Identification of a New Candidate Locus for Ebstein Anomaly in 1p36.2

Abstract

Ebstein anomaly (EA) is a rare congenital heart defect (CHD) with a poorly characterized genetic etiology. However, some EA patients carry deletions in 1p36, all of which have been reported to carry distal deletions and share loss of the PRDM16 gene, which is currently considered the most likely candidate for EA development in this region. Here, we report a patient with an 11.96-Mb proximal 1p36 deletion, without loss of PRDM16, who presented with EA and a proximal deletion phenotype. This finding suggests that PRDM16 loss is not required for the development of EA in 1p36 deletions and that the loss of an additional proximal locus in 1p36 is also likely associated with EA. Our data suggest that a distal locus containing the SKI gene and a proximal locus containing the CHD-associated genes RERE and UBE4B are the most probable etiological factors for EA in patients with 1p36 deletion syndrome.

Genetic Analysis Algorithm for the Study of Patients with Multiple Congenital Anomalies and Isolated Congenital Heart Disease

“…As a consequence of a de novo unbalanced rearrangement, a newborn presented two pathogenic CNVs: a deletion in 1p36 and a duplication in 7q35. He presented some of the clinical characteristics already described in the 1p36 microdeletion syndrome, such as Ebstein’s anomaly [ 53 , 54 , 100 ] and hydrocephalus, which was previously described in patients with duplications in 7q [ 51 , 52 ] most probably due to an increased dose of SHH [ 101 ]. In addition, he presented VSD and intrauterine growth retardation, reported for both imbalances [ 53 , 54 , 102 ].…”

Integrated microRNA and mRNA Expression Profiling Identifies Novel Targets and Networks Associated with Ebstein’s Anomaly

“…EA occurs mostly sporadically, and familial transmission has been rarely observed [6]. It is a genetically heterogeneous disease, in which microdeletions in 1p36 and 8p23.1, and a missense mutation in the actin-binding protein Filamin A (FLNA), have been described [5][6][7][8].…”

“…Reproductive and environmental factors have also been suggested to play a role in the development of EA [5,6,8]. Although the exact mechanism of CHDs development is still largely unknown, several protein-coding genes have been identified to play a restricted functional role in cardiac development.…”

“…EA occurs mostly sporadically, and familial transmission has been rarely observed [ 6 ]. It is a genetically heterogeneous disease, in which microdeletions in 1p36 and 8p23.1, and a missense mutation in the actin-binding protein Filamin A ( FLNA ), have been described [ 5 , 6 , 7 , 8 ]. Reproductive and environmental factors have also been suggested to play a role in the development of EA [ 5 , 6 , 8 ].…”

“…It is a genetically heterogeneous disease, in which microdeletions in 1p36 and 8p23.1, and a missense mutation in the actin-binding protein Filamin A ( FLNA ), have been described [ 5 , 6 , 7 , 8 ]. Reproductive and environmental factors have also been suggested to play a role in the development of EA [ 5 , 6 , 8 ]. Although the exact mechanism of CHDs development is still largely unknown, several protein-coding genes have been identified to play a restricted functional role in cardiac development.…”