Atrioventricular canal defect and genetic syndromes: The unifying role of sonic hedgehog

Abstract

The atrioventricular canal defect (AVCD) is a congenital heart defect (CHD) frequently associated with extracardiac anomalies (75%). Previous observations from a personal series of patients with AVCD and "polydactyly syndromes" showed that the distinct morphology and combination of AVCD features in some of these syndromes is reminiscent of the cardiac phenotype found in heterotaxy, a malformation complex previously associated with functional cilia abnormalities and aberrant Hedgehog (Hh) signaling. Hh signaling coordinates multiple aspects of left-right lateralization and cardiovascular growth. Being active at the venous pole the secondary heart field (SHF) is essential for normal development of dorsal mesenchymal protrusion and AVCD formation and septation. Experimental data show that perturbations of different components of the Hh pathway can lead to developmental errors presenting with partially overlapping manifestations and AVCD as a common denominator. We review the potential role of Hh signaling in the pathogenesis of AVCD in different genetic disorders. AVCD can be viewed as part of a "developmental field," according to the concept that malformations can be due to defects in signal transduction cascades or pathways, as morphogenetic units which may be altered by Mendelian mutations, aneuploidies, and environmental causes.

Genetics of atrioventricular canal defects

“…However, Shh signaling pathway is deeply implicated also in ciliary function and acts on the DMP to drive the proper development of the cardiac AVC. In fact, in human beings, Shh pathway dysregulation has a well known impact on different types of AVCD [23]. This molecular considerations are supported by the striking phenotypical similarities between sonogram images of HPE (due to SHH deficiency in brain development) ( Fig.…”

“…Ciliopathies with AVCD can be divided in syndromes with polydactyly and syndromes without polydactyly. Among syndromes with polydactyly, ciliary dysfunction through abnormal processing of the Hh proteins has been documented in Ellis-van Creveld and other shortrib polydactyly, Smith-Lemli-Opitz, and oral-facialdigital type IV syndromes [22,23,49] while ciliary function is directly involved in Bardet-Biedl, oral-facialdigital I and VI syndromes [20,21,50,51].…”

“…Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, retinitis pigmentosa, postaxial polydactyly, genitourinary malformations, cognitive impairment, and CHD [68]. Laterality defects are described, including AVCD, dextrocardia without structural cardiac defects and abdominal situs inversus [23,69,70]. The AVCD can be considered the "classic" CHD in this syndrome.…”

“…The ciliary membranes harbor receptors for crucial signaling cascades, including Hedgehog signaling [18,19]. A link between AVCD and cilia abnormalities through a specific pathogenetic pathway involving Hedgehog signaling has been recognized in several syndromes with AVCD [20][21][22][23].…”

Heterozygous missense mutations inNFATC1are associated with atrioventricular septal defect

“…In the same series, isolated AVSD accounted for 25% of affected individuals (Digilio et al., ). In addition to DS and HTX, other disorders having AVSD as associated feature include Ellis‐van Creveld syndrome (MIM# 225500), Oro–Facio‐Digital syndrome II (MIM# 252100), Kaufman–McKusick syndrome (MIM# 236700), Smith–Lemli–Opitz syndrome (MIM# 270400), CHARGE syndrome (MIM# 214800), and Noonan syndrome (MIM# 163950) (Digilio et al., , ). AVSD typically occurs in patients with 8p23 and 3p25‐26 deletion syndromes (Giglio et al., ; Green et al.…”