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

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 hybrid...

Fuld beskrivelse

Bibliografiske detaljer
Main Authors: Hannes, F, Sharp, A, Mefford, H, de Ravel, T, Ruivenkamp, C, Breuning, M, Fryns, J, Devriendt, K, Van Buggenhout, G, Vogels, A, Stewart, H, Hennekam, R, Cooper, G, Regan, R, Knight, S, Eichler, E, Vermeesch, JR
Format: Journal article
Sprog:English
Udgivet: 2009
_version_ 1826286820638326784
author Hannes, F
Sharp, A
Mefford, H
de Ravel, T
Ruivenkamp, C
Breuning, M
Fryns, J
Devriendt, K
Van Buggenhout, G
Vogels, A
Stewart, H
Hennekam, R
Cooper, G
Regan, R
Knight, S
Eichler, E
Vermeesch, JR
author_facet Hannes, F
Sharp, A
Mefford, H
de Ravel, T
Ruivenkamp, C
Breuning, M
Fryns, J
Devriendt, K
Van Buggenhout, G
Vogels, A
Stewart, H
Hennekam, R
Cooper, G
Regan, R
Knight, S
Eichler, E
Vermeesch, JR
author_sort Hannes, F
collection OXFORD
description 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 highresolution 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.
first_indexed 2024-03-07T01:49:24Z
format Journal article
id oxford-uuid:998d0f92-a858-4f78-bae8-87f3fd9da5f9
institution University of Oxford
language English
last_indexed 2024-03-07T01:49:24Z
publishDate 2009
record_format dspace
spelling oxford-uuid:998d0f92-a858-4f78-bae8-87f3fd9da5f92022-03-27T00:15:08ZRecurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variantJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:998d0f92-a858-4f78-bae8-87f3fd9da5f9EnglishSymplectic Elements at Oxford2009Hannes, FSharp, AMefford, Hde Ravel, TRuivenkamp, CBreuning, MFryns, JDevriendt, KVan Buggenhout, GVogels, AStewart, HHennekam, RCooper, GRegan, RKnight, SEichler, EVermeesch, JRBackground: 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 highresolution 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.
spellingShingle Hannes, F
Sharp, A
Mefford, H
de Ravel, T
Ruivenkamp, C
Breuning, M
Fryns, J
Devriendt, K
Van Buggenhout, G
Vogels, A
Stewart, H
Hennekam, R
Cooper, G
Regan, R
Knight, S
Eichler, E
Vermeesch, JR
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
work_keys_str_mv AT hannesf recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT sharpa recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT meffordh recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT deravelt recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT ruivenkampc recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT breuningm recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT frynsj recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT devriendtk recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT vanbuggenhoutg recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT vogelsa recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT stewarth recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT hennekamr recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT cooperg recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT reganr recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT knights recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT eichlere recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant
AT vermeeschjr recurrentreciprocaldeletionsandduplicationsof16p1311thedeletionisariskfactorformrmcawhiletheduplicationmaybeararebenignvariant