8p23.1 duplication syndrome differentiated from copy number variation of the defensin cluster at prenatal diagnosis in four new families.

Background: The 8p23.1 duplication syndrome and copy number variation of the 8p23.1 defensin gene cluster are cytogenetically indistinguishable but distinct at the molecular level. To our knowledge, the 8p23.1 duplication syndrome has been described at prenatal diagnosis only once and we report our experience with four further apparent duplications ascertained at prenatal diagnosis.

Methods: Additional material at band 8p23.1 was detected using conventional G-banded cytogenetics in each case. Multiplex Ligation-dependent Probe Amplification (MLPA) or Fluorescence In Situ Hybridisation (FISH) were used depending on whether only DNA (Cases 1 and 4) or cytogenetic preparations (Cases 2 and 3) were available from the laboratory of origin. The extent of the duplication in Case 1 was retrospectively determined using array Comparative Genomic Hybridisation (array CGH).

Results: Three cases of 8p23.1 duplication syndrome were found (Cases 1 to 3). Two were de novo and continued to term and the third, a paternally transmitted duplication, was terminated because of a previous child with psychomotor delay and 8p23.1 duplication syndrome. Case 1 was ascertained with a hypoplastic left heart but the ventricular septal and interventricular defects, in Cases 2 and 3 respectively, were found after ascertainment for advanced maternal age. By contrast, case 4 was a maternally transmitted copy number variation of the defensin cluster with normal outcome.

Conclusions: Our data underline the need to differentiate 8p23.1 duplications from copy number variation of the defensin cluster using FISH, MLPA or array CGH. Cardiac defects were ascertained by ultrasound in only one of the three duplication 8p23.1 pregnancies but were visible in two of the three at 21 to 22 weeks gestation. Our results provide further evidence that both deletion and duplication of the GATA4 transcription factor can give rise to a variety of conotruncal heart defects with variable penetrance and expressivity.