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Antonella Izzo [1] and Rosanna Manco [1] and Tiziana de Cristofaro [2] and Ferdinando Bonfiglio [3] and Rita Cicatiello [1] and Nunzia Mollo [1] and Marco De Martino [2] and Rita Genesio [1] and Mariastella Zannini [2] and Anna Conti [1] and Lucio Nitsch [1]

Academic Editor: Davide Barbagallo

1, Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy, unina.it

2, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy, cnr.it

3, Department of Biosciences and Nutrition, Karolinska Institutet, 17177 Stockholm, Sweden, ki.se

Received May 12, 2017; Revised Jul 20, 2017; Accepted Aug 2, 2017

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Down Syndrome (DS) is a major cause of congenital heart defects (CHD), mainly represented by atrioventricular canal defect (AVCD), ventricular septal defect (VSD), and tetralogy of Fallot (TOF) [1]. Most of them derive from the abnormal development of the endocardial cushions [1, 2]. Defects of the outflow tract are also frequent.

Attempts to identify chromosome 21 (Hsa21) genes possibly contributing to the DS phenotype have focused in the past on the Down syndrome critical region (DSCR). The DSCR hypothesis assumed that one or more genes in this region may be sufficient to produce the specific DS features when present in three copies [3].

A chromosome segment spanning from D21S3 to PFKL in band 21q22.3 was considered a critical region for cardiac anomalies in DS (DS-CHD) [4]. Later, a 5.4 Mb genomic region was identified in the DS mouse model Dp (16) associated to congenital heart defects similar to that observed in DS subjects [5]. This region, which spans from Tiam1 and Kcnj6 and includes 52 Hsa21 ortholog genes, was further narrowed to 3.7 Mb [6] from Ifnar1 and Kcnj6 (35 Hsa21 ortholog genes). The two CHD critical regions described by Barlow and by Liu, identified according to different criteria, were mapped to very different loci of Hsa21. Discrepancies like this one suggest today that the origins of trisomic phenotypes are more complicated than formerly assumed and that they possibly involve multiple gene interactions.

Another interesting detail is that only about 50%...

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