Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

H. Mefford, A. Sharp, C. Baker, A. Itsara, Z. Jiang, K. Buysse, S. Huang, V. Maloney, J. Crolla, D. Baralle, A. Collins, C. Mercer, K. Norga, T. De Ravel, K. Devriendt, E. Bongers, N. De Leeuw, W. Reardon, S. Gimelli, F. BenaR. Hennekam, A. Male, L. Gaunt, J. Clayton-Smith, I. Simonic, S. Park, S. Mehta, S. Nik-Zainal, C. Woods, H. Firth, G. Parkin, M. Fichera, S. Reitano, M. Lo Giudice, K. Li, I. Casuga, A. Broomer, B. Conrad, M. Schwerzmann, L. Räber, S. Gallati, P. Striano, A. Coppola, J. Tolmie, E. Tobias, C. Lilley, L. Armengol, Y. Spysschaert, P. Verloo, A. De Coene, L. Goossens, G. Mortier, F. Speleman, E. Van Binsbergen, M. Nelen, R. Hochstenbach, M. Poot, L. Gallagher, M. Gill, J. McClellan, M. C. King, R. Regan, C. Skinner, R. Stevenson, S. Antonarakis, C. Chen, Xavier P. Estivill, B. Menten, G. Gimelli, S. Gribble, S. Schwartz, J. Sutcliffe, T. Walsh, S. Knight, J. Sebat, C. Romano, C. Schwartz, J. Veltman, B. De Vries, J. Vermeesch, J. Barber, L. Willatt, M. Tassabehji, E. Eichler

Research output: Contribution to journalArticle

525 Citations (Scopus)

Abstract

BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10-7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

Original languageEnglish
Pages (from-to)1685-1699
Number of pages15
JournalNew England Journal of Medicine
Volume359
Issue number16
DOIs
Publication statusPublished - 16 Oct 2008
Externally publishedYes

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Chromosomes
Pediatrics
Phenotype
Intellectual Disability
Microcephaly
Human Genome
Autistic Disorder
Cataract
Genotype
Technology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mefford, H., Sharp, A., Baker, C., Itsara, A., Jiang, Z., Buysse, K., ... Eichler, E. (2008). Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine, 359(16), 1685-1699. https://doi.org/10.1056/NEJMoa0805384

Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. / Mefford, H.; Sharp, A.; Baker, C.; Itsara, A.; Jiang, Z.; Buysse, K.; Huang, S.; Maloney, V.; Crolla, J.; Baralle, D.; Collins, A.; Mercer, C.; Norga, K.; De Ravel, T.; Devriendt, K.; Bongers, E.; De Leeuw, N.; Reardon, W.; Gimelli, S.; Bena, F.; Hennekam, R.; Male, A.; Gaunt, L.; Clayton-Smith, J.; Simonic, I.; Park, S.; Mehta, S.; Nik-Zainal, S.; Woods, C.; Firth, H.; Parkin, G.; Fichera, M.; Reitano, S.; Lo Giudice, M.; Li, K.; Casuga, I.; Broomer, A.; Conrad, B.; Schwerzmann, M.; Räber, L.; Gallati, S.; Striano, P.; Coppola, A.; Tolmie, J.; Tobias, E.; Lilley, C.; Armengol, L.; Spysschaert, Y.; Verloo, P.; De Coene, A.; Goossens, L.; Mortier, G.; Speleman, F.; Van Binsbergen, E.; Nelen, M.; Hochstenbach, R.; Poot, M.; Gallagher, L.; Gill, M.; McClellan, J.; King, M. C.; Regan, R.; Skinner, C.; Stevenson, R.; Antonarakis, S.; Chen, C.; Estivill, Xavier P.; Menten, B.; Gimelli, G.; Gribble, S.; Schwartz, S.; Sutcliffe, J.; Walsh, T.; Knight, S.; Sebat, J.; Romano, C.; Schwartz, C.; Veltman, J.; De Vries, B.; Vermeesch, J.; Barber, J.; Willatt, L.; Tassabehji, M.; Eichler, E.

In: New England Journal of Medicine, Vol. 359, No. 16, 16.10.2008, p. 1685-1699.

Research output: Contribution to journalArticle

Mefford, H, Sharp, A, Baker, C, Itsara, A, Jiang, Z, Buysse, K, Huang, S, Maloney, V, Crolla, J, Baralle, D, Collins, A, Mercer, C, Norga, K, De Ravel, T, Devriendt, K, Bongers, E, De Leeuw, N, Reardon, W, Gimelli, S, Bena, F, Hennekam, R, Male, A, Gaunt, L, Clayton-Smith, J, Simonic, I, Park, S, Mehta, S, Nik-Zainal, S, Woods, C, Firth, H, Parkin, G, Fichera, M, Reitano, S, Lo Giudice, M, Li, K, Casuga, I, Broomer, A, Conrad, B, Schwerzmann, M, Räber, L, Gallati, S, Striano, P, Coppola, A, Tolmie, J, Tobias, E, Lilley, C, Armengol, L, Spysschaert, Y, Verloo, P, De Coene, A, Goossens, L, Mortier, G, Speleman, F, Van Binsbergen, E, Nelen, M, Hochstenbach, R, Poot, M, Gallagher, L, Gill, M, McClellan, J, King, MC, Regan, R, Skinner, C, Stevenson, R, Antonarakis, S, Chen, C, Estivill, XP, Menten, B, Gimelli, G, Gribble, S, Schwartz, S, Sutcliffe, J, Walsh, T, Knight, S, Sebat, J, Romano, C, Schwartz, C, Veltman, J, De Vries, B, Vermeesch, J, Barber, J, Willatt, L, Tassabehji, M & Eichler, E 2008, 'Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes', New England Journal of Medicine, vol. 359, no. 16, pp. 1685-1699. https://doi.org/10.1056/NEJMoa0805384
Mefford H, Sharp A, Baker C, Itsara A, Jiang Z, Buysse K et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine. 2008 Oct 16;359(16):1685-1699. https://doi.org/10.1056/NEJMoa0805384
Mefford, H. ; Sharp, A. ; Baker, C. ; Itsara, A. ; Jiang, Z. ; Buysse, K. ; Huang, S. ; Maloney, V. ; Crolla, J. ; Baralle, D. ; Collins, A. ; Mercer, C. ; Norga, K. ; De Ravel, T. ; Devriendt, K. ; Bongers, E. ; De Leeuw, N. ; Reardon, W. ; Gimelli, S. ; Bena, F. ; Hennekam, R. ; Male, A. ; Gaunt, L. ; Clayton-Smith, J. ; Simonic, I. ; Park, S. ; Mehta, S. ; Nik-Zainal, S. ; Woods, C. ; Firth, H. ; Parkin, G. ; Fichera, M. ; Reitano, S. ; Lo Giudice, M. ; Li, K. ; Casuga, I. ; Broomer, A. ; Conrad, B. ; Schwerzmann, M. ; Räber, L. ; Gallati, S. ; Striano, P. ; Coppola, A. ; Tolmie, J. ; Tobias, E. ; Lilley, C. ; Armengol, L. ; Spysschaert, Y. ; Verloo, P. ; De Coene, A. ; Goossens, L. ; Mortier, G. ; Speleman, F. ; Van Binsbergen, E. ; Nelen, M. ; Hochstenbach, R. ; Poot, M. ; Gallagher, L. ; Gill, M. ; McClellan, J. ; King, M. C. ; Regan, R. ; Skinner, C. ; Stevenson, R. ; Antonarakis, S. ; Chen, C. ; Estivill, Xavier P. ; Menten, B. ; Gimelli, G. ; Gribble, S. ; Schwartz, S. ; Sutcliffe, J. ; Walsh, T. ; Knight, S. ; Sebat, J. ; Romano, C. ; Schwartz, C. ; Veltman, J. ; De Vries, B. ; Vermeesch, J. ; Barber, J. ; Willatt, L. ; Tassabehji, M. ; Eichler, E. / Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. In: New England Journal of Medicine. 2008 ; Vol. 359, No. 16. pp. 1685-1699.
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abstract = "BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10-7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.",
author = "H. Mefford and A. Sharp and C. Baker and A. Itsara and Z. Jiang and K. Buysse and S. Huang and V. Maloney and J. Crolla and D. Baralle and A. Collins and C. Mercer and K. Norga and {De Ravel}, T. and K. Devriendt and E. Bongers and {De Leeuw}, N. and W. Reardon and S. Gimelli and F. Bena and R. Hennekam and A. Male and L. Gaunt and J. Clayton-Smith and I. Simonic and S. Park and S. Mehta and S. Nik-Zainal and C. Woods and H. Firth and G. Parkin and M. Fichera and S. Reitano and {Lo Giudice}, M. and K. Li and I. Casuga and A. Broomer and B. Conrad and M. Schwerzmann and L. R{\"a}ber and S. Gallati and P. Striano and A. Coppola and J. Tolmie and E. Tobias and C. Lilley and L. Armengol and Y. Spysschaert and P. Verloo and {De Coene}, A. and L. Goossens and G. Mortier and F. Speleman and {Van Binsbergen}, E. and M. Nelen and R. Hochstenbach and M. Poot and L. Gallagher and M. Gill and J. McClellan and King, {M. C.} and R. Regan and C. Skinner and R. Stevenson and S. Antonarakis and C. Chen and Estivill, {Xavier P.} and B. Menten and G. Gimelli and S. Gribble and S. Schwartz and J. Sutcliffe and T. Walsh and S. Knight and J. Sebat and C. Romano and C. Schwartz and J. Veltman and {De Vries}, B. and J. Vermeesch and J. Barber and L. Willatt and M. Tassabehji and E. Eichler",
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TY - JOUR

T1 - Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

AU - Mefford, H.

AU - Sharp, A.

AU - Baker, C.

AU - Itsara, A.

AU - Jiang, Z.

AU - Buysse, K.

AU - Huang, S.

AU - Maloney, V.

AU - Crolla, J.

AU - Baralle, D.

AU - Collins, A.

AU - Mercer, C.

AU - Norga, K.

AU - De Ravel, T.

AU - Devriendt, K.

AU - Bongers, E.

AU - De Leeuw, N.

AU - Reardon, W.

AU - Gimelli, S.

AU - Bena, F.

AU - Hennekam, R.

AU - Male, A.

AU - Gaunt, L.

AU - Clayton-Smith, J.

AU - Simonic, I.

AU - Park, S.

AU - Mehta, S.

AU - Nik-Zainal, S.

AU - Woods, C.

AU - Firth, H.

AU - Parkin, G.

AU - Fichera, M.

AU - Reitano, S.

AU - Lo Giudice, M.

AU - Li, K.

AU - Casuga, I.

AU - Broomer, A.

AU - Conrad, B.

AU - Schwerzmann, M.

AU - Räber, L.

AU - Gallati, S.

AU - Striano, P.

AU - Coppola, A.

AU - Tolmie, J.

AU - Tobias, E.

AU - Lilley, C.

AU - Armengol, L.

AU - Spysschaert, Y.

AU - Verloo, P.

AU - De Coene, A.

AU - Goossens, L.

AU - Mortier, G.

AU - Speleman, F.

AU - Van Binsbergen, E.

AU - Nelen, M.

AU - Hochstenbach, R.

AU - Poot, M.

AU - Gallagher, L.

AU - Gill, M.

AU - McClellan, J.

AU - King, M. C.

AU - Regan, R.

AU - Skinner, C.

AU - Stevenson, R.

AU - Antonarakis, S.

AU - Chen, C.

AU - Estivill, Xavier P.

AU - Menten, B.

AU - Gimelli, G.

AU - Gribble, S.

AU - Schwartz, S.

AU - Sutcliffe, J.

AU - Walsh, T.

AU - Knight, S.

AU - Sebat, J.

AU - Romano, C.

AU - Schwartz, C.

AU - Veltman, J.

AU - De Vries, B.

AU - Vermeesch, J.

AU - Barber, J.

AU - Willatt, L.

AU - Tassabehji, M.

AU - Eichler, E.

PY - 2008/10/16

Y1 - 2008/10/16

N2 - BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10-7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

AB - BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10-7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

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U2 - 10.1056/NEJMoa0805384

DO - 10.1056/NEJMoa0805384

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AN - SCOPUS:54049094444

VL - 359

SP - 1685

EP - 1699

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

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