Sex chromosome abnormalities

Pseudo autosomal regions (PAR)

Vital for XY pairing, major regions of homology between X and Y chromosomes

2 reasons why sex chromosome abnormalities is more tolerated than autosomal

1. Y chromosome contains very little active genetic material. Most genes implicated in sex determination and fertility.

2. Majority of an extra X chromosome can be silenced/inactivated. Only one needs to be fully activated.

X-inactivation centre

• located at Xq13

• encodes the XIST gene (X-inactivation specific transcript)

• If there is only one in a cell → no inactivation occurs

Steps in X-inactivation

1. Transcribed XIST RNA spreads in both directions along the chromosome

2. XIST RNA coats X chromatin and prevents DNA from being transcribed

3. RNA coated regions promote methylation and inactivation

Klinefelter Syndrome karyotype

47,XXY

Klinefelter syndrome phenotype

• Almost always infertile

• Physically normal until puberty

• Hypogonadism

• Undeveloped secondary sex characteristics

• Gynecomastia

• one X chromosome inactivated

Most frequent cause of male infertility

Y chromosome deletion. Most common = AZFc region (Azoospermia Factor c) - contains DAZ gene (deleted in azoospermia)

Turner syndrome karyotype

45,X

Turner syndrome phenotype

• high in-utero lethality

• Ovarian failure is almost certain

• in mosaic form ovarian function can be intact

Xp deletion

short stature and congenital malformations

Xq deletion

often only have gonadal dysfunction

XIST deletion

Can result in functional disomy resulting in severe phenotype

Xp isochromosomes

Result in loss of XIC → functionally trisomic for p arm → almost always lethal, severe phenotype

Xq isochromosomes

often mosaic → amenorrhoea common → some features of turner syndrome present

Not detectable by mircoarray, only by conventional cytogenetics or FISH

Balanced rearrangements

Adjacent 1 or 2

1. Meiotic arrest: gametes aren’t produced, primary infertility, usually a large or complex genetic imbalance

2. Unviable pregnancy: conception achieved and recognisable but miscarriage, usually a large genetic imbalance

Adjacent 1

child with abnormality: viable conception resulting in birth, abnormal phenotype, usually a small genetic imbalance.

SRY gene

Located on p arm of Y chromosome, near PAR1 → can be exchanged in X-Y recombination. Integral in initiating testicular development.

Swyer Syndrome Karyotype

46,XY Female

Swyer Syndrome phenotype

Dysgenetic (abnormal) steak gonads (gonads replaced with fibrous tissue). Externally female but internally male. Genital tract feminises, but does not produce hormones. Amenorrhea and failure of normal pubertal development. 50% change of gonadoblastoma.

High Risk 1st Trimeter screen

Pregnancy associated plasma protein A, free beta-hCG, Ultrasound nuchal translucency, Ultrasound absence of nasal bone, maternal age.

Non-invasive prenatal testing

Maternal peripheral blood → NIIPT Sequences and microarrays of Cell-free DNA (cfDNA) from the placenta

invasive prenatal testing

Amniocentesis (14-18 weeks gestation, cells are unhealthy, many unviable), Chorionic villus sampling (10-12 weeks gestation)

Main difference in lab procedure of prenatal vs POC

Amniocytes are grown and harvested in place on a glass slip.

Prenatal cultures

AF cells seeded over small coverslips inside flask with a surface tension bubble on slip. Due to low cells, Aminocytes form distinct colonies.

Prenatal FISH

Is a screen only → conventional cytogenetics should be reviewed.

Mechanism behind maternal age and aneuploidy

Attributed to degradation of the meiotic apparatus → spindle formation breakdown → chromosomes drifting around instead of lining up at the central plate = increased likelihood of ending in a nondisjunctional event.

Advanced maternal age

35 years or older

Most common single known chromosomal cause of intellectual disability

Trisomy 21 (Down syndrome)

Down syndrome karyotype

47,XY,+21

Down syndrome phenotype

• mental retardation

• epicanthic eyefold

• broad flat face

• slanting eyes

• short nose

• single palm crease

• congenital heart disease

• diminished muscle tone

Patau Syndrome genotype

Trisomy 13

• 90% due to maternal NDJ

Patau Syndrome phenotype

• Microphthalmia

• Cleft lip and/or palate

• Clenched hands and polydactyly

• Brain and spinal cord abnormalities

• Deafness

• Cardiac abnormalities

• Median 12.5 day survival rate

Edwards syndrome genotype and karyotype

Trisomy 18, 47,XX,+18, 90% maternal meiotic non-disjunction

Edwards syndrome (Trisomy 18) phenotype

• Rocker bottom feet

• Clenched hand, with overlap of 2nd and 5th fingers, over the 3rd and 4th.

• Intrauterine growth retardation

• Micrognathia

• low set ears

• Median survival rate of 9 days

Unexpected chromosomal abnormalities

1. Autosomal trisomy other than trisomy 21

2. Sex chromosome aneuploidy

3. A structural rearrangement

4. Mosaicism

Cytogenetic abnormalities identified at spontaneous abortion are represented by

60% autosomal trisomies

False mosaicism

Maternal cell contamination in a POC or prenatal, cultural artefacts → confined to one culture or colony.

Development of mosaicism

depends on which cell undergoes NDJ and at which stage of development

Mosaicism outcomes/types

a. Generalised mosaicism affecting both the foetus and placenta

b. confined placental mosaicism with normal and abnormal cell lineages present

c. confined placental mosaicism with only an abnormal cell lineage present

d. mosaicism confined to the embryo.