Common Aneuploidies

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Additional episodes that might be helpful for today:

What is aneuploidy?

  • The occurrence of one or more extra or missing chromosomes leading to an unbalanced complement.

  • Screening for aneuploidy occurs with either serum screening or cell free DNA.

    • Diagnostic testing for aneuploidy is done with chorionic villus sampling or amniocentesis.

      • As we discussed on the screening 2 episode; fluorescent in situ hybridization (FISH) can evaluate initially for common aneuploidies.

      • Karyotypes are the confirmatory testing for common aneuploidy, as well as other ways to get aneuploidy we’ll review (triploidy, balanced translocations).

      • Microarray can find other major aneuploidies, but can’t find triploidy or balanced translocations.

How does aneuploidy occur?

  • Meiosis is the process of cell division that produces gametes – eggs and sperm. 

    • Goal is to create daughter cells with a haploid chromosome number (in humans – 23).

    • The two gametes generally fuse to create a diploid zygote with 46 chromosomes.

      • If there’s an issue in the cell division process for a gamete, they may come into this fusion with an extra or missing chromosome.

    • Remember in cell division, we have multiple phases: prophase, metaphase, anaphase, telophase.

      • We’ll break it down simply into the stages you need to remember to get those bonus points!

  • Meiosis is broken into two phases: meiosis I and meiosis II.

    • In meiosis I, the starting cell is diploid – but after replication, ends up with 4n chromatids (held in 2n chromosome pairs, or sister chromatids). 

      • In prophase I, each pair of chromosomes lines up and matches with a homologous partner. This allows for the phenomenon of crossing over, where homologous portions of the chromosomes can rearrange and exchange portions of their DNA.

        • This is where things can get dicey for a particular type of uncommon aneuploidy, known as a translocation. 

          • That is, rather than recombining with a portion of the homologous chromosome, it attaches to a different chromosome.

          • These translocations can be:

            • Balanced, where the genetic information is not gained or lost, but just rearranged differently. 

              • So for example: A piece of chromosome 21 joins onto chromosome 14, and a piece of chromosome 14 joins onto the break at 21. 

                • The cell at this point still technically is diploid – but there can be problems with this later on!

            • Unbalanced, where the genetic information is split unequally.

              • In the same example: a piece of chromosome 21 joins onto 14, but the piece from 14 is lost.

          • A particular type of translocation is known as a Robertsonian translocation, which is where the full long arms of two acrocentric chromosomes are joined together.

            • The acrocentric chromosomes are where the short arms are extremely short - these are 13, 14, 15, 21, and 22 in humans.

            • One of the most discussed is a 14:21 translocation, which is responsible for some Down syndrome.

              • These translocations typically result in familial cases of aneuploidy, as a parent may be a balanced carrier of an abnormal chromosome – issues don’t arise for aneuploidy until they start trying to have children, and the chromosome complement ends up unbalanced in offspring.

      • In the female reproductive cycle, eggs arrest in the cell cycle at prophase I, and only complete the remainder of meiosis prior to that egg’s ovulation.

        • So an egg can be arrested for 30-40 years! 

        • Ultimately, with this extended pause, meiosis I in oocytes is where the majority of nondisjunction events occur.

      • To complete meiosis I:

        • Metaphase I: the homologous pair lines up across the metaphase plate (like a cell equator) to prepare for division

        • Anaphase I: the homologues are separated to the opposite ends of the cell

          • Or not, if they can’t be separated! – This is nondisjunction.

        • Telophase I: the new cells are haploid in chromosome pairs.

    • We then move to meiosis II, where the sister chromatids are split into haploid pairs:

      • Metaphase II: the sister chromatids line up across the metaphase plate.

      • Anaphase II: the sister chromatids are separated to the opposite ends of the cell.

        • This is another point where nondisjunction can occur (less common than in meiosis I, though)!

      • Telophase II: the new cells are haploid with 23 single chromosomes (no longer in pairs).

The robertsonian translocation and gamete production

Trisomy 21: Down Syndrome

  • Syndrome resulting from the addition of an extra chromosome 21. 

  • Most common aneuploidy: affects about 1 in 700 births in the USA.

  • Occurs via:

    • Nondisjunction event: 95% of occurrences

    • Robertsonian translocation: 5% of occurrences

    • Mosaicism: infrequent (~1-2% max)

      • This is where some cell lines have aneuploidy, and others do not. This occurs usually in early mitosis of the zygote, where the embryo during cell division recognizes the extra chromosome and tries to “kick it out” with aneuploidy rescue. We won’t spend too much time on that today! 

  • Prenatal testing characteristics of trisomy 21:

    • Cell free DNA: excellent test performance with 99% sensitivity and specificity.

      • However, false positives still occur frequently, particularly in low-prevalence populations (i.e., around 50% false-positive risk in women aged 25).

    • Serum screening: 

      • Low msAFP

      • Low estriol

      • High HCG

      • High inhibin A

    • Ultrasound:

      • 1st trimester: elevated NT (64-70%), absent/hypoplastic nasal bone.

      • 2nd trimester:

        • Various soft markers all have significance for T21: pyelectasis, echogenic bowel, echogenic cardiac focus, short femur.

        • Most significant soft marker: thickened nuchal fold (LR 11-18 for T21)

        • Practically pathognomonic findings:

          • “Double bubble sign” – duodenal atresia - familiarize yourself with this ultrasound as it’s very commonly tested!

          • Cardiac anomalies in ~50% – particularly significant / common are atrioventricular septal defects.

DOUBLE BUBBLE - RADIOPAEDIA

Trisomy 18: Edward syndrome 

  • Syndrome resulting from additional chromosome 18.

  • Frequency: about 1 in 2k - 6k live births in USA.

  • Occurs via:

    • Nondisjunction event: over 95% of cases

    • Mosaicism: around 4-5% of cases

    • Translocations: rare, but has been reported.

  • Prenatal testing characteristics:

    • Cell free DNA: good, with over 96% sensitivity and over 99% specificity.

      • However, given its infrequency, the positive-predictive value can still be low – 40% PPV in a woman at age 35. 

    • Serum screening:

      • All analytes decrease (though inhibin A can be normal).

    • Ultrasound:

      • 1st trimester: elevated NT, absent / hypoplastic nasal bone.

      • 2nd trimester: multiple characteristic signs:

        • Choroid plexus cysts are the most common soft-marker (though non-specific)

        • “Strawberry skull” – flattened occiput, pointed frontal bones

        • Clenched hands with overlapping fingers

        • Rocker-bottom feet

        • Cardiac anomalies

        • Esophageal atresia, diaphragmatic hernias

        • Growth restriction

STRAWBERRY SKULL

Trisomy 13: Patau syndrome

  • Syndrome resulting from additional chromosome 13

  • Frequency: about 1 in 10k-16k live births in USA

  • Occurs via:

    • Nondisjunction event: most common

    • Chromosome 13 is one of the acrocentric chromosomes so Robertsonian translocation can occur and familial forms have been reported.

    • Mosaicism is also possible.

  • Prenatal testing characteristics:

    • Cell free DNA: similar story to trisomy 18. Sensitivity is around 91% and specificity over 99%.

      • Given the low prevalence, positive-predictive values can still be low – around 20% for a woman at age 35. 

    • Serum screening:

      • No well-defined pattern, but elevated msAFP may be present given common CNS and other anomalies present in this syndrome.

    • Ultrasound:

      • 1st trimester: elevated NT, absent / hypoplastic nasal bone

      • 2nd trimester: multiple characteristic signs, but remember: midline and CNS are classic:

        • Holoprosencephaly: failure to divide brain into cerebral hemispheres (so no midline falx cerebri)

        • Facial anomalies: cleft lip/palate, proboscis, micropthalmia/anopthalmia or cyclops eye

        • Cardiac abnormalities - up to 80%

        • Omphalocele

        • Enlarged echogenic kidneys or horseshoe kidney

ALOBAR HOLOPROSENCEPALY - RADIOPAEDIA

Monosomy X: Turner Syndrome

  • Syndrome results from a missing sex chromosome - so 45, XO.

    • 80% of the time this is paternally derived – one of the few circumstances this is the case!

  • Frequency: 1 in 2k-5k live births

  • Occurs via:

    • Nondisjunction event: most common

      • On the paternal side, given the mismatch of X and Y, the Y chromosome can be subject to “getting lost” in meiosis.

    • Mosaicism can also occur with Turner syndrome in about 50% of individuals

      • Cell lines are able to be mixed as 45, XO/46, XX, or 45, XO / 46, XY most commonly

        • If Y chromosome is detected, gonadectomy is advised to reduce risk of gonadoblastoma in later life. 

  • Prenatal testing characteristics:

    • Cell free DNA: overall has about 90% sensitivity and over 99% specificity.

      • Similarly: PPV is limited by prevalence

      • cfDNA also has difficulty with mosaicism and delineating this specifically. 

    • Ultrasound:

      • The most commonly tested finding: cystic hygroma

        • Present in 1st and/or 2nd trimester

        • Can also present with more generalized edema

      • Horseshoe kidney, cardiac abnormalities may also be present.

CYSTIC HYGROMA - RADIOPAEDIA