22q11.2 recurrent region (central, B/C-D) (includes CRKL)

Rump et al. (2014) reported 10 novel 22q11.2 B-D (6) and C-D (4) deletions. These deletions were identified in 24 total individuals (12 B-D and 12 C-D). Clinical features were variable and included developmental delay, behavioral problems, dysmorphic facial features, growth delay, skeletal/digital abnormalities, congenital heart anomalies, renal abnormalities, genital anomalies, ear infections, and additional, less common features. Of the 9 cases for which parental testing was performed, 7 were found to be inherited. Among carrier parents, 3 were noted to be asymptomatic and 4 were affected.

Clements et al. (2017) reported 18 patients with 22q11.2 B-D (14) or C-D (4) deletions. The reported neurological features included global developmental delay, intellectual disability, ADHD, ODD (oppositional defiant disorder), OCD, Anxiety, and MDD (major depressive disorder). Additional clinical findings include congenital heart defects, GERD (gestroesophaeal reflux disease), chronic constipation, ophthalmologic anomalies, and kidney abnormalities (medullary nephrocalcinosis and solitary, low-lying kidney). Approximately 69% of deletions were reported to be de novo. Parental phenotype was not documented in this study.

Burnside (2015) reviewed clinical findings of 23 patients with 22q11.2 deletions involving the B/C-D region including 45 additional patients from the literature. Clinical features were highly variable with the most common features being growth retardation, immune deficiency/recurrent infections, CNS anomalies/seizures, developmental delay, intellectual disability, skeletal anomalies, cardiovascular defects, psychiatric/behavioral problems, genitourinary anomalies, and dysmorphic features. Parental testing was performed in 7 of the novel patients reported in this study, with 4 of the deletions being de novo, 2 being inherited, and 1 unknown. Parental phenotypes were not included in this paper.

Verhagen et al. (2012) reported 5 novel 22q11.2 B-D (1) and C-D (4) deletions. These deletions were identified in 8 total individuals (2 B-D and 6 C-D). Clinical features were variable and included developmental delay, behavioral and/or psychiatric problems, dysmorphic facial features, microcephaly, congenital heart defects, genital anomalies, as well as additional less common features. Parental testing was performed in 4 cases, with 3/4 probands inheriting the deletion from a parent. 3 carrier parents were noted to be asymptomatic, and 1 was de novo. Parental phenotypes were not included in this paper.

Lopez-Rivera et al. (2017) reported clinical findings for 9 individuals with 22q11.2 C-D deletions. Of these patients, 7 were identified in a cohort of over 2000 patients affected by congenital kidney and urinary tract anomalies. The reported findings in these patients include renal agenesis, renal hypodysplasia, and cortical cysts. The extrarenal features reported in these patients were limited, with undescended testis being the only one that was observed in more than one patient. Ten additional patients with a C-D deletion were identified in the Children’s Hospital of Philadelphia 22q11.2 deletion database, two of which were found to have kidney and urinary tract defects, including renal agenesis and renal hyperechogenicity. The reported extrarenal features included speech delay and dysphagia. Functional studies in both Zebrafish and Mice were consistent with CRKL being a critical gene within the region. Parental studies were not reported for these patients.