Array-CGH in patients with Kabuki-like phenotype: identification of two patients with complex rearrangements including 2q37 deletions and no other recurrent aberration

Abstract

Background: Kabuki syndrome (KS) is a multiple congenital anomaly syndrome characterized by specific facial features, mild to moderate mental retardation, postnatal growth delay, skeletal abnormalities, and unusual dermatoglyphic patterns with prominent fingertip pads. A 3.5 Mb duplication at 8p23.1-p22 was once reported as a specific alteration in KS but has not been confirmed in other patients. The molecular basis of KS remains unknown.

Methods: We have studied 16 Spanish patients with a clinical diagnosis of KS or KS-like to search for genomic imbalances using genome-wide array technologies. All putative rearrangements were confirmed by FISH, microsatellite markers and/or MLPA assays, which also determined whether the imbalance was de novo or inherited.

Results: No duplication at 8p23.1-p22 was observed in our patients. We detected complex rearrangements involving 2q in two patients with Kabuki-like features: 1) a de novo inverted duplication of 11 Mb with a 4.5 Mb terminal deletion, and 2) a de novo 7.2 Mb-terminal deletion in a patient with an additional de novo 0.5 Mb interstitial deletion in 16p. Additional copy number variations (CNV), either inherited or reported in normal controls, were identified and interpreted as polymorphic variants. No specific CNV was significantly increased in the KS group.

Conclusion: Our results further confirmed that genomic duplications of 8p23 region are not a common cause of KS and failed to detect other recurrent rearrangement causing this disorder. The detection of two patients with 2q37 deletions suggests that there is a phenotypic overlap between the two conditions, and screening this region in the Kabuki-like patients should be considered.

Figure 1

Facial phenotype of 2 Kabuki-like (A:KS2; B:KS14) and 2 Kabuki patients (C:KS7; D:KS12). Note that KS2 and KS14 also show some features characteristic of the 2q37 deletion.

Figure 2

Detection and validation of the 2q genomic imbalances. A and B: Plot of M-Values of clones on chromosome 2 and ideogram showing alterations in KS2 (A) and KS14 (B) patients. C: Microsatellite analysis showing the parental origin of these de novo alterations (KS2: Maternal chromosome; KS14: Paternal chromosome). D: FISH analysis with BACs RP11-367B19 (red) (2q37.2), RP11-637O3 (green) (2q37.3) and RP11-265M24 (green) (2q36.3) probes confirming de novo aberration originated in the maternal chromosome.

Figure 3

Electropherograms of MLPA assay with specific synthetic probes. A: Duplication pattern of probes for the ARID4A and KIAA0586 genes in the KS6 patient and her father. B: Duplication pattern of the UNG2 probe in KS7 patient and in his mother. C: Deletion pattern of two specific probes for SLFN11 and SLFN12 genes in the KS9 patient and his mother.

Figure 4

Detection and validation of 16p11.2 deletion in KS14. A and B: Plot of M-Values of clones on chromosome 16 and ideogram showing the deleted interval in the patient. C: Deletion patterns of MLPA at specific 16p11.2 probes (SPN and ALDOA genes) showing the de novo event in the patient with respect to parental samples and a control. D: Microsatellite analysis showing the maternal origin of the de novo deletion