15q13 recurrent region (BP3-BP4) (includes APBA2)

Rosenfeld et al. (2011) reported three unrelated probands (Subjects 1-3) with deletion of the 15q13 (BP3-BP4) region identified by routine aCGH testing and compared clinical findings to BP3-BP4 patients previously reported in the literature, as well as a patient (Subject 4) with an atypical BP3-BP4 deletion (partially overlapping this region). Clinical findings in more than 50% of BP3-BP4 deletion carriers, summarized in Table 2, include DD/ID (7/7), hypotonia (5/6), ocular features (5/6), dysmorphic features (6/7), failure to thrive (4/6), short stature (4/7), and microcephaly (4/7). The authors note, through genotype-phenotype correlation, that certain features seen in association with the larger BP3-BP5 deletion may be attributed to the BP3-BP4 region. The deletion of Subject 2 was de novo, while the deletion of Subjects 1 and 3 were inherited from mothers who were clinically unaffected. Other patients from the literature have inherited deletions. Two deletions were reported in control cohorts. Enrichment studies failed to show a statistically significant enrichment of these deletions. The authors note, “…a comparison of these cases with each other and with those in the literature shows some phenotypic similarities…we propose that deletions of the BP3–BP4 interval can contribute to an abnormal phenotype. However, there is still phenotypic variability among subjects, and a consistent and recognizable phenotype is not present.”

van Bon et al. (2009) reported clinical findings of a proband (Patient 19) with deletion of the 15q13 (BP3-BP4) region, which included failure to thrive, hypotonia, microcephaly, craniofacial dysmorphism. This deletion was paternally inherited (father with normal cognitive function) and was also present in a 5-year-old brother and paternal uncle, who both had normal development. Another brother, aged 4, also had ID and did not have the BP3-BP4 deletion, demonstrating evidence of non-segregation. The authors note, “The limited data so far indicate that the BP3–BP4 deletion is a novel copy number variation of doubtful clinical significance, especially as the phenotype of both the BP3–BP5 cases (case 16 and 17) was not more severely affected than that of patients with a deletion comprising BP4–BP5 only.”

Sharp et al. (2008) reported clinical findings of a proband (Individual 543/06) with deletion of the 15q13.3 (BP3-BP4) region, which included developmental delay, dysmorphic features (including iris coloboma), and a kidney anomaly (ureteral ectasia). The deletion was inherited from the unaffected father of this patient. The authors state, “Therefore, we interpret this BP3-BP4 deletion as probably representing a benign copy number variant, although we cannot exclude that it may instead be a pathogenic deletion with incomplete penetrance.”