Chromosomal Abnormality Screening

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What does Harmony screen for?

Harmony is viewed as a reliable screening test and can be seen as the first universal tier antenatal screening test for the most common chromosomal conditions – making up approximately 80% of all chromosomal conditions. Please see table for a summary of the key abnormalities that are screened by Harmony.

The chromosomal conditions that Harmony screens for can be broken down into trisomies, sex chromosome aneuploidies and microdeletions.

Trisomies

Trisomy is the word used to describe the presence of an extra chromosome in the cells. The Harmony test looks for trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome).

Trisomy 21 (Down syndrome)

Down syndrome is a well understood condition that occurs when there is an extra copy of chromosome 21, meaning there are three copies instead of the expected two. It is a common chromosomal condition and occurs in about 1 in every 800 babies 1. While the chance of having a baby with Down syndrome increases as women age, it can occur in any pregnancy. There are many different features and symptoms associated with Down syndrome, however, not everyone with Down syndrome will have them all. The symptoms and severity vary from one to another.

While intellectual disability is a feature of Down syndrome, early intervention programs have been shown to be very effective in assisting people with Down syndrome to reach their full potential and lead productive lives. Medical conditions, such as heart defects, are more common in people with Down syndrome and can affect life expectancy, however, increased understanding in Down syndrome means that most individuals will live into their 60s.

Potential Symptoms

  • Hypotonia (floppy muscle tone)
  • Characteristic facial features
  • A crease across the palm of the hands
  • Mild to moderate intellectual disabilitymm
  • General development problems
  • Congenital heart conditions
  • Other health problems

1. U.S. National Library of Medicine. Genetics Home Reference. Down Syndrome. https://ghr.nlm.nih.gov/condition/down-syndrome. Accessed September 13, 2019.

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Trisomy 18 (Edwards syndrome)

Edwards syndrome (trisomy 18) is a very serious chromosomal condition that occurs when there is an extra copy of chromosome 18, meaning there are three copies instead of the expected two. Edwards syndrome occurs in about 1 in 5,000 newborns 1. Unfortunately, most babies with Edwards syndrome will miscarry, and of those babies that are born with Edwards syndrome, most will live for just a short time. While the chance of having a baby with Edwards syndrome increases as women age, it can occur in any pregnancy. Some of the features can be seen in a baby affected with Edwards syndrome on ultrasound early in pregnancy and can be investigated further.

Potential Symptoms

  • Failure to grow/small for gestational age
  • Developmental delay and intellectual disability
  • Characteristic facial features
  • Small face and chin
  • Abnormalities of the hands and feet overlapping fingers, rocker-bottom feet
  • Multiple organ abnormalities - heart, brain, kidneys, gastrointestinal system other health problems

1. U.S. National Library of Medicine. Genetics Home Reference. Trisomy 18. https://ghr.nlm.nih.gov/condition/trisomy-18. Accessed September 13, 2019.

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Trisomy 13 (Patau syndrome)

Patau syndrome (trisomy 13) is a very serious chromosomal condition that occurs when there is an extra copy of chromosome 13, meaning there are three copies instead of the expected two. Patau syndrome occurs in about 1 in 16,000 1 newborns. Unfortunately, most babies with Patau syndrome will miscarry and those babies that are born with Patau syndrome will live for just a short time. While the chance of having a baby with Patau syndrome increases as women age, it can occur in any pregnancy. Some of the features can be seen in a baby affected with Patau syndrome on ultrasound early in pregnancy and can be investigated further.

Potential Symptoms

  • Severe intellectual disability
  • Characteristic facial features
  • Small or absent eyes
  • Cleft lip and palate
  • Polydactyly (more than 5 fingers/toes)
  • Incomplete brain development
  • Failure to grow/small for gestational age
  • Multiple organ abnormalities

1. U.S. National Library of Medicine. Genetics Home Reference. Trisomy 13. https://ghr.nlm.nih.gov/condition/trisomy-13. Accessed September 13, 2019.

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Sex Chromosome Aneuploidies

Sex chromosome aneuploidies (SCA) occur when there are changes in the expected number of the chromosomes associated with sex, the X and Y chromosomes. The most common sex chromosome aneuploidies are Klinefelter syndrome, Triple X syndrome, Jacob’s syndrome and Turner syndrome.

People with sex chromosome aneuploidies are sometimes mosaic, meaning they have some cells that have the sex chromosome aneuploidy and some cells that have the expected number of chromosomes. Mosaicism can affect the severity of the phenotype and can also make accurate testing more difficult. People with sex chromosome aneuploidies generally have relatively few physical or intellectual changes and many people with sex chromosome aneuploidies are never diagnosed because they do not have any clinical symptoms.

NIPT for SCA testing also has a lower positive predictive value (PPV) than testing for the common trisomies (Down syndrome, Edwards syndrome and Patau syndrome). This means there is a lower chance a woman who receives a high probability result is actually carrying a baby with a SCA. This can result in unnecessary anxiety for the pregnant woman and her family. For these reasons, consideration should be given before selecting this additional testing option and appropriate pre and post-test genetic counselling should be provided.

47,XXY (Klinefelter syndrome)

Klinefelter syndrome is a sex chromosome aneuploidy that occurs in males when there are two copies of the X chromosome instead of the usual one. The syndrome affects about 1 in 650 newborn boys 1. Many males with Klinefelter syndrome will never be diagnosed.

Some males with Klinefelter syndrome will be mosaic, where some of their cells have two X chromosomes and the other cells have one X chromosome. Babies that are born with Klinefelter syndrome could have a number of the features and symptoms, however, not everyone will have them all and severity will vary significantly.

Mosaicism plays a role in the varied features and severity of Klinefelter syndrome. The average intellectual capacity of people with Klinefelter syndrome is within the normal range, however, their IQ may be slightly lower than their siblings. Males with Klinefelter syndrome could be slower to develop emotional maturity than their peers.

Potential Symptoms

  • Learning difficulties - language related
  • Developmental delay
  • Delayed or incomplete pubertal development
  • Hypogonadism (small testes)
  • Infertility
  • Weight carried around the middle, long limbs
  • Gynecomastia (breast development)
  • Increased risk of breast cancer
  • Slightly taller in height

1. U.S. National Library of Medicine. Genetics Home Reference. Klinefelter Syndrome. https://ghr.nlm.nih.gov/condition/klinefelter-syndrome. Accessed September 13, 2019.

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Monosomy X (Turner syndrome)

Turner syndrome, or Monosomy X, is a sex chromosome aneuploidy that occurs in females when there is only one copy of the X chromosome instead of the usual two. The condition occurs in about 1 in 2,500 newborn girls worldwide 1. Unfortunately, many pregnancies with Turner syndrome will miscarry in the first or second trimester.

Over half of babies with Turner syndrome will be mosaic, where some of their cells have just one X chromosome and the other cells have two X chromosomes. Babies that are born with Turner syndrome could have a number of the features and symptoms, however, not everyone will have them all and severity will vary significantly. Mosaicism plays a role in the varied severity of Turner syndrome.

Potential Symptoms

  • Short stature
  • Subtle changes in physical appearances
  • Infertility
  • Heart defect
  • Health conditions - hypothyroidism, diabetes, autoimmune disease
  • Vision and hearing issues
  • Learning difficulties

1. U.S. National Library of Medicine. Genetics Home Reference. Turner Syndrome. https://ghr.nlm.nih.gov/condition/turner-syndrome. Accessed September 13, 2019.

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47,XYY - Jacob's syndrome

Jacob’s syndrome is a sex chromosome aneuploidy that occurs in males when there are two copies of the Y chromosome instead of the usual one. This condition occurs in about 1 in 1,000 newborn boys 1, however, many males with Jacob’s syndrome never come to clinical attention so it could be more common.

Some males with Jacob’s syndrome will be mosaic, where some of their cells have two Y chromosomes and the other cells have the usual one Y chromosome. Many babies that are born with Jacob’s syndrome do not have any clinical features and symptoms. There are no fertility issues associated with Jacob’s syndrome. Males with Jacob’s syndrome are usually very tall and may have severe acne during adolescence.

The average intellectual capacity of males with Jacob’s syndrome is within the normal range, however, their IQ may be slightly lower than their siblings.

Learning difficulties have been associated in some people with Jacob’s syndrome, usually involving speech and language. There are many misconceptions about males with Jacob’s syndrome; previously, it was sometimes called the supermale disease and was associated with being overly aggressive and lacking in empathy. Recent studies have disproven this and these traits are no longer associated with Jacob’s syndrome.

1. U.S. National Library of Medicine. Genetics Home Reference. 47,XYY Syndrome. https://ghr.nlm.nih.gov/condition/47xyy-syndrome. Accessed September 13, 2019.

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47,XXX - Triple X syndrome

Triple X syndrome is a sex chromosome aneuploidy that occurs in females when there is an extra copy of the X chromosome so there are three copies instead of the usual two. It is a chromosomal condition occurring in about 1 in every 1,000 1 female births, however, it is estimated that only 10% of females with Triple X syndrome ever come to clinical attention so it could be more common.

Some females with Triple X syndrome will be mosaic, where some of their cells have two X chromosomes and the other cells have three X chromosomes. Babies that are born with Triple X syndrome could have a number of the features and symptoms, however, not everyone will have them all and severity will vary significantly.

Some females with Triple X syndrome will not have any features. Mosaicism plays a role in the varied features and severity of Triple X syndrome. The average intellectual capacity of people with Triple X syndrome is within the normal range, however, their IQ may be slightly lower than their siblings. Females with Triple X syndrome do not have issues with fertility.

Potential Symptoms

  • Increased risk of premature ovarian failure
  • Learning difficulties
  • Increased risk of anxiety, depression, attention deficit, psychological conditions
  • Motor and speech delays
  • Tall stature

1. U.S. National Library of Medicine. Genetics Home Reference. Triple X Syndrome. https://ghr.nlm.nih.gov/condition/triple-x-syndrome. Accessed September 13, 2019.

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22q11.2 microdeletion (DiGeorge syndrome)

As part of the Harmony screening test menu, Australian Clinical Labs is now offering 22q11.2 deletion or DiGeorge syndrome testing. 22q11.2 deletion syndrome affects an estimated 1 in 1,000 pregnancies 5,6. It is the second most common genetic cause of heart defects and developmental delay after Down syndrome 4, and is the underlying cause of Di-George and Velocardiofacial syndromes (VCFS). 22q11.2 microdeletion is not reliably detected by routine prenatal screening or karyotype 4. Unlike trisomies, maternal age is not a risk factor for the microdeletion 2 and family history cannot reliably predict its occurrence as more than 90% of affected individuals have no family history 5.

The features of this syndrome vary widely, even among affected members of the same family.

The performance of the Harmony test for 22q11.2 microdeletion was evaluated in a study including over 1,900 samples, including 129 with confirmed deletions. The Harmony test was able to reliably identify pregnancies at risk for 22q11.2 deletions of 3Mb and smaller with a low false-positive rate 1.

Download 22q validation summary

22Q11.2 DELETION VIDEO A/PROF SAAD

References:

  1. Stokowski et al. Prenat Diagn. 2015 Dec; 35(12): 1243-1246.
  2. Demonstrated by 59 peer reviewed published studies using the Harmony prenatal test as of Jan 2019.
  3. Data on file.
  4. Norton et al. N Engl J Med. 2015 Apr 23; 372 (17): 1589-97.
  5. Grati et al. Prenat Diagn 2015; 35: 801-809.
  6. Wapner et al. N Engl J Med 2012; 367: 2175-2184.
A 22q11.2 deletion may not be detected in all fetuses. It is not validated for use in pregnancies with more than one fetus or for women with a 22q11.2 duplication or deletion. Due to the limitations of the test, a NO EVIDENCE OF A DELETION OBSERVED result does not guarantee that a fetus is unaffected by a chromosomal or genetic condition. In cases of HIGH PROBABILITY results and/or other clinical indications of a chromosomal condition, confirmatory testing is necessary for diagnosis.

If further information regarding testing is required, or you need to discuss a patient, please contact:
Assoc. Prof. Mirette Saad on P: (03) 9538 6777 or E: Mirette.Saad@clinicallabs.com.au.