session 5 population genetics Flashcards
what criteria determine if a disorder is suitable for screening?
- prevalence known
- treatment available
- effective, safe and simple and ethical test
- clinically well-defined disorder
- significant morbidity/mortality
- intervention improves outcome
- cost-effective
what are potential issues of using genomics in NBS?
- no phenotype
- VUS
- incidental findings
- expensive
- variable age of onset and penetrance
- cost of genetic counselling and follow-up
what is the WHO definition of infertility?
• Failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse (WHO).
• No cause is identified in 25-30% couples = unexplained infertility.
• >80% couples will conceive within 1y
what are non-genetic causes of infertility?
why could it be useful to know the cause?
chemotherapy, smoking, obesity, maternal age, infections, POF + polycystic ovaries, endometriosis, uterine abnormalities, injury, low sperm count
determining cause useful for recurrence risks, prognosis, treatments eg. testicular sperm retrieval
what is the incidence of Recurrent miscarriage, defined as the loss of three or more consecutive pregnancies?
, affects 1% of couples
what proportion of male infertility do genetic factors account for? what are the 4 categories of male infertility?
15%
1. sperm quality
2. sprm quantity
3. obstruction of the ducts
4. Hypothalamic-pituitary disturbance
name sex chromosome abnormalities associated with male infertility (6 options)? what are clinical features?
- Kleinfelter 47, XXY - most frequent cause. 15% are mosaic 47,XXY/46,XY (more likely to have residual sperm). clinical features = hypogonadism, gynecomastia, low testosterone and azoospermia or oligospermia. if there is residual sperm can use ICSI after PGD to achieve pregnancy. hormone replacement therapy can be given. caused by non-disjunction meiosis 1 (male) or meiosis II (female)
- 45,X/46,XY mosaicism - azoospermia and low testosterone levels. 10% have abnormal, ambiguous or female genitalia.
- 46,XX male Disorder of Sex Development (DSD). may have Yp material present (SRY) or XX/XXY mosaicism. 75% have SRY gene present (SRY+) caused by meiosis 1 abnormal exchange. may present with gynecomastia, azoospermia and small testes. 15% have genital ambiguity.
- Y isochromosome 46,X,i(Y) - may be mosaic with 45,X cell line. may be infertile male or female with turner syndrome features and ambiguous genitalia. male infertility due to loss of AZF (Yq11.2)
- x;autosome translocations- spermatogenic arrest due to disruption of the sex vesicle
6.Y;autosome translocations - infertility due to disruption of sex vesicle or disruption of AZF loci. ring & marker chromosomes also disrupt the sex vesicle
how do deletions of the azoospermia factor AZF region occur? (yq11.2)
non-allelic homologous recombination
what genes do AZFa remove? what is the phenotype?
complete deletion (rare) removes USP9Y and DDX3Y. most severe phenotype : Sertoli cell-only syndrome (SCOS), bilaterally small testes and azoospermia. sperm retrieval not possible
what are features of AZFb deletion? what % of AZF deletions does this account for?
5% of deletions. large 6.2Mb deletion removes 32 genes.
azoospermia and sperm retrieval not possible.
what are features of AZFc deletion? what % of AZF deletions does this account for? what genes are removed?
3.5Mb including 12 genes
80% of deletions - less severe
50% have residual sperm for ICSI
Interstitial or terminal deletions that include AZFc only are mediated by recombination between the b2/b4 amplicon repeats and result in a variable infertility phenotype - sertoli cell only syndrome (SCOS). azoospermia or oligozoospermia (reduced sperm count)
- DAZ genes removed (involved in germ cell development). But two other copies on autosomal genes which is why there may be residual sperm. Deletions also reported in fertile males.
how does cftr relate to infertility in males?
what % of these cases have cftr mutations?
how can it be treated?
what is the most likely genotypes of CFTR-relaed disorder causing infertility?
when does p.(Arg117His) cause cf and when does it cause cbavd?
CBAVD or CUAVD results in interference in sperm transport. CUAVD may be fertile or infertile.
caused by CFTR variants in 80% of cases
Almost all males with CF have obstructive azoospermia due to CBAVD
treatment with ICSI
partner should undergo carrier screening
• Isolated CBAVD is a CFTR-related disorder
- majority have one severe and one mild mutation eg. severe+5T ( polyT tract in intron 8 influences efficiency of exon 9 splicing) and remaining have two mild mutations
- • 5T allele not fully penetrant for CBAVD and TG tract length may modify the effect of 5T
• p.(Arg117His) also common – associated with CF when in cis with 5T but CBAVD with 7T/9T
what is primary and secondary amenorrhea
absence of periods. Primary if never had a period or secondary if follows after previously having periods
what is primary ovarian insufficiency (POI)?
the ovaries stop functioning normally before the age of 40y
what proportion of female infertility is caused by genetics?
name syndromes and genetic causes of infertility in females?
10% - chromosomal abnormalities Comprise the largest proportion of cases
Turner syndrome - complete or partially missing X chromosome, . >99% of 45,X conceptuses result in spontaneous loss. short stature, amenhorrea, infertility, congenital heart defects, increased NT. frequently mosaic. Paternal nondisjunction accounts for 70% cases. variable phenotype due to level and distribution of abnormal cell line. structural abnormalities include i(X)(q10), 46,X,+mar , 45,X/46,XX or 45,X/47, XXX , 46, X,del(Xp). give hormone therapy and eostrogen
x;autosome translocation carriers - preferential silencing of normal X so functionally balanced gamete. This skewed X inactivation can reveal recessive X linked diseases eg. DMD. POF associated with breakpoints in CR1 or CR2. If fertile there is risk of unbalanced offspring.
X-X translocations - infertility inevitable
Swyer syndrome - XY females complete gonadal dysgenesis and infertility. • 15% caused by pathogenic variants in SRY
FMR1 - CGG premutation 59-200 repeats POI
46,XX gonadal dysgenesis - primary amenhorrea, POF, hypergonadotrophic hypogonadism, lack of puberty. most cases unexplained
what is the genetic testing strategy for infertility?
- specific phenotype = targeted testing eg. CFTR for CBAVD
- less specific phenotypes = karyotype + Y chr microdeletions in azoospermic male of FMR1 in females with POF
-array for POC after 3rd miscarriage. karyotype parents if unbalanced arrangement in fetus - DSD NGS panel or microarray
what is Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency?
• CYP21A2 (AR) condition
where lack of 21-hydroxylase activity - excess of androgens produced. infertility
• Amount of functional enzyme determines the severity – salt-wasting type (75%, most severe), simple virilizing type to non-classical CAH
: females gave ambiguous genitalia in salt-wasting and simple virilizing type
- can be detected using non invasive prenatal sexing to determine if fetus is female - administer dexamethosone to reduce masculinisation
what is androgen insensitivity syndrome?
• Loss of function variants in the androgen receptor gene AR Xq12, - XLR
o Complete androgen insensitivity syndrome (CAIS): - : external sex characteristics of females, primary amenorrhea and infertile
o Partial and mild forms have residual sensitivity so can have spectrum of phenotypes from normal female, both male and female or normal male sex characteristics but are often infertile
- also causes SBMA - CAG repeats
what is a Disorder of Sex Development? what are the 3 subtypes?
congenital condition where development of chromosomal, gonadal/ anatomical sex is atypical
1)sex chromosome DSD
2) 46,XY DSD
3) 46, XX DSD
name the 4 sex chromosome DSD
- 45, X turner syndrome and variants
- 47, XXY kleinfelter - (also XXYY and XXXY and XXXXY cause kleinfelter)
- 45, X/46, XY mixed gonadal dysgenesis
- 46 XX/46XY chimeric ovotesticular DSD
name some 46,XY DSD? what are clinical features?
- disorders of testicular development - eg. complete or partial gonadal dysgenesis eg. 46,XY phenotypic female= Swyer syndrome (complete gonadal dysgenesis) - caused by SRY mutation.
Swyer syndrome= ‘streak’ gonads, female external genitalia, failure of pubertal development, infertile
2.disorders of androgen synthesis and action eg. Leydig cell hypoplasia & androgen insensitivity syndrome- caused by AR gene mutations. female external genitalia and infertile.
name some 46,XX DSD?
If phenotypic male - 90% carry SRY gene. usually from X-Y translocation. Hypogonadism + gynaecomastia common. External genitalia range from normal male to ambiguous
- disorders of ovarian development eg. testicular DSD = phenotypic male or gonadal dysgenesis (FSHR mutation) = phenotypic female
- androgen excess eg. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency - AR CYP21A2 gene.
46,XX= masculinisation of external genitalia
46,XY= normal male genitalia
• Mother treated with dexamethosone during pregnancy.
• AR disorder of enzymes - increased androgen synthesis.
• Increased androgen synthesis during embryonic development results in virilisation of external genitalia in 46,XX foetuses
what testing is carried out for DSD? which condition is considered a medical emergency?
- QF-PCR + chromosome analysis via karyotype requested to identify chromosome complement
- Panel testing may be appropriate in patients with abnormal sex chr karyotypes if karyotype result does not explain DSD phenotype
considered medical emergency in neonates born with ambiguous genitalia due to potential association with glucocorticoid + mineralocorticoid deficiencies in CAH, + parental anxiety to assign correct sex
• Longer-term patient care= clinical + diagnostic evaluation (assist with gender assignment), surgical management, hormone replacement therapy + psychosocial care
mention 4 genes involved in DSD?
SRY - 46,XX male Disorder of Sex Development (DSD).
SOX9 - gonadal dysgenesis
AR - androgen insensitivity
CYP21A2 - CAH
SF1- gonadal dysgenesis
WT1- gonadal dysgenesis
FOXL2
what is i(Xq)? what disorder can it cause? what gene is missing and what feature does this cause?
why is there no isochromosome of the Xp arm?
Isochromosome for the long arm of the X chromosome
Turner syndrome - loss of PAR1 region on Xp (SHOX)
a mosaic with a normal 46,XX cell line, 45,X cell line, or both - may be fertile
Decreased expression of the SHOX gene in PAR is associated with short stature
No isochromosome of the short arm is viable as XIST would be absent.
