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. 2008 Oct 16;359(16):1685-99.
doi: 10.1056/NEJMoa0805384. Epub 2008 Sep 10.

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

Heather C Mefford  1 , Andrew J Sharp, Carl Baker, Andy Itsara, Zhaoshi Jiang, Karen Buysse, Shuwen Huang, Viv K Maloney, John A Crolla, Diana Baralle, Amanda Collins, Catherine Mercer, Koen Norga, Thomy de Ravel, Koen Devriendt, Ernie M H F Bongers, Nicole de Leeuw, William Reardon, Stefania Gimelli, Frederique Bena, Raoul C Hennekam, Alison Male, Lorraine Gaunt, Jill Clayton-Smith, Ingrid Simonic, Soo Mi Park, Sarju G Mehta, Serena Nik-Zainal, C Geoffrey Woods, Helen V Firth, Georgina Parkin, Marco Fichera, Santina Reitano, Mariangela Lo Giudice, Kelly E Li, Iris Casuga, Adam Broomer, Bernard Conrad, Markus Schwerzmann, Lorenz Räber, Sabina Gallati, Pasquale Striano, Antonietta Coppola, John L Tolmie, Edward S Tobias, Chris Lilley, Lluis Armengol, Yves Spysschaert, Patrick Verloo, Anja De Coene, Linde Goossens, Geert Mortier, Frank Speleman, Ellen van Binsbergen, Marcel R Nelen, Ron Hochstenbach, Martin Poot, Louise Gallagher, Michael Gill, Jon McClellan, Mary-Claire King, Regina Regan, Cindy Skinner, Roger E Stevenson, Stylianos E Antonarakis, Caifu Chen, Xavier Estivill, Björn Menten, Giorgio Gimelli, Susan Gribble, Stuart Schwartz, James S Sutcliffe, Tom Walsh, Samantha J L Knight, Jonathan Sebat, Corrado Romano, Charles E Schwartz, Joris A Veltman, Bert B A de Vries, Joris R Vermeesch, John C K Barber, Lionel Willatt, May Tassabehji, Evan E Eichler
Affiliations

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

Heather C Mefford et al. N Engl J Med. .

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=1.1x10(-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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Figures

Figure 1
Figure 1. High-Density Oligonucleotide-Array Mapping of Chromosome 1q21.1 Rearrangements in the Study Patients
Sixteen 1q21.1 deletions (Panel A) and seven 1q21.1 duplications (Panel B) from patients without other chromosomal abnormalities were identified on chromosome 1q21.1. The region of minimal rearrangement is located from approximately 143,650,000 to 145,000,000 bp (pink shading) and contains two assembly gaps and eight genes in the National Center for Biotechnology Information Reference Sequence (RefSeq) collection. In Panel B, a patient with a microdeletion (Patient 1) is shown for comparison with the duplication carriers (Patients 1 through 7 shown). Segmental-duplication blocks are shown, with the approximate breakpoint (BP) regions indicated with green shading. The microdeletion associated with the thrombocytopenia-absent radius (TAR) syndrome is shaded in blue. For each patient, deviations from 0 of probe log2 ratios are depicted by vertical bars, with those exceeding a threshold of 1.5 SD from the mean probe ratio shown in green or red to represent relative gains or losses, respectively; bars below this threshold are black (gains) or gray (losses). Segmental duplications of increasing similarity are also shown, as horizontal bars highlighted with green shading: 90 to 98% (gray bars), >98 to 99% (yellow bars), and >99% (orange bars). Results for Patients 17 through 20 with deletions and Patient 8 with a duplication are shown in Figure 3 in the Supplementary Appendix. Patient 21 with a deletion and Patient 6 with a duplication were evaluated only by means of the screening platform listed in Table 1A in the Supplementary Appendix, because of insufficient DNA for additional oligonucleotide-array analysis (data not shown).
Figure 1
Figure 1. High-Density Oligonucleotide-Array Mapping of Chromosome 1q21.1 Rearrangements in the Study Patients
Sixteen 1q21.1 deletions (Panel A) and seven 1q21.1 duplications (Panel B) from patients without other chromosomal abnormalities were identified on chromosome 1q21.1. The region of minimal rearrangement is located from approximately 143,650,000 to 145,000,000 bp (pink shading) and contains two assembly gaps and eight genes in the National Center for Biotechnology Information Reference Sequence (RefSeq) collection. In Panel B, a patient with a microdeletion (Patient 1) is shown for comparison with the duplication carriers (Patients 1 through 7 shown). Segmental-duplication blocks are shown, with the approximate breakpoint (BP) regions indicated with green shading. The microdeletion associated with the thrombocytopenia-absent radius (TAR) syndrome is shaded in blue. For each patient, deviations from 0 of probe log2 ratios are depicted by vertical bars, with those exceeding a threshold of 1.5 SD from the mean probe ratio shown in green or red to represent relative gains or losses, respectively; bars below this threshold are black (gains) or gray (losses). Segmental duplications of increasing similarity are also shown, as horizontal bars highlighted with green shading: 90 to 98% (gray bars), >98 to 99% (yellow bars), and >99% (orange bars). Results for Patients 17 through 20 with deletions and Patient 8 with a duplication are shown in Figure 3 in the Supplementary Appendix. Patient 21 with a deletion and Patient 6 with a duplication were evaluated only by means of the screening platform listed in Table 1A in the Supplementary Appendix, because of insufficient DNA for additional oligonucleotide-array analysis (data not shown).
Figure 2
Figure 2. Pedigrees of Eight Probands with a 1q21.1 Deletion
Squares indicate males, and circles females. Additional phenotypic information is available in Table 1. CHD denotes coronary heart disease, DD developmental delay, and MR mental retardation.
Figure 3
Figure 3. High-Density Oligonucleotide-Array Comparative Genomic Hybridization of Chromosome 1q21.1 Deletions in Three Study Patients
There were nearly identical breakpoints in the three patients, with the minimal 1.35-Mb deletion in chromosome 1 in the region of 142,000,000 to 146,500,000 bp (according to National Center for Biotechnology Information build 35). For each patient, deviations from 0 of probe log2 ratios are depicted by vertical bars, with those exceeding a threshold of 1.5 SD from the mean probe ratio shown in red to represent relative losses; bars below this threshold are black (gains) or gray (losses). Additional phenotypic information is available in Table 1 (for Patients 7 and 9) and in Table 4 in the Supplementary Appendix (available with the full text of this article at www.nejm.org) (for Patient S5).
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