Atrioventricular canal defect in Bardet-Biedl syndrome: Clinical evidence supporting the link between atrioventricular canal defect and polydactyly syndromes with ciliary dysfunction536

Abstract

To the Editor: Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by obesity, retinitis pigmentosa, postaxial polydactyly, genito-urinary malformations, cognitive impairment, and congenital heart defect (CHD).1.Beales P.L. Elcioglu N. Woolf A.S. Parker D. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey.1:STN:280:DC%2BD3czjt1yjtg%3D%3D1087463010874630J Med Genet. 1999; 36: 437-446Google Scholar Molecular basis of BBS are complex. Genetic heterogeneity is demonstrated by the identification of nine different BBS genes (BBS1–BBS9) cloned in the genome.2.Slavotinek A.M. Stone E.M. Mykytyn K. Heckenlively J.R. Mutations in MKKS cause Bardet-Biedl syndrome.1:CAS:528:DC%2BD3cXmsVKkurw%3D10.1038/79116Nat Genet. 2000; 26: 15-16Google Scholar, 3.Katsanis N. Beales P.L. Woods M.O. Lewis R.A. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.1:CAS:528:DC%2BD3cXmsVKku7s%3D10.1038/79201Nat Genet. 2000; 26: 67-70Google Scholar, 4.Nishimura D.Y. Searby C.C. Carmi R. Elbedour K. Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2).1:CAS:528:DC%2BD3MXjt1Wqsbc%3D10.1093/hmg/10.8.865Hum Molec Genet. 2001; 10: 865-874Google Scholar, 5.Mykytyn K. Braun T. Carmi R. Haider N.B. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.1:CAS:528:DC%2BD3MXktFOrtbo%3D10.1038/88925Nat Genet. 2001; 28: 188-191Google Scholar, 6.Mykytyn K. Nishimura D.Y. Searby C.C. Shastri M. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome.1:CAS:528:DC%2BD38Xls1Ors7g%3D10.1038/ng935Nat Genet. 2002; 31: 435-438Google Scholar, 7.Badano J.L. Ansley S.J. Leitch C.C. Lewis R.A. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2.1:CAS:528:DC%2BD3sXitFajsro%3D10.1086/368204Am J Hum Genet. 2003; 72: 650-658Google Scholar, 8.Ansley S.J. Badano J.L. Blacque O.E. Hill J. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.1:CAS:528:DC%2BD3sXnvV2hsLw%3D10.1038/nature02030Nature. 2003; 425: 628-633Google Scholar, 9.Chiang A.P. Nishimura D. Searby C. Elbedour K. Comparative genomic analysis identifies an ADP-Ribosylation Factor-like gene as the cause of Bardet-Biedl syndrome (BBS3).1:CAS:528:DC%2BD2cXnt1WgtL8%3D10.1086/423903Am J Hum Genet. 2004; 75: 475-484Google Scholar, 10.Fan Y. Esmail M.A. Ansley S.J. Blacque O.E. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome.1:CAS:528:DC%2BD2cXntFSku78%3D10.1038/ng1414Nat Genet. 2004; 36: 989-993Google Scholar, 11.Li J.B. Gerdes J.M. Haycraft C.J. Fan Y. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene.1:CAS:528:DC%2BD2cXktlCqt7w%3D10.1016/S0092-8674(04)00450-7Cell. 2004; 117: 541-552Google Scholar, 12.Nishimura D.Y. Swiderski R.E. Searby C.C. Berg M. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene.1:CAS:528:DC%2BD2MXht1ygtLfJ10.1086/498323Am J Hum Genet. 2005; 77: 1021-1033Google Scholar Additionally, the genetic interaction between different loci was suspected to be involved, and triallelic inheritance has been demonstrated in several instances.13.Katsanis N. Ansley S.J. Badano J.L. Eichers E.E. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.1:CAS:528:DC%2BD3MXntFCrurs%3D10.1126/science.1063525Science. 2001; 293: 2256-2259Google Scholar,14.Beales P.L. Badano J.L. Ross A.J. Ansley S.J. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.1:CAS:528:DC%2BD3sXjslagurw%3D10.1086/375178Am J Hum Genet. 2003; 72: 1187-1199Google Scholar The BBS phenotype overlaps with clinical manifestations of many syndromes. For example, a recessive mutation in a BBS gene has been recently identified in six fetuses clinically diagnosed as having Meckel or “Meckel-like” syndrome, demonstrating that the antenatal presentation of BBS may mimic Meckel syndrome.15.Karmous-Benailly H. Martinovic J. Gubler M.-C. Sirot Y. Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome.1:CAS:528:DC%2BD2MXhsFKrsbc%3D10.1086/428679Am J Hum Genet. 2005; 76: 493-504Google Scholar Meckel syndrome is a fetal-lethal condition presenting with renal cysts, hepatic fibrosis, postaxial polydactyly, and occipital encephalocele.16.Mecke S. Passarge E. Encephalocele, polycystic kidneys, and polydactyly as an autosomal recessive trait simulating certain other disorders: the Meckel syndrome.1:STN:280:DyaE3M3lsV2qsg%3D%3D4997715Ann Genet. 1971; 14: 97-103Google Scholar,17.Salonen R. The Meckel syndrome: clinicopathological findings in 67 patients.1:STN:280:DyaL2M%2FitVWruw%3D%3D10.1002/ajmg.1320180414Am J Med Genet. 1984; 18: 671-689Google Scholar The clinical diagnosis of BBS generally becomes clear during childhood, in concomitance with the development of obesity and retinal dystrophy as characteristic “markers” of the syndrome. The evolution of the phenotype with time makes the concept of clinical overlap of BBS with other condition not new. In fact, it has been previously shown that the BBS phenotype overlaps with clinical manifestations of McKusick-Kaufman syndrome,3.Katsanis N. Beales P.L. Woods M.O. Lewis R.A. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.1:CAS:528:DC%2BD3cXmsVKku7s%3D10.1038/79201Nat Genet. 2000; 26: 67-70Google Scholar,18.David A. Bitoun P. Lacombe D. Lambert J.C. Hydrometrocolpos and polydactyly: a common neonatal presentation of Bardet-Biedl and McKusick-Kaufman syndromes.1:STN:280:DyaK1Mzpt1Okug%3D%3D17629731762973J Med Genet. 1999; 36: 599-603Google Scholar,19.Slavotinek A.M. Biesecker L.G. Phenotypic overlap of McKusick-Kaufman syndrome with Bardet-Biedl syndrome: a literature review.1:STN:280:DC%2BD3M7it1aquw%3D%3D10.1002/1096-8628(20001127)95Am J Med Genet. 2000; 95 (:3<208::AID-AJMG5>3.0.CO;2-J): 208-215Google Scholar an autosomal recessive condition characterized by hydrometrocolpos, postaxial polydactyly and CHD.20.McKusick V.A. Bauer R.L. Koop C.E. Scott R.B. Hydrometrocolpos as a simply inherited malformation.1:STN:280:DyaF2c7jtVamtQ%3D%3D10.1001/jama.1964.03070110015003JAMA. 1964; 189: 813-816Google Scholar,21.Kaufman R.L. Hartmann A.F. McAllister W.H. Family studies in congenital heart disease II: a syndrome of hydrometrocolpos, postaxial polydactyly and congenital heart disease.Birth Defects. 1972; 8: 85-87Google Scholar The phenotypic overlap between BBS and McKusick-Kaufman syndrome has been recognized, following the observation that infants initially diagnosed with McKusick-Kaufman syndrome, owing to the presence of polydactyly and vaginal abnormalities, develop later obesity and retinal dystrophy, resulting in the diagnosis of BBS.18.David A. Bitoun P. Lacombe D. Lambert J.C. Hydrometrocolpos and polydactyly: a common neonatal presentation of Bardet-Biedl and McKusick-Kaufman syndromes.1:STN:280:DyaK1Mzpt1Okug%3D%3D17629731762973J Med Genet. 1999; 36: 599-603Google Scholar,19.Slavotinek A.M. Biesecker L.G. Phenotypic overlap of McKusick-Kaufman syndrome with Bardet-Biedl syndrome: a literature review.1:STN:280:DC%2BD3M7it1aquw%3D%3D10.1002/1096-8628(20001127)95Am J Med Genet. 2000; 95 (:3<208::AID-AJMG5>3.0.CO;2-J): 208-215Google Scholar As occurring for Meckel syndrome,15.Karmous-Benailly H. Martinovic J. Gubler M.-C. Sirot Y. Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome.1:CAS:528:DC%2BD2MXhsFKrsbc%3D10.1086/428679Am J Hum Genet. 2005; 76: 493-504Google Scholar molecular studies demonstrated that mutations in McKusick-Kaufman syndrome gene cause a subset of BBS patients.2.Slavotinek A.M. Stone E.M. Mykytyn K. Heckenlively J.R. Mutations in MKKS cause Bardet-Biedl syndrome.1:CAS:528:DC%2BD3cXmsVKkurw%3D10.1038/79116Nat Genet. 2000; 26: 15-16Google Scholar,3.Katsanis N. Beales P.L. Woods M.O. Lewis R.A. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.1:CAS:528:DC%2BD3cXmsVKku7s%3D10.1038/79201Nat Genet. 2000; 26: 67-70Google Scholar CHD is occasionally found in patients with BBS,1.Beales P.L. Elcioglu N. Woolf A.S. Parker D. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey.1:STN:280:DC%2BD3czjt1yjtg%3D%3D1087463010874630J Med Genet. 1999; 36: 437-446Google Scholar although studies on CHDs in BBS are effectively rare and very old, mostly published before the cloning of several BBS genes.1.Beales P.L. Elcioglu N. Woolf A.S. Parker D. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey.1:STN:280:DC%2BD3czjt1yjtg%3D%3D1087463010874630J Med Genet. 1999; 36: 437-446Google Scholar,22.Elbedour K. Zucker N. Zalzstein E. Barki Y. Carmi R. Cardiac abnormalities in the Bardet-Biedl syndrome: echocardiographic studies of 22 patients.1:STN:280:DyaK2M7gtVamtA%3D%3D10.1002/ajmg.1320520208Am J Med Genet. 1994; 52: 164-169Google Scholar,23.Crinò A. Tonini G. Vido L. Balsamo A. La sindrome di Bardet-Biedl: studio multicentrico italiano.Riv Ital Pediatr. 1994; 20: 530-536Google Scholar The CHDs more frequently found in BBS were aortic valve anomalies, atrial septal defect, pulmonary stenosis, and dilated cardiomyopathy.1.Beales P.L. Elcioglu N. Woolf A.S. Parker D. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey.1:STN:280:DC%2BD3czjt1yjtg%3D%3D1087463010874630J Med Genet. 1999; 36: 437-446Google Scholar,22.Elbedour K. Zucker N. Zalzstein E. Barki Y. Carmi R. Cardiac abnormalities in the Bardet-Biedl syndrome: echocardiographic studies of 22 patients.1:STN:280:DyaK2M7gtVamtA%3D%3D10.1002/ajmg.1320520208Am J Med Genet. 1994; 52: 164-169Google Scholar,23.Crinò A. Tonini G. Vido L. Balsamo A. La sindrome di Bardet-Biedl: studio multicentrico italiano.Riv Ital Pediatr. 1994; 20: 530-536Google Scholar Hypertrophy of the left ventricle was often reported as acquired cardiac defect due to renal disease and systemic hypertension.22.Elbedour K. Zucker N. Zalzstein E. Barki Y. Carmi R. Cardiac abnormalities in the Bardet-Biedl syndrome: echocardiographic studies of 22 patients.1:STN:280:DyaK2M7gtVamtA%3D%3D10.1002/ajmg.1320520208Am J Med Genet. 1994; 52: 164-169Google Scholar Nevertheless, accurate review of published reports of BBS and overlapping BBS-McKusick-Kaufman syndrome shows that atrioventricular canal defect (AVCD) is the prevalent CHD,15.Karmous-Benailly H. Martinovic J. Gubler M.-C. Sirot Y. Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome.1:CAS:528:DC%2BD2MXhsFKrsbc%3D10.1086/428679Am J Hum Genet. 2005; 76: 493-504Google Scholar,19.Slavotinek A.M. Biesecker L.G. Phenotypic overlap of McKusick-Kaufman syndrome with Bardet-Biedl syndrome: a literature review.1:STN:280:DC%2BD3M7it1aquw%3D%3D10.1002/1096-8628(20001127)95Am J Med Genet. 2000; 95 (:3<208::AID-AJMG5>3.0.CO;2-J): 208-215Google Scholar,20.McKusick V.A. Bauer R.L. Koop C.E. Scott R.B. Hydrometrocolpos as a simply inherited malformation.1:STN:280:DyaF2c7jtVamtQ%3D%3D10.1001/jama.1964.03070110015003JAMA. 1964; 189: 813-816Google Scholar,24.Digilio M.C. Marino B. Toscano A. Giannotti A. Atrioventricular canal defect without Down syndrome: A heterogeneous malformation.10.1002/(SICI)1096-8628(19990716)85Am J Med Genet. 2000; 85 (:2<140::AID-AJMG8>3.0.CO;2-A): 140-146Google Scholar,25.Pyeritz R.E. O'Neal Humphries J. Partial endocardial cushion defect and persistence of the left superior vena cava draining into the left atrium in a 34-year-old man with features of the Kaufman and Marfan syndromes.1:STN:280:DyaL3c7hvVKgsQ%3D%3D7354578Johns Hopkins Med J. 1980; 146: 28-32Google Scholar and dextrocardia without structural cardiac defects and abdominal situs inversus have also been described.8.Ansley S.J. Badano J.L. Blacque O.E. Hill J. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.1:CAS:528:DC%2BD3sXnvV2hsLw%3D10.1038/nature02030Nature. 2003; 425: 628-633Google Scholar,26.Sudhakar B. Rajaiah N. Gopinath T.P. Dextrocardia with situs inversus in Laurence-Moon-Biedl syndrome.1:STN:280:DyaL1c7os1OgtQ%3D%3D3446685J Assoc Physicians India. 1987; 35: 724-726Google Scholar,27.Lorda-Sanchez I. Ayuso C. Ibanez A. Situs inversus and Hirschsprung disease: Two uncommon manifestations in Bardet-Biedl syndrome.1:STN:280:DC%2BD3c%2FmvVCjsA%3D%3D10.1002/(SICI)1096-8628(20000103)90Am J Med Genet. 2000; 90 (:1<80::AID-AJMG14>3.0.CO;2-E): 80-81Google Scholar Additionally, polysplenia in the setting of heterotaxia has been reported in two sibs with BBS described by McLoughlin et al.,28.McLoughlin T.G. Krovetz L.J. Schiebler G.L. Heart disease in the Laurence-Moon-Biedl-Bardet syndrome.1:STN:280:DyaF2M%2FhsFamsw%3D%3D10.1016/S0022-3476(64)80403-0J Pediatr. 1964; 65: 388-399Google Scholar although the diagnosis of BBS was questioned for these patients.29.Cohen MM. Craniosynostosis: Diagnosis, evaluation, and management. New York: Raven Press, 1986; 497.Google Scholar Moreover, dextrocardia in the setting of situs inversus has been described in Meckel syndrome,30.Moerman P. Verbeken E. Fryns J.P. Goddeeris P. Association of Meckel syndrome with M-anisosplenia in one patient.1:STN:280:DyaL3s7gtlGqsw%3D%3D10.1111/j.1399-0004.1982.tb01425.xClin Genet. 1982; 22: 143-147Google Scholar,31.Shen-Schwarz S. Dave H. Meckel syndrome with polysplenia: case report and review of the literature.1:STN:280:DyaL1M7msVegsA%3D%3D10.1002/ajmg.1320310212Am J Med Genet. 1988; 31: 349-355Google Scholar and in “Meckel-like” syndrome.32.Fraser F.C. Jequier S. Chen M.F. Chondrodysplasia, situs inversus totalis, cleft epiglottis and larynx, hexadactyly of hands and feet, pancreatic cystic dysplasia, renal dysplasia/absence, micropenis and ambigous genitalia, imperforate anus.1:STN:280:DyaK3c%2Fos12isg%3D%3D10.1002/ajmg.1320340316Am J Med Genet. 1989; 34: 401-405Google Scholar, 33.Brueton L.A. Dillon M.J. Winter R.M. Ellis-van Creveld syndrome, Jeune syndrome, and renal-hepatic-pancreatic dysplasia: separate entities or disease spectrum?.1:STN:280:DyaK3c3hvV2lsw%3D%3D10.1136/jmg.27.4.252J Med Genet. 1990; 27: 252-255Google Scholar, 34.Balci S. Bostanoglu S. Altinok G. Ozaltin F. Three sibs diagnosed prenatally with situs inversus totalis, renal and pancreatic dysplasia and cysts.1:STN:280:DC%2BD3c7kt1Whsw%3D%3D10.1002/(SICI)1096-8628(20000131)90Am J Med Genet. 2000; 90 (:3<185::AID-AJMG1>3.0.CO;2-Y): 185-187Google Scholar Additionally, we observed a patient with BBS and AVCD, which was included in our personal series of 14 patients with AVCD and postaxial polydactyly.24.Digilio M.C. Marino B. Toscano A. Giannotti A. Atrioventricular canal defect without Down syndrome: A heterogeneous malformation.10.1002/(SICI)1096-8628(19990716)85Am J Med Genet. 2000; 85 (:2<140::AID-AJMG8>3.0.CO;2-A): 140-146Google Scholar,35.Digilio M.C. Marino B. Ammirati A. Borzaga U. Cardiac malformations in patients with oral-facial-skeletal syndromes: Clinical similarities with heterotaxia.1:STN:280:DyaK1M3ntVCktw%3D%3D10.1002/(SICI)1096-8628(19990604)84Am J Med Genet. 1999; 84 (:4<350::AID-AJMG8>3.0.CO;2-E): 350-356Google Scholar Clinical features of this patient included macrocephaly, obesity, retinal dystrophy affecting periphery and the macular area, a post-minimus postaxial polydactyly of right hand and complete postaxial polydactyly of right foot with a well-formed toe, mild mental retardation, and CHD. Echocardiography showed viscero-atrial situs solitus with levocardia, concordant atrioventricular and ventriculo-arterial connections, and a partial form of AVCD with double mitral orifice. Thereafter, AVCD and laterality defects seem to be an important clue for the diagnosis of BBS in some cases. Actually, a possible association of cardiac malformations with syndromes with postaxial polydactyly is well-known, and published reports demonstrated a specific link with AVCD and cardiac malformations usually occurring in heterotaxia.35.Digilio M.C. Marino B. Ammirati A. Borzaga U. Cardiac malformations in patients with oral-facial-skeletal syndromes: Clinical similarities with heterotaxia.1:STN:280:DyaK1M3ntVCktw%3D%3D10.1002/(SICI)1096-8628(19990604)84Am J Med Genet. 1999; 84 (:4<350::AID-AJMG8>3.0.CO;2-E): 350-356Google Scholar,36.Digilio M.C. Marino B. Giannotti A. Dallapiccola B. Specific congenital heart defects in RSH/Smith-Lemli-Opitz syndrome: Postulated involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly or heterotaxia.1:CAS:528:DC%2BD3sXivFWqsLk%3D10.1002/bdra.10010Birth Defects Research (Part A). 2003; 67: 149-153Google Scholar The association between AVCD with or without common atrium is rare in the non-syndromic patients, while it is characteristic of heterotaxia syndrome with asplenia37.Phoon C.K. Neill C.A. Asplenia syndrome: Insight into embryology through an analysis of cardiac and extracardiac anomalies.1:STN:280:DyaK2c7pslWjsw%3D%3D10.1016/0002-9149(94)90338-7Am J Cardiol. 1994; 73: 581-587Google Scholar or polysplenia.38.Peoples W.M. Moller J.H. Edwards J.E. Polysplenia: a review of 146 cases.1:STN:280:DyaL3s3ntlWltw%3D%3D10.1007/BF02076338Pediatr Cardiol. 1983; 4: 129-138Google Scholar CHDs in heterotaxia include AVCD, common atrium, anomalous systemic and pulmonary venous drainage, persistent left superior vena cava with unroofed coronary sinus, and conotruncal defects.37.Phoon C.K. Neill C.A. Asplenia syndrome: Insight into embryology through an analysis of cardiac and extracardiac anomalies.1:STN:280:DyaK2c7pslWjsw%3D%3D10.1016/0002-9149(94)90338-7Am J Cardiol. 1994; 73: 581-587Google Scholar,39.Webber S.A. Taylor G.P. Colwell K. Sandor G.G.S. Extracardiac malformations in asplenia syndrome.Cardiol Young. 1992; 2: 136-140Crossref Scopus (9) Google Scholar Among syndromes with postaxial polydactyly, the combination of AVCD and common atrium is particularly frequent in the oral-facial-digital syndromes, in short rib-polydactyly syndromes including Ellis-van Creveld syndrome, and in their related transitional phenotypes (Table 1).35.Digilio M.C. Marino B. Ammirati A. Borzaga U. Cardiac malformations in patients with oral-facial-skeletal syndromes: Clinical similarities with heterotaxia.1:STN:280:DyaK1M3ntVCktw%3D%3D10.1002/(SICI)1096-8628(19990604)84Am J Med Genet. 1999; 84 (:4<350::AID-AJMG8>3.0.CO;2-E): 350-356Google Scholar On the other hand, the association of AVCD and anomalous pulmonary venous return is specifically associated with Smith-Lemli-Opitz syndrome (Table 1).36.Digilio M.C. Marino B. Giannotti A. Dallapiccola B. Specific congenital heart defects in RSH/Smith-Lemli-Opitz syndrome: Postulated involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly or heterotaxia.1:CAS:528:DC%2BD3sXivFWqsLk%3D10.1002/bdra.10010Birth Defects Research (Part A). 2003; 67: 149-153Google Scholar,40.Lin A.E. Ardinger H.H. Ardinger H. Cunniff C. Cardiovascular malformations in Smith-Lemli-Opitz syndrome.1:STN:280:DyaK2s7nslSiuw%3D%3D10.1002/(SICI)1096-8628(19970131)68Am J Med Genet. 1997; 68 (:3<270::AID-AJMG5>3.0.CO;2-Q): 270-278Google ScholarTable 1Syndromes associating atrioventricular canal defect (AVCD) and postaxial polydactyly Recent experimental evidences regarding BBS are intriguing in regard to CHD and situs abnormalities. In fact, a role for several BBS proteins in regulating ciliary function has been demonstrated.10.Fan Y. Esmail M.A. Ansley S.J. Blacque O.E. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome.1:CAS:528:DC%2BD2cXntFSku78%3D10.1038/ng1414Nat Genet. 2004; 36: 989-993Google Scholar,11.Li J.B. Gerdes J.M. Haycraft C.J. Fan Y. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene.1:CAS:528:DC%2BD2cXktlCqt7w%3D10.1016/S0092-8674(04)00450-7Cell. 2004; 117: 541-552Google Scholar,41.Ansley S.J. Badano J.L. Blacque O.E. Hill J. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.1:CAS:528:DC%2BD3sXnvV2hsLw%3D10.1038/nature02030Nature. 2003; 425: 628-633Google Scholar,42.Kim J.C. Badano J.L. Sibold S. Esmail M.A. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.1:CAS:528:DC%2BD2cXjsFSnt7c%3D10.1038/ng1352Nat Genet. 2004; 36: 462-470Google Scholar It must be noticed that many clinical aspects of BBS can be explained by a ciliary defect. The finding of AVCD as partial manifestation of heterotaxia in some patients with BBS is in agreement with the involvement of BBS proteins in ciliary function, since dysfunction of the nodal cilium is known to cause left-right axis defects in vertebrates.43.Supp D.M. Wite D.P. Potter S.S. Brueckner M. Mutation in an axonemal dynein affects left-right asimmetry in inversus viscerum mice.10.1038/40140Nature. 1997; 389: 063-966Google Scholar,44.Okada Y. Nonaka S. Tanaka Y. Saijoh Y. Abnormal nodal flow precedes situs inversus in iv and inv mice.1:CAS:528:DyaK1MXntFCgs7g%3D10.1016/S1097-2765(00)80197-5Mol Cell. 1999; 4: 459-468Google Scholar Interestingly, it has recently been demonstrated that knockout male mouse embryos lacking the gene of oral-facial-digital syndrome type 1 (Ofd1) have failure of left-right axis specification with abnormal cardiac tube retaining a midline position or reversal of the heart loop.45.Ferrante M.I. Zullo A. Barra Bimonte S. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification.1:CAS:528:DC%2BD2MXhtlCmtr7E10.1038/ng1684Nat Genet. 2006; 38: 112-117Google Scholar Ultrastructural analysis showed a lack of cilia in the embryonic node, and a specific role for the Ofd1 protein in cilium assembly through basal body dysfunction has been demonstrated.45.Ferrante M.I. Zullo A. Barra Bimonte S. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification.1:CAS:528:DC%2BD2MXhtlCmtr7E10.1038/ng1684Nat Genet. 2006; 38: 112-117Google Scholar As an additional observation, the MKS1 gene has recently found to be mutated in families with Meckel syndrome linked to 17q, and comparative genomic and protemics data implicate MKS1 in ciliary functions.46.Kittala M. Tallila J. Salonen R. Kopra O. MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome.10.1038/ng1714Nat Genet. 2006; 38: 155-157Google Scholar In conclusion, AVCD and laterality defects seem to be an important feature for early diagnosis of BBS. Ciliary dysfunction may have a fundamental role in determining specific cardiac phenotypes in several syndromes with postaxial polydactyly and CHD. Mutations in proteins necessary for cilium formation and functionality must be considered when investigating syndromes with postaxial polydactyly and cardiac laterality defects.