Recurrent reciprocal deletions and duplications of 16p13.11: The deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant
Femke D Hannes 1, Andrew J Sharp 2, Heather C Mefford 3, Thomy de Ravel 1, Claudia A Ruivenkamp 4, Martijn H Breuning 4, Jean-Pierre Fryns 1, Koen Devriendt 1, Griet Van Buggenhout 1, Annick Vogels 1, Helen H Stewart 5, Raoul C Hennekam 6, Gregory M Cooper 2, Regina Regan 7, Samantha JL Knight 7, Evan E Eichler 2 and Joris R Vermeesch 1*
1 Catholic University of Leuven, Belgium
2 University of Washington School of Medicine, United States
3 University of Wahington School of Medicine, United States
4 Leiden University Medical Center, Netherlands
5 Oxford Radcliffe Hospitals NHS Trust, Churchill Hospital, United Kingdom
6 Academic Medical Center, University of Amsterdam, Netherlands
7 Wellcome Trust Centre for Human Genetics, United Kingdom
* To whom correspondence should be addressed. E-mail: joris.vermeesch{at}med.kuleuven.be.
Accepted 7 January 2008
 | Abstract |
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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.
