13. Genetic causes of Infertility Flashcards
How is infertility defined?
Failure to achieve pregnancy after 12 months
What are the 4 main causes of infertility in males?
- Sex chromosome abnormalities
- Structural chromosome rearrangements
- Y chromosome microdeletions
- CF
What is the most common cause of infertility in males?
Klinfelter syndrome - 47,XXY
What is the clinical phenotype of KS?
Hypogonadism, infertility due to azoo/oligospermia, decreased endocrine function, speech delay, dev delay, gynaecomastia, small testes, tall stature
Other than KS, what sex chromosome abnormalities cause male infertility?
- 45,X/46,XY mosaicism
- 46,XX male DSD - majority have Yp material including SRY
- Y isochromosome
Why can balanced translocations and inversions cause infertility in males?
Failure to complete synapsis - activates the meiotic pachytene checkpoint causing cell death
Spermatogenic cells are more vulnerable
How do balanced rearrangements of autosomes impact female fertility?
Oocytes bypass pachytene checkpoint –> recurrent miscarriage rather than infertility as gametes are unbalanced so offspring are not viable
What are the common Y chr microdeletions?
Azoospermia factor regions
AZFa, AZFb, AZFc
How do Y chr microdeletions arise?
Non-allelic homologous recombination
What is the most severe Y chr deletion?
What is the phenotype?
AZFa - includes USP9Y & DDX3Y
Sertoli cell-only syndrome (SCOS), bilaterally small testes and azoospermia
What is the most common Y chr deletion?
What is the phenotype?
AZFc - includes DAZ genes
Variable phenotype, generally compatible with residual spermatogenesis - 50% chance of retrieval by ISCI
How do CFTR mutations cause infertility?
CBAVD - congenital bilateral absence of the vas deferens –> interference with sperm transport
What is the phenotype of CBAVD?
Obstructive azoospermia due to CBAVD in almost all CF males
Isolated CBAVD is a CFTR-related disorder
What genotypes can cause isolated CBAVD?
1x classical + 1x non-classical
2x non-classical
1x classical + 5T
1x classical + Arg117His with 5T
What is the phenotype of Turner syndrome?
Congenital ovarian hypoplasia = POF, streak gonads, infertility, hypergonadotropic hypogonadism
Short stature, webbed neck, skeletal abnormalities, heart defects
Frequently mosaic
Why might an X;autosome translocation carrier be infertile?
Males infertile due to disruption of the X-Y bivalent at meiosis
Females infertile if breakpoints are within Xq13-22 critical regions - associated with POF
Other than infertility, what might be a consequence of an X;autosome translocation?
If XIC is on der(X), the X segment on autosome derivative is not inactivated
Female might therefore be affected by XLR disorder (e.g. DMD)
What is the cause of Swyer syndrome?
SRY mutations cause 46,XY females
What is the phenotype of Swyer syndrome?
Complete gonadal dysgenesis
Typical female external genitalial & normal uterus and fallopian tubes but streak gonads leading to amenorrhea, pubertal failure and infertility
Risk of gonadoblastoma
How do FMR1 mutations cause infertility?
FMR1 CGG premutations (59-200 repeats) associated with FXPOI
What are the 4 main causes of infertility in females?
- Chromosome abnormalities e.g. Turners, balanced rearrangments
- Swyer syndrome
- FMR1
- 46,XX gonadal dysgenesis
What other disorders are associated with infertility?
- Congenital hypogonadotropic hypogonadism - insufficient secretion of pituitary gonadotropins (Kallman, idiopathic, part of syndrome)
- Noonan syndrome - similar presentation to Turners
- CAH due to 21-hydroxylase deficiency
- PWS
- Androgen insensitivity syndrome
- DM1
How is 46,XX gonadal dysgenesis characterised?
Female phenotype but fail to proceed through puberty
Hypergonadotropic hypogonadism
Streak gonads
What causes 46,XX gonadal dysgenesis?
FSHR (AR)
BMP15 (XL) - exclusively affects females who inherited mutation from unaffected father
