THE PERPLEXING PREVALENCE OF FAMILIAL NESTED 22q11.2 DELETIONS. D. M. McDonald-McGinn, L. DiCairano, J. T. Goulet, A. Capezzuto, A. Krajewski, C. Franconi, M. McNamara, D. E. McGinn, B. S. Emanuel, E. H. Zackai Div Human Gen, Children's Hosp Philadelphia, Philadelphia, PA.
Introduction: The 22q11.2 deletion is most often de novo and classically extends from segmental duplications A-D including loss of TBX1 an important developmental gene within the A-B region causally associated with typical features such as congenital heart disease. In contrast, TBX1 is present in patients with B-D and C-D nested deletions where overlapping features still include conotruncal anomalies and familial inheritance is common. Here we report the perplexing prevalence of familial nested 22q11.2 deletions, as well as associated phenotypes. Methods: 603/1188 individuals with 22q11.2DS (50%) in our cohort had deletion sizing by enhanced FISH, CGH, GWAS or MLPA. Phenotypic features were catalogued prospectively under IRB approval. Results: 526/603 patients (87%) had A-D deletions whereas 13% were nested. Of the latter, whose deletions did not include the A-B/TBX1 region, 20 probands had B-D and 3 C-D deletions. Parental studies in 15/20 B-D and 2/3 C-D families revealed 9/15 (60%) B-D and 1/2 C-D deletions were familial. Of these, 5/9 B-D deletions were paternally inherited, as was the familial C-D deletion. Anomalies typically associated with the A-D deletion were also identified with B-D deletions, albeit less frequently, including: CHD (31%); VPI/SMCP (38%); chronic infection (46%); hypocalcemia/growth hormone deficiency (24%); GERD (36%); and learning differences (61%). The C-D deletion also resulted in typical features including: CHD; chronic infection; hypernasal speech; and developmental delay. 3/9 parents with B-D deletions had significant findings including developmental delay, ADHD and short stature. The father with the C-D deletion has a Masters Degree in Education but reported lifelong learning deficits in math. Conclusions: In the largest series to date, we confirm that the majority of 22q11.2 deletions extend from A-D and are de novo. However, we report the noteworthy finding that nested B-D and C-D deletions are frequently familial. This may reflect a milder overall phenotype or the effect of modifier genes but this observation is critical for providing accurate genetic counseling. Moreover, this may well inform our understanding of developmental genes beyond TBX1 such as CRKL1 and SNAP29 or position effects to explain the phenotypic overlap with the standard deletion but importantly, based on this data, we urge practitioners to be vigilant in screening parents of all affected children regardless of their clinical history.
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