A Palindrome-Like Structure on 16p13.3 Is Associated with the Formation of Complex Structural Variations and Haploinsufficiency.

encodes a splicing factor recently implicated in developmental disorders due to a statistical enrichment of de novo mutations. Using data from the 100,000 Genomes Project, four unrelated individuals with intellectual disability (ID) were identified, each harbouring de novo whole gene deletions of . Deletions ranged between 248 and 482 kb in size and all distal breakpoints clustered within a complex 144 kb palindrome situated 75 kb upstream of Strikingly, three of the deletions were complex, with inverted internal segments of 45-94 kb. In one proband-mother duo, de novo status was inferred by haplotype analysis. Together with two additional patients who harboured smaller predicted protein-truncating variants (p.Arg632 and p.Ala2223Leufs13), we estimate the prevalence of this condition in cohorts of patients with unexplained ID to be ~1/1300. Phenotypic blending, present for two cases with additional pathogenic variants in and , hampered the phenotypic delineation of this recently described condition. Our data highlights the benefits of genome sequencing for resolving structural complexity and inferring de novo status. The genomic architecture of 16p13.3 may give rise to relatively high rates of complex rearrangements, adding to the list of loci associated with recurrent genomic disorders.