9
Q

What is asthenozoospermia

A

Reduced sperm motility (<40% motility)

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10
Q

What is teratozoospermia

A

Morphologically abnormal sperm

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11
Q

Examples of sex chromosome abnormalities causing infertility

A
  • 47XXY Klinefelter syndrome
  • 45,X/46,XY mosaicism
  • 46,XX male DSD
  • Y isochromosome
  • X autosome translocation
  • Y autosome translocation
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12
Q

Review of Klinefelter syndrome

A
  • 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)
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13
Q

45,X/46,XY mosaicism

A
  • 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
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14
Q

Review of 46,XX male DSD

A
  • 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
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15
Q

Review of Y isochromosome

A
  • 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.
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16
Q

X autosome translocations

A

-leads to spermatogenic arrest, leading to azoospermia/infertility

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17
Q

Y autosome translocations

A
  • 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
18
Q

Are spermatogenic cells more vulnerable to pachytene checkpoint

A
  • yes

- Oocytes tend to bypass the checkpoint, leading to chromosome imbalance.

19
Q

What activates the pachytene checkpoint

A

Failure to complete synapsis, usually due to chromosomal abnormalities. Leads to cell death

20
Q

What is a bivalent

A

A pair of chromosomes in a tetrad, held together by at least 1 crossover (during pachynema stage of meiotic prophase 1)

21
Q

How many times more do infertile men have autosomal translocations

A

4-10x

22
Q

How many times more do infertile men have Robertsonian translocations

A

9x

23
Q

Review of Y chromosome microdeletions

A

-1 in 4000 men, 2-10% of azoospermic or oligospermic men

24
Q

How do Y chromosomal microdeletions arise

A

Homolgous recombination between azoospermic factor (AZF) regions.

25
Q

What is the most frequent Y chromosomal deletion

A
  • AZFc (b2/b4)
  • Removes 3.5Mb, including 12 genes.
  • 80% of deletions
  • Variable clinical phenotype, often residual spermatogenesis
26
Q

Which y chromosome genes are deleted in azoospermia

A

DAZ genes

27
Q

Review of DAZ genes

A
  • 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.
28
Q

Proportion of CAVD, CUAVD, CBAVD caused by CFTR pathogenic variants

A

80% cases

29
Q

Clinical characteristics of CBAVD

A
  • Agenesis of seminal vesicles.

- Reduced volume, acidic pH, absence of spermatozoa in semen.

30
Q

How can pregnancy be achieved in CBAVD patients

A

-Sperm retrieval and ICSI (intracytoplasmic sperm injection)

31
Q

What is the most common CF mutation combination in CBAVD

A
  • 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)
32
Q

Main types of female infertility

A
  • Turner syndrome
  • Swyer syndrome
  • FXPOI (FMR1)
  • 46,XX gonadal dysgenesis
  • CF
33
Q

Review of Turner syndrome

A
  • 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
34
Q

What proportion of Turners syndrome cases have Y chromosome material

A
  • 6-11%

- Carries the risk of gonadoblastoma

35
Q

Review of Swyer syndrome

A
  • 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
36
Q

Review of FXPOI

A
  • FMR1 triplet repeat expansion- CGG in first untranslated exon
  • 20% of premutation carriers have POI
  • FMR1 RNA toxicity may affect oogenesis
37
Q

What is the size range for FMR1 premutation alleles

A

59-200 repeats (may expand to a full mutation in one generation)

38
Q

Review of 46,XX gonadal dysgenesis

A
  • Hypergonadotrophic hypogonadism (impaired response of the gonads to gonadotrophins)
  • Ranges from primary amenorrhea, lack of pubertal development to POF
  • Mutations in FSHR, BMP15, NR5A1
39
Q

Why may females with CF have infertility

A
  • Thicker cervical mucus makes it harder for sperm to penetrate cervix
  • Poor nutrition can lead to irregular ovulation
  • 20% have fertility issues
40
Q

Other genetic causes of infertility

A
  • 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.
41
Q

Genetic testing strategy

A
  • 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.

Path 19.04 (20 decks)

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