Atrioventricular canal defect is the classic congenital heart disease in Bardet–Biedl syndrome

Abstract

To the Editor, We read with great interest the recent study of Gumus, Tuncez, Oz, and Guvenc (2020), who performed exome sequencing analysis in individuals diagnosed of Bardet– Biedl (BBS) and reported an atrioventricular canal defect (AVCD) in a patient carrying a silent LZTFL1 variant. LZTFL1 (BBS17) encodes a ubiquitously expressed protein that interacts with BBS protein complexes and acts as an important negative regulator of BBSome ciliary trafficking and Sonic hedgehog (Shh) signaling. In the discussion, the authors state that AVCD is a very rare cardiac anomaly among BBS patients.Wewould like to point out that AVCD and laterality defects are important and not so rare features in BBS. Cardiac involvement in BBS has originally been described as aortic valve anomalies (aortic stenosis), atrial septal defect, pulmonary stenosis, and dilated cardiomyopathy. However, these clinical observations were made before most BBS genes were discovered. In parallel to the molecular advances in defining BBS, cardiac phenotype was also better characterized. Reviews of BBS case series and of overlapping syndromes (i.e., BBS–McKusick– Kaufman syndrome) revealed that AVCD, dextrocardia without structural cardiac defects, and abdominal situs inversus were also present. Moreover, clinical evidence from personal series revealed that isolated AVCD or in association with defects that are particularly frequent in the setting of heterotaxy such as common atrium or anomalous pulmonary venous return seem to be an important clinical feature of BBS (Digilio et al., 1999). AVCD have also recently been described in several BBS case reports, the latest of them being the one of Olson and colleagues in 2019who stated that the prevalence of laterality defects such as situs inversus and heterotaxy in patients with BBS is higher than reported in the general population (Olson, Krentz, Finta, Okorie, & Haws, 2019). In the last decade, 19 BBS-related genes (BBS1–BBS19) have been identified, showing critical roles in ciliary morphogenesis and function. Since 1999, clinical observations revealed cardiac anatomical similarities between patients with polydactyly syndromes and heterotaxy and polysplenia with a high prevalence of AVCD (Digilio et al., 1999). Followingmolecular studies on transgenic mice have shown that cilia are required for left-right body axis determination through Shh signaling in secondary heart field and confirmed ciliary dysfunction through Shh signaling impairment in several disorders with polydactyly (Ansley et al., 2003). Indeed, the link between AVCD and BBS is not surprising thanks to anatomical observations andmolecular studies that showed that genes implicated in syndromes with AVCD encode for proteins involved in ciliogenesis (Digilio et al., 2019). Clinical observations and molecular studies therefore support the fact that AVCD in the setting of cardiac laterality defects is to be considered the most important congenital heart disease closely associated to BBS as a feature of ciliopathy (Digilio, Calcagni, De Luca, Guida, & Marino, 2020).