Genomic disorders are frequently caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome 16 specific low copy repeat, termed LCR16. Our BAC array CGH screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) detected 5 patients with deletions and 5 with apparently reciprocal duplications of 16p13 and covers 1.65 Mb, including 15 RefSeq genes. In addition, 3 atypical rearrangements overlapping or flanking this region were detected. Fine mapping by high resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population proves that 16p13.11 deletions are significantly associated with MR/MCA (p=0.0048). Despite phenotypic variability, common features were observed: 3 deletion patients presented with MR, microcephaly and epilepsy (2 of which had also short stature), while 2 other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication appears to be a common variant in the population (5/1682, 0.29%). These findings demonstrate that deletions inherited from normal parents are likely causal for the patients' phenotype which causes a paradigm shift in (cyto)genetic counseling.
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