First report of hypoplastic left heart syndrome in 3p- syndrome and review of candidate genes

Abstract

Objective: 3p deletion syndrome is a rare monosomal disease that encompasses deletions throughout the short arm of chromosome 3. It is often in the distal region (3p25-pter), but variations in breakpoints and a complex clinical manifestation exist, with congenital heart defects being considered rare. We present the first case of hypoplastic left heart syndrome and minor dysmorphic features associated with 3p- syndrome. Furthermore, we aim to establish a gene-phenotype association.

Case description: The diagnosis was made by karyotyping, followed by a literature investigation and in silico bioinformatic analysis about the possible candidate genes associated with congenital heart defects or hypoplastic left heart syndrome in 3p- syndrome. All genes analyzed that could affect heart formation are located in the 3p25.3 region, adjacent to the deleted region in the newborn from our case (3p26). Taking into account the technical limitations of the karyotype and the strength of evidence from each gene evaluated and locus proximity, it is likely that an unidentified partial break in the CAV3 gene occurred.

Comments: We identified an indirect relation between gene CAV3 and hypoplastic left heart syndrome due to its strong association with cardiomyopathies and isolated cardiac defects. Furthermore, the cytogenetic band from our case is new information for the delimitation of a critical cardiac region on 3p syndrome, a discussion that has been ongoing since 1986. Thus, we reinforce the importance of cytogenetic investigation in patients with hypoplastic hearts and dysmorphia, assisting in diagnosis, definition of prognosis, and genetic counseling for the family.

Figure 1. Hemodynamic of hypoplastic left heart syndrome MA/AA hearts. The hypoplastic left heart syndrome of our patient is characterized by underdeveloped left heart structures, including a diminutive left ventricle, with mitral and aortic valve atresia, ventricular septal defect, and aortic isthmus hypoplasia. The left ventricle has little strength to bump the blood during systole and no way of receiving arterial blood from left atrium, which leads to a systolic insufficiency. To overpower that, arterial blood bypasses the left ventricle by following through the patent foramen ovale, from the left atrium to the right atrium, and then coming through normal circulation until the pulmonary artery. From there, it takes the patent arterial duct connection with the aorta, enabling it to be distributed to the rest of the body. Because of patent foramen ovale, the baby presents with cyanosis. The pulmonary artery dilates in response to the extra volume (systolic volume) it receives. The right ventricle compensates for the preload and afterload of the nonfunctional ventricle by contracting vigorously to supply the body. In this scenario, right ventricle volume is force filled, leading to elevated internal pressure, enlargement of the right ventricle cavity dimensions, and the development of mild diastolic dysfunction. Also, the aorta is inhibited by the development of right-side structures, presenting itself thinner than usual.

Figure 2. Representation of the patient chromosome 3p26 deletion. The deleted genes are listed in the box, according to the locus order. Our target gene (CAV3) is represented outside the box in its respective distance from the deleted region.