In addition to identifying new potentially pathogenic loci, the large number of cases provides the opportunity to identify atypical deletions (i.e. characterized by noncanonical breakpoints and likely generated by a non-NAHR mutational mechanism) and refine the critical region of known genomic disorders. For example, we identified three individuals with smaller, atypical deletions within the 17q21.31 microdeletion syndrome region18,24,25 (Figure 3B). These patients’ breakpoints contrast with those of 23 patients carrying the canonical 480 kbp deletion mediated by unequal crossover between directly orientated SDs—a genomic architecture largely restricted to individuals of European descent26. Detailed clinical information on two individuals with the atypical deletion (Figure 3C), showed strong phenotypic similarity with the known syndrome including a pronounced philtrum, epicanthic folds, cupped ears and skeletal defects of the hand (Supplementary Note, Supplementary Table 11). The strong phenotypic similarity refines the dosage-sensitive region to only three genes (Figure 3B), including MAPT, which is disrupted by one of these atypical deletions.
