Elucidating the diagnostic odyssey of 22q11.2 deletion syndrome

Abstract

Clinical molecular testing has been available for 22q11.2 deletion syndrome (22q11.2DS) for over two decades yet under-recognition and diagnostic delays are common. To characterize the "diagnostic odyssey" in 22q11.2DS we studied 202 well-characterized unrelated adults, none ascertained through an affected relative. We used a regression model to identify clinical and demographic factors associated with length of time to molecular diagnosis. Kaplan-Meier analysis compared time to diagnosis for the molecular testing era (since 1994) and earlier birth cohorts. The results showed that the median time to molecular diagnosis of the 22q11.2 deletion was 4.7 (range 0-20.7) years. Palatal and cardiac anomalies, but not developmental delay/intellectual disability, were associated with a shorter time to molecular diagnosis. Non-European ethnicity was associated with longer time to diagnosis. Inclusion of a cohort from another 22q11.2DS center increased power to observe a significantly earlier diagnosis for patients born in the molecular testing era. Nonetheless, only a minority were diagnosed in the first year of life. On average, patients were seen in seven (range 2-15) different clinical specialty areas prior to molecular diagnosis. The findings indicate that even for those born in the molecular testing era, individuals with 22q11.2DS and their families face a diagnostic odyssey that is often prolonged, particularly in the absence of typical physical congenital features or for those of non-European ancestry. The results support educational efforts to improve clinical recognition and testing, and ultimately newborn screening as a means of maximizing early detection that would provide the best opportunity to optimize outcomes.

Keywords: DiGeorge syndrome; developmental delay; feeding difficulties; neurology; psychosis proneness; recurrent infections; scoliosis; seizures; surgical complications; velocardiofacial syndrome.

Figure 1. Length of time to molecular diagnosis of 22q11.2 deletion syndrome (22q11.2DS) for three sub-groups in (A) a Canadian and (B) in a combined North American cohort

Kaplan-Meier curves showing time to molecular diagnosis of 22q11.2DS for individuals born in the era of molecular testing (group 3, grey dotted line), i.e., 1994 to 1997 inclusive, and for individuals who were children (group 2, red solid line) or were adults (group 1, blue dashed line) in the molecular era. A. The median time to diagnosis was 3.8 years (range 0.1-19; 95% CI 2.1-4.7 years) for the 41 subjects born in the era of molecular testing (Group 3), the median diagnostic delay was 4.9 years (range 0.1-20.7 years; 95% CI 3.5 to 6.7 years) for those who were children (Group 2), and 5.7 years (range 0-18.5 years; 95% CI 4.2 to 7.9 years) for those who were adults (Group 1). The log rank test showed there was no significant difference between these curves (p=0.082). There were no censored values. B. After adding 51 US subjects to Group 3, the median diagnostic delay was 3.3 years (range 0-19.0 years; 95% CI 2.1 to 4.2) for the total 92 subjects born in the era of molecular testing. Also shown are Group 4 (n=61 pediatric US subjects born in 1998 and thereafter, green double dash line), with a median diagnostic delay of 1.6 years (range 0-12.3 years; 95% CI 0. 6 to 2.3 years). There were two censored values each in group 3 and 4 where the ‘event’ of interest, a molecular diagnosis of 22q11.2DS, occurred at birth (i.e. diagnostic age 0). The log rank test revealed significant differences overall when comparing the survival curves of the four groups (p<0.0001). Subsequent comparisons of these four curves were made with Bonferroni’s correction for multiple comparisons. Significant differences were found between groups 1 and 3 (p=0.0043), 1 and 4 (p<0.0001), 2 and 3 (p=0.0011) and 2 and 4 (p<0.0001). There were no significant differences between groups 1 and 2 (p=0.99) and 3 and 4 (p=0.63).