Identification of a recurrent microdeletion at 17q23.1q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities

Abstract

Segmental duplications, which comprise approximately 5%-10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are approximately 2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is approximately 2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These characteristics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that microdeletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome.

Figure 1

Summary of Microarray Analysis of Individuals with Copy Number Imbalances at 17q23.1q23.2 At the top of the figure is a partial idiogram showing chromosome bands 17q22-17q23.2 with genomic coordinates corresponding to the hg18 build of the human genome. Orange boxes represent segmental duplications (seg dups), with paired segmental duplications indicated by blue boxes. The location and orientation of the 18 kb inverted duplication and the 15 kb direct duplication contained within the paired segmental duplications are indicated by arrows marked A and B, respectively. The complex segmental duplication structure of this region has been simplified for illustrative purposes. Diagrams show the deletions in seven individuals with microdeletions at 17q23.1q23.2. Six of the seven deletions were refined with a high-density, 244K oligonucleotide microarray (patients 1–4, 6, and 7). A 105K oligonucleotide microarray was used for patient 5. Vertical dashed lines indicate the 2.2 and 2.8 Mb deletion sizes in the individuals. Blue boxes represent all known genes annotated in OMIM in the deletion region. OMIM genes TBX2 and TBX4 are shown as yellow boxes.

Figure 2

Representative FISH Image Showing Deletion at 17q23 in Patient 2 BAC clone RP11-289K16 from 17q23.1 is labeled in red, and chromosome 17 centromere probe D17Z1 is labeled in green as a control. The absence of a red signal on one homolog (arrow) indicates deletion at 17q23.1.

Figure 3

Facial Features of Individuals with Microdeletion at 17q23.1q23.2 (A) Patient 1 at 3 years. Note high eyebrows and right epicanthal fold. (B) Patient 6 at 4 years. Note mild frontal bossing and rounded nasal tip. (C and D) Patient 7 at 22 months. Note long eyelashes, protuberant ears, small mouth, and mild micrognathia. (E and F) Patient 4 at 16 years. With the exception of some prominence of the forehead, this patient was not noted to be dysmorphic.

Figure 4

Hand and Foot Abnormalities in Individuals with Microdeletion at 17q23.1q23.2 (A) Feet of patient 1. In this individual, 2–3 syndactyly is familial and likely independent of this syndrome. (B and C) Right foot and hands of patient 4. Note the long, thin fingers and toes, with the second toe longer than the great toe. (D) X-rays of feet of patient 3. The second digit of both feet is elongated compared to the great toe, and multiple bipartite growth plates are seen throughout the metatarsal heads. (E) X-rays of feet of patient 4. There is slight shortening of the fourth and fifth rays bilaterally.

Figure 5

X-rays Showing Musculoskeletal Findings Reminiscent of Mutations of TBX4 and Small Patella Syndrome (A–C) Patellar X-rays for patient 2. Note abnormally laterally positioned ossification centers of the patella, which is delayed for age. The patella is normally located on the sunrise view, suggesting intermittent subluxation. (D–F) X-rays for patient 4. (D) There is lateral subluxation of the patella bilaterally. The patellae are small. The medial tibial plateau is mildly hypoplastic, with mild relative overgrowth of the femoral condyle medially. (E) The lateral portion of the distal tibial epiphysis is hypoplastic bilaterally. There is a tilting of the talar dome. (F) The anteroposterior pelvis shows mildly shallow right acetabulum with slight widening of the supra-acetabular iliac bone. There is coxa magna and a short femoral neck on the right with varus deformity, with the greater trochanter slightly higher than the superior right femoral head. The right femoral head is not completely covered by the acetabulum, with the lateral third uncovered. There is minimal superior subluxation. The left femoral head is approximately 15% uncovered by the bony acetabulum. The femoral head is normal in contour. There are axe-cut notches of the infra-acetabulae (arrows).