The morbid genome of ciliopathies: an update.
Stargardt
allelism
noncoding
oligogenic
Blended Phenotype
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
01
11
2019
accepted:
29
01
2020
revised:
28
01
2020
pubmed:
15
2
2020
medline:
28
4
2021
entrez:
15
2
2020
Statut:
ppublish
Résumé
Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.
Identifiants
pubmed: 32055034
doi: 10.1038/s41436-020-0761-1
pii: S1098-3600(21)00832-7
doi:
Substances chimiques
SCLT1 protein, human
0
Sodium Channels
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1051-1060Commentaires et corrections
Type : ErratumIn
Références
Bernabé-Rubio M, Alonso MA. Routes and machinery of primary cilium biogenesis. Cell Mol Life Sci. 2017;74:4077–4095.
doi: 10.1007/s00018-017-2570-5
Kempeneers C, Chilvers MA. To beat, or not to beat, that is question! The spectrum of ciliopathies. Pediatr Pulmonol. 2018;53:1122–1129.
doi: 10.1002/ppul.24078
Braun DA, Hildebrandt F. Ciliopathies. Cold Spring Harb Perspect Biol. 2017;9:a028191.
doi: 10.1101/cshperspect.a028191
Shaheen R, Szymanska K, Basu B, et al. Characterizing the morbid genome of ciliopathies. Genome Biol. 2016;17:242.
doi: 10.1186/s13059-016-1099-5
Phelps IG, Dempsey JC, Grout ME, et al. Interpreting the clinical significance of combined variants in multiple recessive disease genes: systematic investigation of Joubert syndrome yields little support for oligogenicity. Genet Med. 2018;20:223.
doi: 10.1038/gim.2017.94
Abu-Safieh L, Al-Anazi S, Al-Abdi L, et al. In search of triallelism in Bardet–Biedl syndrome. Eur J Hum Genet. 2012;20:420.
doi: 10.1038/ejhg.2011.205
Monies D, Abouelhoda M, Assoum M, et al. Lessons learned from large-scale, first-tier clinical exome sequencing in a highly consanguineous population. Am J Hum Genet. 2019;104:1182–1201.
doi: 10.1016/j.ajhg.2019.04.011
Richards S, Aziz N, Bale S, et al. 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. 2015;17:405.
doi: 10.1038/gim.2015.30
Chen JH, Geberhiwot T, Barrett TG, Paisey R, Semple RK. Refining genotype–phenotype correlation in Alström syndrome through study of primary human fibroblasts. Mol Genet Genomic Med. 2017;5:390–404.
doi: 10.1002/mgg3.296
Shaheen R, Sebai MA, Patel N, et al. The genetic landscape of familial congenital hydrocephalus. Ann Neurol. 2017;81:890–897.
doi: 10.1002/ana.24964
Shaheen R, Alsahli S, Ewida N, et al. Biallelic mutations in TTC26 (IFT56) cause severe biliary ciliopathy in humans. Hepatology. 2019 Oct 8; https://doi.org/10.1002/hep.30982 [Epub ahead of print].
Abu-Safieh L, Alrashed M, Anazi S, et al. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013;23:236–247.
doi: 10.1101/gr.144105.112
Safieh LA, Aldahmesh M, Shamseldin H, et al. Clinical and molecular characterisation of Bardet–Biedl syndrome in consanguineous populations: the power of homozygosity mapping. J Med Genet. 2010;47:236–241.
doi: 10.1136/jmg.2009.070755
Maddirevula S, Alzahrani F, Al–Owain M, et al. Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. 2019;21:736.
doi: 10.1038/s41436-018-0138-x
Breslow DK, Hoogendoorn S, Kopp AR, et al. A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies. Nat Genet. 2018;50:460.
doi: 10.1038/s41588-018-0054-7
Dorn KV, Hughes CE, Rohatgi R. A smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev Cell. 2012;23:823–835.
doi: 10.1016/j.devcel.2012.07.004
Pusapati GV, Hughes CE, Dorn KV, et al. EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia. Dev Cell. 2014;28:483–496.
doi: 10.1016/j.devcel.2014.01.021
Yamaguchi A, Kaneko T, Inai T, Iida H. Molecular cloning and subcellular localization of Tektin2-binding protein 1 (Ccdc 172) in rat spermatozoa. J Histochem Cytochem. 2014;62:286–297.
doi: 10.1369/0022155413520607
Tu F, Sedzinski J, Ma Y, Marcotte EM, Wallingford JB. Protein localization screening in vivo reveals novel regulators of multiciliated cell development and function. J Cell Sci. 2018;131:jcs206565.
doi: 10.1242/jcs.206565
Shoaib E, Abdelhamed Z, Szymanska K, Bell S, Morrison E, Johnson C. Biochemical characterization of transmembrane proteins (TMEMs) in the ciliary transition zone. Cilia. 2015;4 Suppl 1:P75.
doi: 10.1186/2046-2530-4-S1-P75
Chih B, Liu P, Chinn Y, et al. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol. 2012;14:61.
doi: 10.1038/ncb2410
Tsuchiya Y, Yoshiba S, Gupta A, Watanabe K, Kitagawa D. Cep295 is a conserved scaffold protein required for generation of a bona fide mother centriole. Nat Commun. 2016;7:12567.
doi: 10.1038/ncomms12567
Firat-Karalar EN, Rauniyar N, Yates IIIJR, Stearns T. Proximity interactions among centrosome components identify regulators of centriole duplication. Curr Biol. 2014;24:664–670.
doi: 10.1016/j.cub.2014.01.067
Zhao H, Zhu L, Zhu Y, et al. The Cep63 paralogue Deup1 enables massive de novo centriole biogenesis for vertebrate multiciliogenesis. Nat Cell Biol. 2013;15:1434.
doi: 10.1038/ncb2880
Nasir A, Le Bail A, Daiker V, Klima J, Richter P, Lebert M. Identification of a flagellar protein implicated in the gravitaxis in the flagellate Euglena gracilis. Sci Rep. 2018;8:7605.
doi: 10.1038/s41598-018-26046-8
Firat-Karalar EN, Sante J, Elliott S, Stearns T. Proteomic analysis of mammalian sperm cells identifies new components of the centrosome. J Cell Sci. 2014;127:4128–4133.
doi: 10.1242/jcs.157008
Kim SK, Shindo A, Park TJ, et al. Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science. 2010;329:1337–1340.
doi: 10.1126/science.1191184
Thomas S, Wright KJ, Corre SL, et al. A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum Mutat. 2014;35:137–146.
doi: 10.1002/humu.22470
Macia MS, Halbritter J, Delous M, et al. Mutations in MAPKBP1 cause juvenile or late-onset cilia-independent nephronophthisis. Am J Hum Genet. 2017;100:323–333.
doi: 10.1016/j.ajhg.2016.12.011
Scheidecker S, Etard C, Pierce NW, et al. Exome sequencing of Bardet–Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet. 2014;51:132–136.
doi: 10.1136/jmedgenet-2013-101785
Monies D, Maddirevula S, Kurdi W, et al. Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation. Genet Med. 2017;19:1144.
doi: 10.1038/gim.2017.22
Kurbegovic A, Côté O, Couillard M, Ward CJ, Harris PC, Trudel M. Pkd1 transgenic mice: adult model of polycystic kidney disease with extrarenal and renal phenotypes. Hum Mol Genet. 2010;19:1174–1189.
doi: 10.1093/hmg/ddp588
Al-Hamed MH, Alsahan N, Rice SJ, et al. Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families. Pediatr Nephrol. 2019;34:1615–1623.
doi: 10.1007/s00467-019-04267-x
Klein D, Ammann F. The syndrome of Laurence-Moon-Bardet-Biedl and allied diseases in Switzerland: clinical, genetic and epidemiological studies. J Neurol Sci. 1969;9:479–513.
doi: 10.1016/0022-510X(69)90091-4
Musarella MA. Patient with Bardet–Biedl syndrome presenting with nystagmus at fifteen months of age. J AAPOS. 2001;5:262–264.
doi: 10.1067/mpa.2001.115592