Lost in translation

Lost in translation

Dr Priya Kadam

Thirty nine-year-old Juhi was cautiously delighted when she learned she was pregnant again. She had previously miscarried a foetus affected with Down Syndrome. During her current pregnancy, she consulted a geneticist who suggested a test for Down Syndrome and a group of disorders called microdeletion syndromes. She opted for the test as it was non-invasive and accurate. Sadly, this time, the foetus was diagnosed with another disorder – 22q11.2 microdeletion syndrome. Though devastated, Juhi appreciated the information she received early in pregnancy, and accordingly made an informed decision. Such information is vital to expectant parents for thought-through early pregnancy decisions and to avoid the distress caused by the birth of an abnormal baby unexpectedly.

Down Syndrome, with an incidence rate of 1 in 800 pregnancies, is the most common genetic/chromosomal disorder and is reasonably known to both the medical fraternity and the general public. From the 1960s, there have been continuously improving approaches to screen for and diagnose this and a few other significant conditions during pregnancy, given the seriousness of these conditions. However, there is another group of clinically relevant disorders caused by the deletion (loss) of a small part of a chromosome, called microdeletion syndromes. This chromosomal loss occurs very early during development and is irreversible. Microdeletion syndromes are clinically important as they are associated with intellectual impairment, learning difficulties, autism and a host of other abnormalities, including those related to the heart and the kidneys. The reported incidence of microdeletion syndromes is 1 in 1000 pregnancies. These conditions are not easy to detect during pregnancy. They were also previously considered rare and therefore not high-priority candidates for screening programmes. Most individuals were/are identified after birth, during childhood or even during adulthood.

Unravelling DiGeorge

Initially, microdeletion syndromes were described when patients with a cluster of specific features (phenotype) were observed together. The genetic basis of these conditions began to be identified around 30 years ago, with the development of techniques such as fluorescent in situ hybridization. With the development of other advanced techniques such as chromosomal microarrays, more and more areas of such repeated and specific chromosomal losses began to be identified, which correlated clinically observed syndromes.

22q11.2 deletion syndrome is commonly known as DiGeorge syndrome. Velocardiofacial syndrome and conotruncal anomaly face syndrome are the most commonly used names for the microdeletion syndrome. It is the second biggest cause of congenital heart disease and developmental delays. Caused by a deletion in a small and variable part of chromosome 22, it has an incidence of 1 in every 2000 births. The syndrome is associated with heart defects, cleft palate, developmental delay, mental and psychiatric disorders, endocrine disorders, distinct facial features and low calcium levels among other features. The condition is associated with premature mortality, based on the severity of individual features. There is no cure and the best management strategy is a multidisciplinary approach aimed at handling individual symptoms. Early management of symptoms greatly improves outcome. Most of the cases occur spontaneously without family history, while in 5-10% of the cases, it is inherited with 50% risk of transmitting the disorder. This risk of carrying an affected pregnancy with microdeletion syndrome is not related to maternal age and the risk remains the same throughout a women’s reproductive period.

The syndrome was clinically described in English language in 1960s in children who presented with the triad of immunodeficiency, hypoparathyroidism and congenital heart disease. However, there is a huge variability in the presentation and the age of recognition of symptoms. Though common, the lack of awareness of the condition and/or testing methods and the huge variability in presentation delay diagnosis. The typical age of molecular diagnosis is around five years after numerous visits to different clinical specialties. Early identification and management is useful to improve the quality of life. Though the condition can be suspected during pregnancy by ultrasonography if certain structural defects and cardiac anomalies are seen, there is no regular screening programme. Some cases may not have signs that can be picked up on an ultrasound.

Cell-free DNA screening

Over the past two to three decades, tests for clear molecular diagnosis have been available. In the past four years, some of these conditions could be screened non-invasively by a new test that examines the cell-free DNA from maternal blood. Non- Invasive pre-natal test (NIPT) is a good screening test for the expectant parents, cost permitting. NIPT, a simple, non-invasive DNA test, involves taking a small amount of blood from the mother’s arm to test for chromosomal abnormalities in the developing foetus. Screening during pregnancy can help empower the expectant parents to be more aware of the condition and accordingly seek medical help.

Other diagnostic tests for microdeletion syndromes include Fluorescent in situ Hybridisation, Multiplex Ligation-dependent Probe Amplification, Quantitative Polymerase Chain Reaction and Chromosomal Microarrays. However, these tests are performed on actual foetal tissue obtained by invasive tests, such as chorionic villus sampling and amniocentesis. They pose a small but significant risk of miscarriage.

Microdeletion syndromes are a group of frequently unsuspected and overlooked disorders at pregnancy evaluation. Greater awareness among clinical fraternity as well as general public and the development of a routine screening programme would serve the population well in identifying these disorders early.

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