In 1967, DiGeorge syndrome entered the medical lexicon (Lischner et al, 1967). More widely known as 22q11.2 deletion syndrome, it is the most common chromosomal condition after Down's syndrome, and has a frequency of around 1 in 4000 live births (O'Donoghue et al, 2023). It is a complex, multi-system disorder with over 180 age-dependent clinical features; in infancy, congenital heart defects, cleft palate and feeding difficulties, immune disorders and hypocalcaemia can be observed (O'Donoghue et al, 2023).
In an Irish study, O'Donoghue et al (2023) found that the families of those with 22q11 deletion syndrome experience difficulties ‘largely regarding the disclosure of diagnoses and the lack of adequate provision of support and information’, and that healthcare professionals have a poor understanding and a low awareness of 22q11 deletion syndrome. Although it is relatively rare, rare diseases are collectively common. Anne Lawlor is the Co-founder and Chair of a 22q11 deletion syndrome support group, 22q11 Ireland, whose daughter Áine was diagnosed with 22q11 deletion syndrome aged 15 years old. Anne explains that ‘over ten thousand rare diseases affect one in seventeen … and genetic screening at birth is vital’ (Winter, 2024). Midlands-based Julie Wootton, who founded the English 22q11 deletion syndrome charity Max Appeal agreed, highlighting that ‘at Max Appeal we're campaigning for 22q11DS to be added to the list of conditions screened through heel-prick tests of newborns’ (Winter, 2024).
Current NHS advice is to consult a GP ‘if you're planning a pregnancy and you have a family history of DiGeorge syndrome, or you have a child with it’ (NHS, 2023). After consultation, possibilities include a blood test of both partners to check for genetic carrier status, having tests during pregnancy such as chorionic villus sampling or amniocentesis, and pre-implantation genetic diagnosis ‘where eggs are fertilised in a laboratory and embryos are tested for genetic problems before they're implanted in the womb – this is not always available on the NHS' (NHS, 2023).
But in the absence of screening, diagnosis can be delayed. For example, Campbell et al (2018) reviewed the medical records of a cohort of 1421 patients with molecularly confirmed 22q11 deletion syndrome from 1992 to 2018. They found that it was easier to arrive at a diagnosis ‘for individuals with cardiac disease, with a median age at diagnosis of 2.6 months compared to those without cardiac issues of 3.1 years’ (Campbell et al, 2018). Further, it proved challenging to make a diagnosis among those without heart disease, ‘with common features such as ear abnormalities, hooding of the eyes, and nose differences or even seemingly more specific abnormalities such as asymmetric crying facies not helping to hasten the time to diagnosis’ (Campbell et al, 2018).
Given the common nature of so-called rare diseases like 22q11 deletion syndrome, and that diagnosis can be delayed owing to a constellation of possible signs and symptoms, is there a case for both prenatal and newborn screening to detect the condition? Hammer et al (2024) observed that ‘diagnosis during the prenatal period allows for appropriate pregnancy management, including enhanced surveillance and interventions that reduce morbidity and improve outcomes in newborns’. The authors further noted that the American College of Medical Genetics and Genomics acknowledges the benefits of such screening and recommends ‘that screening for 22q11 [deletion syndrome] microdeletion by prenatal cell-free DNA testing be offered to all pregnant patients’ (Hammer et al, 2024).
Bevilacqua et al (2021) reported their findings of a targeted cell-free DNA test of maternal plasma samples with an increased likelihood of a 22q11.2 chromosomal deletion. If routinely implemented, the test ‘could improve detection of foetal 22q11 deletion syndrome and guide pregnancy management without increasing the likelihood of a false-positive result’ (Bevilacqua et al, 2021). The authors determined test sensitivity and specificity using a multi-centre analysis that evaluated 735 clinical samples, which included 358 from prospectively enrolled pregnancies and 377 stored clinical samples. They concluded that using the test ‘to screen for 22q11 [deletion syndrome] could enhance identification of pregnancies at risk for 22q11 [deletion syndrome] without significantly increasing the likelihood of maternal anxiety and unnecessary invasive procedures related to a false-positive result’ (Bevilacqua et al, 2021).
Highlighting the progress that has been made in non-invasive prenatal screening since the introduction of cell-free DNA screening in 2011, Soster et al (2023) noted that the availability of prenatal identification of 22q11 deletion syndrome ‘allows parents to make informed reproductive choices and may have benefit for both perinatal management and maternal health and may help to avoid a potential “diagnostic odyssey” for an affected child’. Another important point is that 22q11 deletion syndrome ‘often occurs de novo, is not associated with maternal age, and affected foetuses may or may not present with ultrasound findings’, which invites the inference that ‘many cases of 22q11 [deletion syndrome] may not otherwise be identified in the prenatal or neonatal period via ultrasound or routine assessment of the patient's family or obstetric history’ (Soster et al, 2023).
Notwithstanding the concerns that some might raise against prenatal screening, there is merit in Soster et al's (2023) observations that ‘given that 22q11 [deletion syndrome] is a relatively common chromosome condition and may have implications for the pregnant person and the foetus, the potential benefits to screening may outweigh the challenges in the setting of education and informed consent’.