The genetic disease explored throughout this report will be 22q11.2 Deletion Syndrome (DS), including the importance of diagnosis through genetic testing. The analysis of the disease and test should examine and answer the inquiry question: “Should genetic testing for the diagnosis of 22q11.2 deletion syndrome be available without cost for newborn born with congenital heart disease?”
DS is currently the second most causes of developmental delay and congenital heart disease. Population screening studies only began in the 1990s. The syndrome has been under-recognised with diagnosis frequently delayed and not achieved until adolescence or adulthood. Some symptoms of the syndrome have been recognised as mild and may not be noticed until they worsen and cause severe problems. Currently in Australia, the number of children with 22q11.2 DS is unknown and health service needs are unclear. The unfamiliarity with the syndrome and late diagnosis not only results in medical complications, but also has an impact on the psychological wellbeing of the child and their family(Shprintzen 2008).Throughout the report by investigating the implication of newborn testing for 22q11.2 DS, we can determine the benefits of an early diagnosis.
About 22q11.2 Deletion Syndrome
The deletion affects approximately 30 to 40 genes, many of which are not yet understood(Smith 2018). An important gene lost in the deletion on chromosome 22 is TBX1, responsible for the characteristic signs and behavioural problems of an individual. The TBX1 gene gives instructions for producing a protein called T-box 1, that plays a vital role in tissue and organ formation during embryonic development. The lack of the protein T-box 1 required for normal development causes changes to the disease phenotype to display distinctive facial features. The T-box 1 protein is necessary for “normal development of muscles and bones of the face and neck, large arteries that carry blood out of the heart, structures in the ear, and glands such as the thymus and parathyroid”(Genetics Home Reference 2020b). Another gene lost in the same region is COMT, which helps explain the increased risk of behavioural signs and mental illness associated with 22q11.2 DS. The COMT gene produces instructions for an enzyme called catechol-O-methyltransferase, responsible for the nervous system, tissues and multiple organs(Genetics Home Reference 2020a).
22q11.2 Deletion Syndrome (DS) has multiple symptoms that include developmental abnormalities and complications(Osmosis 2016). Affected individuals also experience learning disabilities, behavioural problems, development delays and mental health conditions(NHS Choices 2017). Individuals with 22q11.2 DS can often be characterised by their distinctive facial features. During growth, skeletal problems in individuals can become evident, often associated with a short stature and abnormalities of spinal bones(Genetics Home Reference 2011). Congenital heart disease is present at birth and highly common, found in 64% of individuals(McDonald-McGinn et al. 1993). People with 22q11.2 DS commonly have a higher risk of infection due to immunodeficiency found in 77% of individuals, low levels of calcium in the blood known as hypocalcaemia, and significant feeding difficulties present in 36% of children(McDonald-McGinn et al. 1993). Individuals are also more prone to developing psychiatric illness later on in life and an early-onset of conditions such Parkinson’s disease with a prevalence of 5.9%(McDonald-McGinn et al. 1993).
Physical characteristics that may be found in individuals with 22q11.2 Deletion Syndrome include:
- Palatal abnormalities found in 67% of individuals, including submucosal cleft palate – can interfere with normal speech(McDonald-McGinn et al. 1993).
- “Certain facial features, such as an underdeveloped chin, low-set ears, wide-set eyes or a narrow groove in the upper lip”(Mayo Clinic 2017).
- Skeletal abnormalities – “95 children between age one and 15 years, 14% were below the fifth percentile in height”(McDonald-McGinn et al. 1993).
- Gastrointestinal abnormalities
- Kidney abnormalities
- Hypoparathyroidism – decreased secretion of parathyroid hormone(NHS Choices 2017), and subsequently low levels of calcium in blood – hypocalcaemia present in 17%-60% of individuals with the syndrome(Genetics Home Reference 2011).
Behavioural problems that may be found in individuals with 22q11.2 Deletion Syndrome include:
- Autism/autism spectrum disorders (20% of children) and difficulty with social interactions(McDonald-McGinn et al. 1993).
- Attention deficit disorder (ADHD)
- Mental health problems (60% of adults) – anxiety, depression and schizophrenia (25% of adults)(McDonald-McGinn et al. 1993).
- Developmental delay and learning difficulties in 70-90% of individuals(McDonald-McGinn et al. 1993).
Age of onset
Symptoms of 22q11.2 Deletion Syndrome can be present at birth, however behavioural problems are more noticeable after 12 months. Heart abnormalities are present from birth, in particular congenital heart disease found in 64% of individuals. The development of walking was found to be delayed with a mean age of 18 months, and many children were nonverbal at 2-3 years. Behavioural differences screened before the age of 10 provide an opportunity for early intervention(McDonald-McGinn et al. 1993).
Current approaches to diagnosis
A diagnosis for 22q11.2 Deletion Syndrome (DS) is often ordered if persistent medical conditions occur and/or a congenital heart defect is identified. The diagnosis is often difficult due to the variety in phenotypes. However the most common identification for 22q11.2 DS a targeted deletion analysis, called a FISH analysis (Fluorescent In Situ Hybridization)(McDonald-McGinn et al. 1993). The FISH test uses blood and can be done during metaphase or interphase to indicate the deletion found on chromosome 22 (ResearchGate 2020). Chromosomal microarray (CMA) using oligonucleotide or SNP arrays can also detect the recurrent deletion(McDonald-McGinn et al. 1993).
Treatment for 22q11.2 Deletion Syndrome (DS)
There is currently no cure for 22q11.2 DS, however treatment can help manage and prevent health issues and development. Palatal abnormalities such as a cleft palate may require surgery. To treat the parathyroid hormone, vitamin D or calcium supplements can be taken. Other treatments depend on the organ systems, and several specialists should be involved to treat and manage 22q11.2 DS. These include(MedicalNewsToday 2020):
- Infectious disease specialists
- Therapists (occupational, physical, speech, developmental and mental)
Furthermore, the table to the right provides information on the “Treatment of Manifestation in Individuals with 22q11.2 DS” (Genetics Home Reference 2011).
22q11.2 Deletion Syndrome occurs 1 in every 3000-6000 births and is evenly distributed between male and female cases (Kraus et al. 2018). It is the second most prevalent genetic syndrome after Down Syndrome. It is also the second most common syndrome associated with congenital heart defects(22q Deletion Syndrome n.d.). However in Australia it is unclear how many cases of 22q11.2 DS there are(Shprintzen 2008).
22q11.2 Deletion Syndrome is an autosomal dominant inheritance spontaneous mutation is enough to cause the condition. In 90% of cases the deletion on chromosome 22 is a random event that occurred during fertilisation where either the egg or sperm loses a section of DNA. In about 10% of cases the deletion is passed from parent to child. If neither parent has the syndrome, the risk of a child with it would be less than 1%. If one parent has the condition, the child has a 50% risk(NHS Choices 2017).
22q11.2 deletion is diagnosed through a targeted deletion analysis, called a FISH analysis (Fluorescent In Situ Hybridization)(McDonald-McGinn et al. 1993). A sample of an individual’s cells is fixed on a glass slide to analyse the DNA. The cells can be taken from blood, bone marrow or amniotic fluid. The slides containing the DNA are heated to separate the double-helix structure into single strands. Fluorescent probes are added to the sample and attaches to a specific piece of DNA(Lab Tests Online AU 2010). The slides are examined using a fluorescence microscopy to examine genetic sequences, in this case deletions. Today newly identified patients (90-95%) are found using FISH(McDonald-McGinn et al. 2015). The variety in phenotypic presentations of 22q11.2 DS makes diagnosis more challenging. FISH is a powerful diagnostic tool capable of detecting deletions and microdeletions and known for its “accuracy and reliability in the diagnosis of chromosome 22q11.2 deletion syndrome in the foetus and/or newborn”(Miller 2008). The FISH test can be applied to the diagnosis of 22q11.2 DS for more common and accessible, allowing for early treatment and management.
Early diagnosis of 22q11.2 Deletion Syndrome (DS) can greatly improve the outcomes an individual may have to face. At the moment Medicare does not cover the costs of the FISH test for newborns(VCGS 2020).
Some cases of the syndrome include mild symptoms which if left unnoticed will worse and cause severe problems. The benefit of early diagnosis of 22q11.2 DS, allows for more opportunities to treat and manage symptoms, providing the individual with a better quality of life. The most common symptom for 22q11.2 DS is congenital heart disease. approximately every 8-10 cases per 1000 births are born with congenital heart disease(Heartkids 2018). By providing screening for each newborn born with congenital heart disease, early treatment can commence. The cost for a postnatal FISH test is $196.35(VCGS 2020). Through early testing and therefore early treatment, future cost strains on individuals and family’s will be reduced. Future management involves several specialists, surgeries and supplements in which planning can be conducted earlier through FISH analysis.
The FISH test involves a small blood sample postnatal and is safe and provides an accurate result. By making the FISH test more accessible in the diagnosis of 22q11.2 deletion the psychological wellbeing of several individuals and families can be helped(Shprintzen 2008). The early diagnosis, preferably postnatal could greatly improve outcomes, thus stressing the importance of universal screening(McDonald-McGinn et al. 1993).
Although there are many benefits to available FISH testing, there are also limitations. A major consideration with testing on newborns is the ethical implication. The blood is taken from the heel of the baby with a prick 3 days after birth, before symptoms start to show(Newborn screening 2018). Although the blood test taken from a newborn is harmless and any harm caused is very minimal, parents may be against the testing of a young child. Early intervention for 22q11.2 Deletion Syndrome (DS) is ideal, however the considerations of parents must also be considered.
Furthermore economic and social considerations on the cost of the test must be considered. The cost of the test is currently not covered by Medicare and by allowing the test to be available members of the public may disagree. The cost of the test can have an impact on the health system, considering the availability for all newborns with congenital heart disease.
The ethical, economic and social considerations must also be considered in order to accurately weigh the risks against the benefits of available testing.
The future implication of allowing genetic testing (FISH) for all newborns born with congenital heart disease without cost would greatly benefit those who test positive for 22q11.2 Deletion Syndrome (DS). Through the implication of early diagnosis, the individuals and families affected are able to prevent and manage the symptoms of 22q11.2 DS early on. The cost for future management for families is very high. By allowing genetic testing without costs, families are able to promote their wellbeing through preparation and research.
Throughout the investigation of the inquiry question “Should genetic testing for the diagnosis of 22q11.2 deletion syndrome be available without cost for newborn born with congenital heart disease?” including the risks and benefits, an outcome has been assessed. By providing genetic testing for newborns with congenital heart disease the lives of several individuals and families will be improved. The test conducted would be a postnatal FISH analysis which shows minimal harm to the newborn but is able to accurately and reliably found in 90-95% of patients(McDonald-McGinn et al. 2015). The benefits of allowing cost free genetic tests outweigh the risks. Parents are able to deny testing for their child, however other families are given the option to conduct genetic test which will greatly benefit them in the long-run. Early diagnosis provides early management and treatment, as well as possible prevention of symptoms. To conclude the implication of newborn cost free testing for 22q11.2 DS is beneficial to the wellbeing of the child and their family and should be made possible.
- 22q Deletion Syndrome n.d., www.nationwidechildrens.org, viewed 6 March 2020, .
- 22q Foundation Australia and New Zealand What is 22q 2020, 22q11, viewed 2 April 2020, .
- 22q11.2 deletion syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program n.d., rarediseases.info.nih.gov, viewed 18 February 2020, .
- Congenital Heart Disease – Heartkids site 2018, Heartkids.org.au.
- DiGeorge and/or Velocardiofacial Syndrome | Children’s Wisconsin 2020, Chw.org, viewed 20 March 2020, .
- DiGeorge sequence – Conditions – GTR – NCBI n.d., www.ncbi.nlm.nih.gov, viewed 18 February 2020, .
- DiGeorge Syndrome | Immune Deficiency Foundation 2013, Primaryimmune.org, viewed 20 March 2020, .
- DiGeorge syndrome (22q11.2 deletion syndrome) – Diagnosis and treatment – Mayo Clinic 2017, Mayoclinic.org, viewed 3 March 2020, .
- DiGeorge syndrome (22q11.2 deletion syndrome) – Symptoms and causes 2017, Mayo Clinic, viewed 3 March 2020, .
- DiGeorge syndrome: Causes, symptoms, and treatment n.d., www.medicalnewstoday.com, viewed 20 March 2020, .
- Fluorescence in situ Hybridisation (FISH) 2010, Labtestsonline.org.au, viewed 2 April 2020, .
- Genetics Home Reference 2011a, 22q11.2 deletion syndrome, Genetics Home Reference, viewed 3 March 2020, .
- ― 2011b, NOTCH2 gene, Genetics Home Reference, viewed 30 March 2020, .
- ― 2013, JAG1 gene, Genetics Home Reference, viewed 30 March 2020, .
- ― 2014, CHD7 gene, Genetics Home Reference, viewed 30 March 2020, .
- ― 2015a, Chromosome 22, Genetics Home Reference, viewed 3 March 2020, .
- ― 2015b, DHCR7 gene, Genetics Home Reference, viewed 30 March 2020, .
- ― 2020a, COMT gene, Genetics Home Reference, viewed 3 March 2020, .
- ― 2020b, TBX1 gene, Genetics Home Reference, viewed 3 March 2020, .
- Interphase FISH Test (postnatal) | VCGS 2020, Vcgs.org.au, viewed 2 April 2020, .
- Kraus, C, Vanicek, T, Weidenauer, A, Khanaqa, T, Stamenkovic, M, Lanzenberger, R, Willeit, M & Kasper, S 2018, ‘DiGeorge syndrome’, Wiener klinische Wochenschrift, vol. 130, no. 7–8, pp. 283–287.
- McDonald-McGinn, DM, Emanuel, BS, Zackai, EH & Hain, HS 1993, 22q11.2 Deletion Syndrome, in MP Adam, HH Ardinger, RA Pagon, SE Wallace, LJ Bean, K Stephens & A Amemiya (eds), PubMed, University of Washington, Seattle, Seattle (WA), viewed 18 February 2020, .
- McDonald-McGinn, DM, Sullivan, KE, Marino, B, Philip, N, Swillen, A, Vorstman, JAS, Zackai, EH, Emanuel, BS, Vermeesch, JR, Morrow, BE, Scambler, PJ & Bassett, AS 2015, ‘22q11.2 deletion syndrome’, Nature Reviews Disease Primers, vol. 1, no. 1, viewed 4 November 2019, .
- Microarray – Rare Disease Institute | Children’s National 2019, childrensnational.org, viewed 6 March 2020, .
- Miller, KA 2008, ‘FISH Diagnosis of 22q11.2 Deletion Syndrome’, Newborn and Infant Nursing Reviews, vol. 8, no. 1, pp. e11–e19, viewed 2 April 2020, .
- Newborn screening 2018, Raising Children Network. Viewed 2 April 2020,
- NHS Choices 2017, DiGeorge syndrome (22q11 deletion), NHS, viewed 21 February 2020, .
- Osmosis 2016, Digeorge syndrome (22q11.2 deletion syndrome) – causes, symptoms, & pathology, YouTube, viewed 24 March 2020, .
- RACGP – Chromosome microarray 2018, Racgp.org.au, viewed 6 March 2020, .
- Shprintzen, RJ 2008, ‘Velo-cardio-facial syndrome: 30 Years of study’, Developmental Disabilities Research Reviews, vol. 14, no. 1, pp. 3–10, viewed 2 April 2020, .