Whole-exome sequencing identified compound heterozygous variants in MMKS in a Chinese pedigree with Bardet-Biedl syndrome
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摘要
Bardet-Biedl syndrome(BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity,developmental delay, and renal defects. At least 21 candidate BBS-associated genes(BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole-exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants(c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants. We also found a missense variant(c.2029G>C, p.E677Q) in NPHP1 and a missense variant(c.2470C>T, p.R824C) in BBS9 in the proband only, which are variants of uncertain significance. The compound heterozygous variants were probably responsible for the BBS phenotype in this Chinese pedigree and the missense mutations in NPHP1 and BBS9 might contribute to the mutation load.
Bardet-Biedl syndrome(BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity,developmental delay, and renal defects. At least 21 candidate BBS-associated genes(BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole-exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants(c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants. We also found a missense variant(c.2029G>C, p.E677Q) in NPHP1 and a missense variant(c.2470C>T, p.R824C) in BBS9 in the proband only, which are variants of uncertain significance. The compound heterozygous variants were probably responsible for the BBS phenotype in this Chinese pedigree and the missense mutations in NPHP1 and BBS9 might contribute to the mutation load.
Bardet-Biedl syndrome(BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity,developmental delay, and renal defects. At least 21 candidate BBS-associated genes(BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole-exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants(c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants. We also found a missense variant(c.2029G>C, p.E677Q) in NPHP1 and a missense variant(c.2470C>T, p.R824C) in BBS9 in the proband only, which are variants of uncertain significance. The compound heterozygous variants were probably responsible for the BBS phenotype in this Chinese pedigree and the missense mutations in NPHP1 and BBS9 might contribute to the mutation load.
引文
Ansley,S.J.,Badano,J.L.,Blacque,O.E.,Hill,J.,Hoskins,B.E.,Leitch,C.C.,Chul Kim,J.,Ross,A.J.,Eichers,E.R.,Teslovich,T.M.,Mah,A.K.,Johnsen,R.C.,Cavender,J.C.,Alan Lewis,R.,Leroux,M.R.,Beales,P.L.,and Katsanis,N.(2003).Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.Nature 425,628-633.
Badano,J.L.,and Katsanis,N.(2006).Life without centrioles:cilia in the spotlight.Cell 125,1228-1230.
Badano,J.L.(2003).Heterozygous mutations in BBS1,BBS2 and BBS6have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.Hum Mol Genet 12,1651-1659.
Bee,Y.M.,Chawla,M.,and Zhao,Y.(2015).Whole exome sequencing identifies a novel and a recurrent mutation in BBS2 gene in a family with Bardet-Biedl syndrome.BioMed Res Int 2015,524754.
Castro-Sánchez,S.,álvarez-Satta,M.,Cortón,M.,Guillén,E.,Ayuso,C.,and Valverde,D.(2015).Exploring genotype-phenotype relationships in Bardet-Biedl syndrome families.J Med Genet 52,503-513.
Ece Solmaz,A.,Onay,H.,Atik,T.,Aykut,A.,Cerrah Gunes,M.,Ozalp Yuregir,O.,Bas,V.N.,Hazan,F.,Kirbiyik,O.,and Ozkinay,F.(2015).Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome:Identification of nine novel mutations across BBS1,BBS2,BBS4,BBS7,BBS9,BBS10 genes.Eur J Med Genets 58,689-694.
Fath,M.A.,Mullins,R.F.,Searby,C.,Nishimura,D.Y.,Wei,J.,Rahmouni,K.,Davis,R.E.,Tayeh,M.K.,Andrews,M.,Yang,B.,Sigmund,C.D.,Stone,E.M.,and Sheffield,V.C.(2005).Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome.Hum Mol Genet 14,1109-1118.
Forsythe,E.,and Beales,P.L.(2013).Bardet-Biedl syndrome.Eur J Hum Genet 21,8-13.
Katsanis,N.(2004).The oligogenic properties of Bardet-Biedl syndrome.Hum Mol Genet 13 Spec No 1,R65-71.
Katsanis,N.,Ansley,S.J.,Badano,J.L.,Eichers,E.R.,Lewis,R.A.,Hoskins,B.E.,Scambler,P.J.,Davidson,W.S.,Beales,P.L.,and Lupski,J.R.(2001).Triallelic inheritance in Bardet-Biedl syndrome,a Mendelian recessive disorder.Science 293,2256-2259.
Kim,J.C.,Badano,J.L.,Sibold,S.,Esmail,M.A.,Hill,J.,Hoskins,B.E.,Leitch,C.C.,Venner,K.,Ansley,S.J.,Ross,A.J.,Leroux,M.R.,Katsanis,N.,and Beales,P.L.(2004).The Bardet-Biedl protein BBS4targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.Nat Genet 36,462-470.
Kim,J.C.,Ou,Y.Y.,Badano,J.L.,Esmail,M.A.,Leitch,C.C.,Fiedrich,E.,Beales,P.L.,Archibald,J.M.,Katsanis,N.,Rattner,J.B.,and Leroux,M.R.(2005).MKKS/BBS6,a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome,is a novel centrosomal component required for cytokinesis.J Cell Sci 118,1007-1020.
Leitch,C.C.,Zaghloul,N.A.,Davis,E.E.,Stoetzel,C.,Diaz-Font,A.,Rix,S.,Alfadhel,M.,Al-Fadhel,M.,Lewis,R.A.,Eyaid,W.,Banin,E.,Dollfus,H.,Beales,P.L.,Badano,J.L.,and Katsanis,N.(2008).Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.Nat Genet 40,443-448.
Li,J.B.,Gerdes,J.M.,Haycraft,C.J.,Fan,Y.,Teslovich,T.M.,May-Simera,H.,Li,H.,Blacque,O.E.,Li,L.,Leitch,C.C.,Lewis,R.A.,Green,J.S.,Parfrey,P.S.,Leroux,M.R.,Davidson,W.S.,Beales,P.L.,Guay-Woodford,L.M.,Yoder,B.K.,Stormo,G.D.,Katsanis,N.,and Dutcher,S.K.(2004).Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene.Cell117,541-552.
Lindstrand,A.,Frangakis,S.,Carvalho,C.M.B.,Richardson,E.B.,McFadden,K.A.,Willer,J.R.,Pehlivan,D.,Liu,P.,Pediaditakis,I.L.,Sabo,A.,Lewis,R.A.,Banin,E.,Lupski,J.R.,Davis,E.E.,and Katsanis,N.(2016).Copy-number variation contributes to the mutational load of Bardet-Biedl syndrome.Am J Hum Genet 99,318-336.
M’hamdi,O.,Ouertani,I.,Maazoul,F.,and Chaabouni-Bouhamed,H.(2011).Prevalence of Bardet-Biedl syndrome in Tunisia.J Community Genet 2,97-99.
Nishimura,D.Y.,Swiderski,R.E.,Searby,C.C.,Berg,E.M.,Ferguson,A.L.,Hennekam,R.,Merin,S.,Weleber,R.G.,Biesecker,L.G.,Stone,E.M.,and Sheffield,V.C.(2005).Comparative genomics and gene expression analysis identifies BBS9,a new Bardet-Biedl syndrome gene.Am J Hum Genet 77,1021-1033.
Ostrowski,L.E.,Blackburn,K.,Radde,K.M.,Moyer,M.B.,Schlatzer,D.M.,Moseley,A.,and Boucher,R.C.(2002).A proteomic analysis of human cilia:identification of novel components.Mol Cell Proteomics 1,451-465.
Pazour,G.J.,and Witman,G.B.(2003).The vertebrate primary cilium is a sensory organelle.Curr Opin Cell Biol 15,105-110.
Rachel,R.A.,May-Simera,H.L.,Veleri,S.,Gotoh,N.,Choi,B.Y.,Murga-Zamalloa,C.,McIntyre,J.C.,Marek,J.,Lopez,I.,Hackett,A.N.,Zhang,J.,Brooks,M.,den Hollander,A.I.,Beales,P.L.,Li,T.,Jacobson,S.G.,Sood,R.,Martens,J.R.,Liu,P.,Friedman,T.B.,Khanna,H.,Koenekoop,R.K.,Kelley,M.W.,and Swaroop,A.(2012).Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis.J Clin Invest 122,1233-1245.
Redin,C.,Le Gras,S.,Mhamdi,O.,Geoffroy,V.,Stoetzel,C.,Vincent,M.C.,Chiurazzi,P.,Lacombe,D.,Ouertani,I.,Petit,F.,Till,M.,Verloes,A.,Jost,B.,Chaabouni,H.B.,Dollfus,H.,Mandel,J.L.,and Muller,J.(2012).Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases:efficient mutation detection in BardetBiedl and Alstr鰉syndromes.J Med Genet 49,502-512.
Richards,S.,Aziz,N.,Bale,S.,Bick,D.,Das,S.,Gastier-Foster,J.,Grody,W.W.,Hegde,M.,Lyon,E.,Spector,E.,Voelkerding,K.,Rehm,H.L.,and Rehm,H.L.(2015).Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med 17,405-423.
Schaefer,E.,Durand,M.,Stoetzel,C.,Doray,B.,Viville,B.,Hellé,S.,Danse,J.M.,Hamel,C.,Bitoun,P.,Goldenberg,A.,Finck,S.,Faivre,L.,Sigaudy,S.,Holder,M.,Vincent,M.C.,Marion,V.,Bonneau,D.,Verloes,A.,Nisand,I.,Mandel,J.L.,and Dollfus,H.(2011).Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes.Eur J Med Genets 54,157-160.
Shiba,D.,Manning,D.K.,Koga,H.,Beier,D.R.,and Yokoyama,T.(2010).Inv acts as a molecular anchor for Nphp3 and Nek8 in the proximal segment of primary cilia.Cytoskeleton 67,112-119.
Stoetzel,C.,Laurier,V.,Davis,E.E.,Muller,J.,Rix,S.,Badano,J.L.,Leitch,C.C.,Salem,N.,Chouery,E.,Corbani,S.,Jalk,N.,Vicaire,S.,Sarda,P.,Hamel,C.,Lacombe,D.,Holder,M.,Odent,S.,Holder,S.,Brooks,A.S.,Elcioglu,N.H.,Silva,E.D.,Da Silva,E.,Rossillion,B.,Sigaudy,S.,de Ravel,T.J.L.,Lewis,R.A.,Leheup,B.,Verloes,A.,Amati-Bonneau,P.,Mégarbané,A.,Poch,O.,Bonneau,D.,Beales,P.L.,Mandel,J.L.,Katsanis,N.,and Dollfus,H.(2006).BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.Nat Genet 38,521-524.
Stoetzel,C.,Muller,J.,Laurier,V.,Davis,E.E.,Zaghloul,N.A.,Vicaire,S.,Jacquelin,C.,Plewniak,F.,Leitch,C.C.,Sarda,P.,Hamel,C.,de Ravel,T.J.L.,Lewis,R.A.,Friederich,E.,Thibault,C.,Danse,J.M.,Verloes,A.,Bonneau,D.,Katsanis,N.,Poch,O.,Mandel,J.L.,and Dollfus,H.(2007).Identification of a novel BBS gene(BBS12)highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome.Am J Hum Genet 80,1-11.
Suspitsin,E.N.,and Imyanitov,E.N.(2016).Bardet-Biedl syndrome.Mol Syndromol 7,62-71.
Suspitsin,E.N.,Sokolenko,A.P.,Lyazina,L.V.,Preobrazhenskaya,E.V.,Lepenchuk,A.Y.,and Imyanitov,E.N.(2015).Exome sequencing of a family with Bardet-Biedl syndrome identifies the common Russian mutation c.1967_1968delTAinsC in BBS7.Mol Syndromol 6,96-98.
Zaghloul,N.A.,and Katsanis,N.(2009).Mechanistic insights into BardetBiedl syndrome,a model ciliopathy.J Clin Invest 119,428-437.
Badano,J.L.,and Katsanis,N.(2006).Life without centrioles:cilia in the spotlight.Cell 125,1228-1230.
Badano,J.L.(2003).Heterozygous mutations in BBS1,BBS2 and BBS6have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.Hum Mol Genet 12,1651-1659.
Bee,Y.M.,Chawla,M.,and Zhao,Y.(2015).Whole exome sequencing identifies a novel and a recurrent mutation in BBS2 gene in a family with Bardet-Biedl syndrome.BioMed Res Int 2015,524754.
Castro-Sánchez,S.,álvarez-Satta,M.,Cortón,M.,Guillén,E.,Ayuso,C.,and Valverde,D.(2015).Exploring genotype-phenotype relationships in Bardet-Biedl syndrome families.J Med Genet 52,503-513.
Ece Solmaz,A.,Onay,H.,Atik,T.,Aykut,A.,Cerrah Gunes,M.,Ozalp Yuregir,O.,Bas,V.N.,Hazan,F.,Kirbiyik,O.,and Ozkinay,F.(2015).Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome:Identification of nine novel mutations across BBS1,BBS2,BBS4,BBS7,BBS9,BBS10 genes.Eur J Med Genets 58,689-694.
Fath,M.A.,Mullins,R.F.,Searby,C.,Nishimura,D.Y.,Wei,J.,Rahmouni,K.,Davis,R.E.,Tayeh,M.K.,Andrews,M.,Yang,B.,Sigmund,C.D.,Stone,E.M.,and Sheffield,V.C.(2005).Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome.Hum Mol Genet 14,1109-1118.
Forsythe,E.,and Beales,P.L.(2013).Bardet-Biedl syndrome.Eur J Hum Genet 21,8-13.
Katsanis,N.(2004).The oligogenic properties of Bardet-Biedl syndrome.Hum Mol Genet 13 Spec No 1,R65-71.
Katsanis,N.,Ansley,S.J.,Badano,J.L.,Eichers,E.R.,Lewis,R.A.,Hoskins,B.E.,Scambler,P.J.,Davidson,W.S.,Beales,P.L.,and Lupski,J.R.(2001).Triallelic inheritance in Bardet-Biedl syndrome,a Mendelian recessive disorder.Science 293,2256-2259.
Kim,J.C.,Badano,J.L.,Sibold,S.,Esmail,M.A.,Hill,J.,Hoskins,B.E.,Leitch,C.C.,Venner,K.,Ansley,S.J.,Ross,A.J.,Leroux,M.R.,Katsanis,N.,and Beales,P.L.(2004).The Bardet-Biedl protein BBS4targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.Nat Genet 36,462-470.
Kim,J.C.,Ou,Y.Y.,Badano,J.L.,Esmail,M.A.,Leitch,C.C.,Fiedrich,E.,Beales,P.L.,Archibald,J.M.,Katsanis,N.,Rattner,J.B.,and Leroux,M.R.(2005).MKKS/BBS6,a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome,is a novel centrosomal component required for cytokinesis.J Cell Sci 118,1007-1020.
Leitch,C.C.,Zaghloul,N.A.,Davis,E.E.,Stoetzel,C.,Diaz-Font,A.,Rix,S.,Alfadhel,M.,Al-Fadhel,M.,Lewis,R.A.,Eyaid,W.,Banin,E.,Dollfus,H.,Beales,P.L.,Badano,J.L.,and Katsanis,N.(2008).Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.Nat Genet 40,443-448.
Li,J.B.,Gerdes,J.M.,Haycraft,C.J.,Fan,Y.,Teslovich,T.M.,May-Simera,H.,Li,H.,Blacque,O.E.,Li,L.,Leitch,C.C.,Lewis,R.A.,Green,J.S.,Parfrey,P.S.,Leroux,M.R.,Davidson,W.S.,Beales,P.L.,Guay-Woodford,L.M.,Yoder,B.K.,Stormo,G.D.,Katsanis,N.,and Dutcher,S.K.(2004).Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene.Cell117,541-552.
Lindstrand,A.,Frangakis,S.,Carvalho,C.M.B.,Richardson,E.B.,McFadden,K.A.,Willer,J.R.,Pehlivan,D.,Liu,P.,Pediaditakis,I.L.,Sabo,A.,Lewis,R.A.,Banin,E.,Lupski,J.R.,Davis,E.E.,and Katsanis,N.(2016).Copy-number variation contributes to the mutational load of Bardet-Biedl syndrome.Am J Hum Genet 99,318-336.
M’hamdi,O.,Ouertani,I.,Maazoul,F.,and Chaabouni-Bouhamed,H.(2011).Prevalence of Bardet-Biedl syndrome in Tunisia.J Community Genet 2,97-99.
Nishimura,D.Y.,Swiderski,R.E.,Searby,C.C.,Berg,E.M.,Ferguson,A.L.,Hennekam,R.,Merin,S.,Weleber,R.G.,Biesecker,L.G.,Stone,E.M.,and Sheffield,V.C.(2005).Comparative genomics and gene expression analysis identifies BBS9,a new Bardet-Biedl syndrome gene.Am J Hum Genet 77,1021-1033.
Ostrowski,L.E.,Blackburn,K.,Radde,K.M.,Moyer,M.B.,Schlatzer,D.M.,Moseley,A.,and Boucher,R.C.(2002).A proteomic analysis of human cilia:identification of novel components.Mol Cell Proteomics 1,451-465.
Pazour,G.J.,and Witman,G.B.(2003).The vertebrate primary cilium is a sensory organelle.Curr Opin Cell Biol 15,105-110.
Rachel,R.A.,May-Simera,H.L.,Veleri,S.,Gotoh,N.,Choi,B.Y.,Murga-Zamalloa,C.,McIntyre,J.C.,Marek,J.,Lopez,I.,Hackett,A.N.,Zhang,J.,Brooks,M.,den Hollander,A.I.,Beales,P.L.,Li,T.,Jacobson,S.G.,Sood,R.,Martens,J.R.,Liu,P.,Friedman,T.B.,Khanna,H.,Koenekoop,R.K.,Kelley,M.W.,and Swaroop,A.(2012).Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis.J Clin Invest 122,1233-1245.
Redin,C.,Le Gras,S.,Mhamdi,O.,Geoffroy,V.,Stoetzel,C.,Vincent,M.C.,Chiurazzi,P.,Lacombe,D.,Ouertani,I.,Petit,F.,Till,M.,Verloes,A.,Jost,B.,Chaabouni,H.B.,Dollfus,H.,Mandel,J.L.,and Muller,J.(2012).Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases:efficient mutation detection in BardetBiedl and Alstr鰉syndromes.J Med Genet 49,502-512.
Richards,S.,Aziz,N.,Bale,S.,Bick,D.,Das,S.,Gastier-Foster,J.,Grody,W.W.,Hegde,M.,Lyon,E.,Spector,E.,Voelkerding,K.,Rehm,H.L.,and Rehm,H.L.(2015).Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med 17,405-423.
Schaefer,E.,Durand,M.,Stoetzel,C.,Doray,B.,Viville,B.,Hellé,S.,Danse,J.M.,Hamel,C.,Bitoun,P.,Goldenberg,A.,Finck,S.,Faivre,L.,Sigaudy,S.,Holder,M.,Vincent,M.C.,Marion,V.,Bonneau,D.,Verloes,A.,Nisand,I.,Mandel,J.L.,and Dollfus,H.(2011).Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes.Eur J Med Genets 54,157-160.
Shiba,D.,Manning,D.K.,Koga,H.,Beier,D.R.,and Yokoyama,T.(2010).Inv acts as a molecular anchor for Nphp3 and Nek8 in the proximal segment of primary cilia.Cytoskeleton 67,112-119.
Stoetzel,C.,Laurier,V.,Davis,E.E.,Muller,J.,Rix,S.,Badano,J.L.,Leitch,C.C.,Salem,N.,Chouery,E.,Corbani,S.,Jalk,N.,Vicaire,S.,Sarda,P.,Hamel,C.,Lacombe,D.,Holder,M.,Odent,S.,Holder,S.,Brooks,A.S.,Elcioglu,N.H.,Silva,E.D.,Da Silva,E.,Rossillion,B.,Sigaudy,S.,de Ravel,T.J.L.,Lewis,R.A.,Leheup,B.,Verloes,A.,Amati-Bonneau,P.,Mégarbané,A.,Poch,O.,Bonneau,D.,Beales,P.L.,Mandel,J.L.,Katsanis,N.,and Dollfus,H.(2006).BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.Nat Genet 38,521-524.
Stoetzel,C.,Muller,J.,Laurier,V.,Davis,E.E.,Zaghloul,N.A.,Vicaire,S.,Jacquelin,C.,Plewniak,F.,Leitch,C.C.,Sarda,P.,Hamel,C.,de Ravel,T.J.L.,Lewis,R.A.,Friederich,E.,Thibault,C.,Danse,J.M.,Verloes,A.,Bonneau,D.,Katsanis,N.,Poch,O.,Mandel,J.L.,and Dollfus,H.(2007).Identification of a novel BBS gene(BBS12)highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome.Am J Hum Genet 80,1-11.
Suspitsin,E.N.,and Imyanitov,E.N.(2016).Bardet-Biedl syndrome.Mol Syndromol 7,62-71.
Suspitsin,E.N.,Sokolenko,A.P.,Lyazina,L.V.,Preobrazhenskaya,E.V.,Lepenchuk,A.Y.,and Imyanitov,E.N.(2015).Exome sequencing of a family with Bardet-Biedl syndrome identifies the common Russian mutation c.1967_1968delTAinsC in BBS7.Mol Syndromol 6,96-98.
Zaghloul,N.A.,and Katsanis,N.(2009).Mechanistic insights into BardetBiedl syndrome,a model ciliopathy.J Clin Invest 119,428-437.