20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits

Abstract

Background: Wolff-Parkinson-White syndrome (WPW) is a bypass re-entrant tachycardia that results from an abnormal connection between the atria and ventricles. Mutations in PRKAG2 have been described in patients with familial WPW syndrome and hypertrophic cardiomyopathy. Based on the role of bone morphogenetic protein (BMP) signalling in the development of annulus fibrosus in mice, it has been proposed that BMP signalling through the type 1a receptor and other downstream components may play a role in pre-excitation.

Methods and results: Using the array comparative genomic hybridisation (CGH), we identified five individuals with non-recurrent deletions of 20p12.3. Four of these individuals had WPW syndrome with variable dysmorphisms and neurocognitive delay. With the exception of one maternally inherited deletion, all occurred de novo, and the smallest of these harboured a single gene, BMP2. In two individuals with additional features of Alagille syndrome, deletion of both JAG1 and BMP2 were identified. Deletion of this region has not been described as a copy number variant in the Database of Genomic Variants and has not been identified in 13 321 individuals from other cohort examined by array CGH in our laboratory.

Conclusions: Our findings demonstrate a novel genomic disorder characterised by deletion of BMP2 with variable cognitive deficits and dysmorphic features and show that individuals bearing microdeletions in 20p12.3 often present with WPW syndrome.

Figure 1

Photographs of individuals with submicroscopic BMP2 deletion (submitted with written consents from the patient or his/her legal guardian for publication in print and online). Patient 1 (A, B) at the age of 12 months, with downslanting palpebral fissures, malar hypoplasia, long philtrum, microstomia, and pectus deformity. Patient 2 (C, D) at the age of 5 years, with macrocephaly, a frontal upsweep, downslanting palpebral fissures, hypertelorism, long philtrum, microstomia, and small ears with thickened helices. Patient 3 (E, F) at the age of 37 years, with hypertelorism, malar hypoplasia and macrocephaly.

Figure 2

Summary of the results using targeted array CGH, FISH and genome wide array CGH analyses in patients 1, 2, and 3. Note the genomic loss of copy-number detected by RP11-116E13 in patients 1, 2, 3 with additional loss of copy-number detected by RP11-973N22 in patients 2, 3 (A, D, circled), identified on the clinical array CGH. FISH confirmed the deletion detected by RP11-116E13 in these patients by the loss of hybridization signal on one copy of chromosome 20 (C, E, deletion represented by the highlighted arrow). Fine mapping of the breakpoints using Illumina HumanHap300 genotyping BeadChip array (317K) in patient 1 (B), showed a de novo 1.1 Mb deletion involving a single gene, BMP2. The 244k Human Genome Agilent microarray showed 2.3 Mb deletion involving multiple genes, including BMP2 in patients 2 and 3 (F, G respectively).

Figure 3

Schematic illustration of the identified deletions of distal chromosome 20p in patients 1-5, with contiguous genes represented between the 4.7-10.6 Mb interval.