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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.
J Med Genet 2009; 46(4):223-32JM

Abstract

BACKGROUND

Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16.

METHODS AND RESULTS

A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. 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 showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%).

CONCLUSION

These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients' phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling.

Authors+Show Affiliations

Center for Human Genetics, Herestraat 49, 3000 Leuven, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18550696

Citation

Hannes, F D., et al. "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." Journal of Medical Genetics, vol. 46, no. 4, 2009, pp. 223-32.
Hannes FD, Sharp AJ, Mefford HC, et al. 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. J Med Genet. 2009;46(4):223-32.
Hannes, F. D., Sharp, A. J., Mefford, H. C., de Ravel, T., Ruivenkamp, C. A., Breuning, M. H., ... Vermeesch, J. R. (2009). 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. Journal of Medical Genetics, 46(4), pp. 223-32. doi:10.1136/jmg.2007.055202.
Hannes FD, et al. 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. J Med Genet. 2009;46(4):223-32. PubMed PMID: 18550696.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Hannes,F D, AU - Sharp,A J, AU - Mefford,H C, AU - de Ravel,T, AU - Ruivenkamp,C A, AU - Breuning,M H, AU - Fryns,J-P, AU - Devriendt,K, AU - Van Buggenhout,G, AU - Vogels,A, AU - Stewart,H, AU - Hennekam,R C, AU - Cooper,G M, AU - Regan,R, AU - Knight,S J L, AU - Eichler,E E, AU - Vermeesch,J R, Y1 - 2008/06/11/ PY - 2008/6/14/pubmed PY - 2009/5/29/medline PY - 2008/6/14/entrez SP - 223 EP - 32 JF - Journal of medical genetics JO - J. Med. Genet. VL - 46 IS - 4 N2 - BACKGROUND: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. METHODS AND RESULTS: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. 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 showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). CONCLUSION: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients' phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling. SN - 1468-6244 UR - https://www.unboundmedicine.com/medline/citation/18550696/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_ L2 - http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=18550696 DB - PRIME DP - Unbound Medicine ER -