Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication

Abstract

Background: Interstitial deletions of 3q29 have been recently described as a microdeletion syndrome mediated by nonallelic homologous recombination between low-copy repeats resulting in an ~1.6 Mb common-sized deletion. Given the molecular mechanism causing the deletion, the reciprocal duplication is anticipated to occur with equal frequency, although only one family with this duplication has been reported.

Results: In this study we describe 14 individuals with microdeletions of 3q29, including one family with a mildly affected mother and two affected children, identified among 14,698 individuals with idiopathic mental retardation who were analyzed by array CGH. Eleven individuals had typical 1.6-Mb deletions. Three individuals had deletions that flank, span, or partially overlap the commonly deleted region. Although the clinical presentations of individuals with typical-sized deletions varied, several features were present in multiple individuals, including mental retardation and microcephaly. We also identified 19 individuals with duplications of 3q29, five of which appear to be the reciprocal duplication product of the 3q29 microdeletion and 14 of which flank, span, or partially overlap the common deletion region. The clinical features of individuals with microduplications of 3q29 also varied with few common features. De novo and inherited abnormalities were found in both the microdeletion and microduplication cohorts illustrating the need for parental samples to fully characterize these abnormalities.

Conclusion: Our report demonstrates that array CGH is especially suited to identify chromosome abnormalities with unclear or variable presentations.

Figure 1

Summary of array CGH results on individuals with microdeletions and microduplications of 3q29. (A) Ideogram of chromosome 3 showing the location of the 3q29 cytogenetic band. (B) Representative SignatureChipWG result plot for an individual with a single copy loss of 11 BAC clones spanning the entire 1.6 Mb common microdeletion region. Each clone represented on the array is arranged along the x-axis according to its location on chromosome 3 with the most distal/telomeric p-arm clones on the left and the most distal/telomeric q-arm clones on the right. The blue line represents the ratios for each clone from the first experiment (control/patient), and the pink line represents the ratios for each clone obtained from the second experiment in which the dyes have been reversed (patient/control). (C) Representative SignatureChipWG result plot for an individual with a single copy gain of 11 BAC clones spanning the entire 1.6 Mb common microdeletion region. (D) Diagram showing the deletion sizes of 13 individuals with microdeletions of 3q29 as refined using the high-density, custom 3q29 oligonucleotide microarray. Vertical dashed lines in D and E indicate the location of the low-copy repeats (LCRs) in the 3q29 interval for which oligonucleotides were not included on the microarray. Blue bars shown at the bottom of the diagram indicate the location of paired LCRs within 3q29; their precise orientation is illustrated by arrows. Orange bars indicate the location of other segmental duplications that share no homology with any other regions on chromosome 3. LCRs A, B, and C are ~40 kb, ~20 kb, and ~20 kb long, respectively, with > 90% identity to their paired counterparts and are simplified for illustrative purposes (based on the Segmental Duplications Database, May 2004 (hg17) draft). (E) Diagram showing the duplication sizes of 17 individuals with microduplications of 3q29 as refined using the high-density, custom 3q29 oligonucleotide microarray. Blue arrows show the location of the LCRs that mediate the common 1.6 Mb microdeletion/microduplication and are not drawn to scale. (F-J) Photographs of five of the 11 individuals with common-sized microdeletions of 3q29. Individuals shown in F and G are siblings.