© Springer-Verlag Italia 2014
Alessandro Giamberti and Massimo Chessa (eds.)The Tricuspid Valve in Congenital Heart Disease10.1007/978-88-470-5400-4_33. Genetics of Ebstein Anomaly
(1)
Medical Genetics, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy
(2)
Pediatric Cardiology, Department of Pediatrics, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy
3.1 Introduction
Ebstein anomaly (EA) is a rare etiologically heterogeneous congenital malformation of the tricuspid valve, accounting for less than 1 % of all congenital heart defects (CHDs) and for 0.3–0.8 % of all patients presenting with CHD in the first year of life [1, 2]. The prevalence of EA is estimated as 1 in 20,000–50,000 live births, with equal male to female occurrence [2].
In the majority of the cases, EA is an isolated non-syndromic defect (80 %), while it is associated with extracardiac anomalies in the setting of chromosomal or Mendelian disorders in about 20 % of the patients [1, 3, 4]. The role of teratogens in the etiology of EA has also been suggested, following the report of lithium therapy during the first trimester of pregnancy and the occurrence of EA in the fetus [5], although more recent case-control epidemiological studies have not confirmed these findings [6].
Clinical epidemiological data before the advent of the new cytogenetic and molecular techniques have shown that EA is non-syndromic in about 77 % of the cases, while chromosomal syndromes were detectable in 5 %, monogenic syndromes in 12 %, and undiagnosed associations with major organ malformations or deformations in the remaining 6 % [1]. More recent observations have added the contribution of microchromosomal anomalies detectable by array CGH as the cause of syndromic EA [4].
3.2 Syndromic Ebstein Anomaly
3.2.1 Chromosomal Anomalies
Several chromosomal anomalies have been described in patients with EA, including deletion 8p23.1 [7, 8], duplication 9p [9], deletion and duplication 11q [10], duplication 15q [11], terminal deletion 18q [4, 12], trisomy 18 [3], and trisomy 21 [13]. Most of these chromosomal imbalances are not specifically associated with EA. Nevertheless, the number of patients with EA and deletion 8p23.1 and terminal deletion 18q seems proportionally high, considering the rarity of both chromosomal anomaly and CHD. It is possible that genes mapping in these chromosomal regions may be causally related to EA.
Deletion 8p23.1 syndrome is clinically characterized by mental retardation, microcephaly, facial dysmorphisms, CHD, and genital anomalies [14–16]. CHD occurs in 40–65 % of these patients, with common defects being atrioventricular canal defect with pulmonary stenosis and tetralogy of Fallot [8, 14, 16–20]. The GATA4 gene, mapping in the 8p23.1 critical region and being expressed throughout the development of the heart, is often deleted in these patients and is the most likely etiology of CHD [19, 21].
Terminal deletion 18q is characterized by developmental delay, growth deficiency, short stature, characteristic facial anomalies with specific ear malformation, cleft lip/palate, delayed myelination, and foot deformities [22]. Cardiac malformations are reported to be diagnosed in 24–36 % of the patients with terminal 18q deletion, predominantly pulmonary valve stenosis and atrial septal defect [23]. Nevertheless, rare CHDs as Ebstein anomaly are also been reported [4, 12]. At present, no single gene mapping inside the terminal region of chromosome 18q is known to be causally related to Ebstein anomaly.
3.2.2 Microchromosomal Anomalies
The introduction of microarray-based technology has led to the identification of novel clinically recognizable genomic disorders. Among these, terminal deletion 1p36 is one of the most common, characterized by mental retardation, epilepsy, and characteristic facial dysmorphisms [24]. CHD is diagnosed in about 50 % of these patients [24], including structural anomalies and cardiomyopathy with characteristics of left ventricular non-compaction. At present, Ebstein anomaly has been reported in 4 patients with deletion 1p36 [4, 24–26], suggesting that this genomic disorder should be considered in patients with syndromic Ebstein anomaly and mental retardation with and without epilepsy. The finding of Ebstein anomaly in patients with deletion 1p36 suggests the presence of a specific causally related gene inside this chromosomal region. Recently, the transcription factor PRDM16 has been identified as an important cause of cardiomyopathy in individuals with the chromosome deletion 1p36 syndrome as well as in non-syndromic forms of left ventricular non-compaction and other forms of dilated cardiomyopathy [27]. Functional studies implicate impaired proliferative capacity during cardiogenesis as a primary mechanism of these PRDM16-related cardiomyopathies [27]. Further studies are needed to assess if this gene could be causally linked with structural cardiac malformations.
The 5q35 microdeletion syndrome, including the cardiogenic NKX2.5 gene, is an addition genomic disorder predicted to be linked to Ebstein anomaly, since it has been previously detected in a syndromic patient with this type of CHD carrying a 2.2 Mb microdeletion [28].
Additionally, it should be expected that the detection of syndromic Ebstein anomaly with deletion 8p23.1 will progressively increase after larger screening by CGHarray is done and microdeletions not detectable by standard technique become evident [4].
3.3 Monogenic Syndromes and Associations
3.4 Non-syndromic Ebstein Anomaly
Non-syndromic Ebstein anomaly is occurring as a sporadic defect in families, although rare instances of familial recurrence of concordant defect have been reported [31–35]. The patterns of inheritance in familial cases were autosomal recessive, with recurrence in sibs, and autosomal dominant with reduced penetrance, with recurrence in uncle/nephew [31–35]. Various discordant CHDs have been reported in pedigrees of a few additional familial cases. No specific predispositions were noted, with the exception of the autosomal dominant segregation of non-syndromic Ebstein anomaly and left ventricular non-compaction in the same family [4, 36].
Molecular etiology of Ebstein anomaly is largely unknown. Mutations in genes involved in the cardiac morphogenesis have been detected in a few patients with Ebstein anomaly, including mutations in NKX2.5 [37–39] and MYH7 genes [40, 41]. Nevertheless, genetic heterogeneity and multifactorial inheritance are probably characteristics of Ebstein anomaly, since mutational screening of NKX2.5 and GATA4 genes in additional patients with Ebstein anomaly is negative [4].
3.5 Teratogens
Lithium therapy during the first trimester of pregnancy was once thought to be strongly associated with the occurrence of EA in the fetus, basing on old series of retrospective case reports [5]. However, more recent epidemiological studies have not confirmed these findings [6]. Considering the rarity of Ebstein anomaly, no definite conclusions can be made, but it should be considered that the risk of lithium therapy during pregnancy is much less than was originally estimated from the retrospective studies.
3.6 Recurrence Risks and Genetic Counseling
Genetic counseling of syndromic Ebstein anomaly is following the inheritance patterns of chromosomal or Mendelian diseases.
In regard to non-syndromic Ebstein anomaly, empiric risk figures are used to calculate the recurrence risks for subsequent pregnancies of couples with an affected child. The recurrence risk of CHD in sibs of patients with Ebstein anomaly is estimated on the order of 1 % if 1 sib is affected [42, 43]. The risk is higher when additional relatives are affected. Particularly, if 2 sibs are affected, the recurrence risk of the couple is corresponding to about 3 % [42, 43].
3.7 Conclusions
Ebstein anomaly is a genetically heterogeneous CHD and was included by Edward Clark in the pathogenetic group of apoptosis defects [44]. Chromosomal or Mendelian disorders are detectable in about 20 % of the patients, while in 80 % the anomaly is an isolated non-syndromic malformation. Deletion 1p36, deletion 8p23.1, and terminal deletion 18q are the more frequent chromosomal imbalances associated with Ebstein anomaly. Several Mendelian syndromes are known to be associated with Ebstein anomaly, although no single disorder is specifically associated with the defect. Likely candidate genes for Ebstein anomaly include GATA4 (patients with del 8p23.1), NKX2.5 (published patients with isolated Ebstein anomaly), and MYH7 genes.
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