Joubert Syndrome in French Canadians and Identification of Mutations in CEP104
2015; Elsevier BV; Volume: 97; Issue: 5 Linguagem: Inglês
10.1016/j.ajhg.2015.09.009
ISSN1537-6605
AutoresMyriam Srour, Fadi F. Hamdan, Dianalee McKnight, Erica E. Davis, Hanna Mandel, Jeremy Schwartzentruber, Brissa Martin, Lysanne Patry, Christina Nassif, Alexandre Dionne‐Laporte, Luis H. Ospina, Emmanuelle Lemyre, Christine Massicotte, Rachel Laframboise, Bruno Maranda, Damian Labuda, Jean‐Claude Décarie, Françoise Rypens, Dorith Goldsher, Catherine Fallet‐Bianco, Jean‐François Soucy, Anne‐Marie Laberge, Catalina Maftei, Kym M. Boycott, Bernard Brais, Renée‐Myriam Boucher, Guy A. Rouleau, Nicholas Katsanis, Jacek Majewski, Orly Elpeleg, Mary K. Kukolich, Stavit A. Shalev, Jacques L. Michaud,
Tópico(s)Congenital Anomalies and Fetal Surgery
ResumoJoubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166∗]) and a de novo splice-site mutation (c.2572−2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs∗3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population. Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166∗]) and a de novo splice-site mutation (c.2572−2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs∗3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population. Joubert syndrome (JBTS [MIM: 213300]) is a predominantly autosomal-recessive disorder characterized by oculomotor apraxia, hypotonia, neonatal breathing abnormalities, ataxia, and variable developmental delay. The hallmark of JBTS is a malformation involving the brainstem and cerebellum and consisting of cerebellar vermis hypoplasia or aplasia, horizontal elongated cerebellar peduncles, and a deep interpeduncular fossa; together, these take on the pathognomonic appearance of a "molar tooth."1Maria B.L. Hoang K.B. Tusa R.J. Mancuso A.A. Hamed L.M. Quisling R.G. Hove M.T. Fennell E.B. Booth-Jones M. Ringdahl D.M. et al."Joubert syndrome" revisited: key ocular motor signs with magnetic resonance imaging correlation.J. Child Neurol. 1997; 12: 423-430Crossref PubMed Scopus (259) Google Scholar A subset of individuals with JBTS also have extraneural manifestations such as polydactyly, retinopathy, cystic kidneys, and liver fibrosis (reviewed by Romani et al.2Romani M. Micalizzi A. Valente E.M. Joubert syndrome: congenital cerebellar ataxia with the molar tooth.Lancet Neurol. 2013; 12: 894-905Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). JBTS is a ciliopathy, given that the majority of the known genes associated with JBTS have been shown to play a role in the development and/or function of the non-motile cilia. The cilium is a compartmentalized extension of the extracellular membrane and functions as an antenna by sensing extracellular signals and transducing them intracellularly. The cilium is composed of a microtubule-based cytoskeleton called the axoneme, which nucleates from the basal body, a modified centriolar structure. At the base of the cilium, Y-shaped structures connect the basal body to the cell membrane, forming the transition zone, which constitutes a diffusion barrier between the cilium and the remainder of the plasma membrane (for a review, see Valente et al.3Valente E.M. Rosti R.O. Gibbs E. Gleeson J.G. Primary cilia in neurodevelopmental disorders.Nat. Rev. Neurol. 2014; 10: 27-36Crossref PubMed Scopus (143) Google Scholar). The majority of genes associated with JBTS encode proteins that localize to the basal body or ciliary transition zone. Many of these proteins physically interact with one another to form large complexes. The most important complex in the pathogenesis of JBTS is the B9 complex (also known as the tectonic complex), in which 9 of its known 15 members are associated with JBTS, Meckel syndrome (MKS [MIM: 249000]), and/or oral-facial-digital syndrome (OFD [MIM: 311200]).4Chih B. Liu P. Chinn Y. Chalouni C. Komuves L.G. Hass P.E. Sandoval W. Peterson A.S. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain.Nat. Cell Biol. 2012; 14: 61-72Crossref Scopus (251) Google Scholar, 5Czarnecki P.G. Shah J.V. The ciliary transition zone: from morphology and molecules to medicine.Trends Cell Biol. 2012; 22: 201-210Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 6Szymanska K. Johnson C.A. The transition zone: an essential functional compartment of cilia.Cilia. 2012; 1: 10Crossref PubMed Scopus (86) Google Scholar, 7Gurrieri F. Franco B. Toriello H. Neri G. Oral-facial-digital syndromes: review and diagnostic guidelines.Am. J. Med. Genet. A. 2007; 143A: 3314-3323Crossref PubMed Scopus (115) Google Scholar MKS and OFD are related ciliopathies whose features overlap those of JBTS. Although JBTS was first described in a French Canadian (FC) family in 1969,8Joubert M. Eisenring J.J. Robb J.P. Andermann F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation.Neurology. 1969; 19: 813-825Crossref PubMed Google Scholar little is known about its molecular etiology in this population. We thus sought to characterize the genetic landscape associated with JBTS in the FC population by studying a large number of unrelated families. Using a stepwise approach of targeted and whole-exome sequencing (WES), we were able to explain most cases and show that mutations in CEP104 cause JBTS. This study was approved by our institutional ethics committee. Informed consent was obtained from all participants or their legal guardians. We identified 43 FC individuals with JBTS (from 35 families). All individuals are of FC ancestry and originate from various regions throughout Quebec. The diagnosis of JBTS was based on the presence of (1) at least one JBTS classical neurological manifestation (oculomotor apraxia, ataxia, or history of breathing abnormalities) and (2) the molar tooth sign (MTS) on brain imaging in at least one affected family member (Figure S1). In addition, four fetuses were included in the study. On prenatal imaging, all fetal subjects showed cerebellar vermis hypoplasia or aplasia and elongated cerebellar peduncles, suggestive of JBTS. We previously explained JBTS in 21 of these individuals (15 families), who showed pathogenic mutations in C5orf42 (MIM: 614571), TMEM231 (MIM: 614949), or CC2D2A (MIM: 612013)9Srour M. Schwartzentruber J. Hamdan F.F. Ospina L.H. Patry L. Labuda D. Massicotte C. Dobrzeniecka S. Capo-Chichi J.M. Papillon-Cavanagh S. et al.FORGE Canada ConsortiumMutations in C5ORF42 cause Joubert syndrome in the French Canadian population.Am. J. Hum. Genet. 2012; 90: 693-700Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 10Srour M. Hamdan F.F. Schwartzentruber J.A. Patry L. Ospina L.H. Shevell M.I. Désilets V. Dobrzeniecka S. Mathonnet G. Lemyre E. et al.FORGE Canada ConsortiumMutations in TMEM231 cause Joubert syndrome in French Canadians.J. Med. Genet. 2012; 49: 636-641Crossref PubMed Scopus (58) Google Scholar (see Table S1). In JBTS-affected individuals from the FC population, these studies established the presence of a complex founder effect involving three recurrent mutations in C5orf42 (c.4006C>T [p.Arg1336Trp], c.7400+1G>A, and Ensembl transcript ENST00000509849, c.4690G>A [p.Ala1564Thr] [GenBank: NM_023073.3]), two recurrent mutations in CC2D2A (c.3376G>A [p.Glu1126Lys] and c.4667A>T [p.Asp1556Val] [GenBank: NM_001080522.2]), and two recurrent mutations in TMEM231 (c.12T>A [p.Tyr4∗] and c.625G>A [p.Asp209Asn] [GenBank: NM_001077418.1]), each of which was previously shown to be present on a common haplotype (see Table S1).9Srour M. Schwartzentruber J. Hamdan F.F. Ospina L.H. Patry L. Labuda D. Massicotte C. Dobrzeniecka S. Capo-Chichi J.M. Papillon-Cavanagh S. et al.FORGE Canada ConsortiumMutations in C5ORF42 cause Joubert syndrome in the French Canadian population.Am. J. Hum. Genet. 2012; 90: 693-700Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 10Srour M. Hamdan F.F. Schwartzentruber J.A. Patry L. Ospina L.H. Shevell M.I. Désilets V. Dobrzeniecka S. Mathonnet G. Lemyre E. et al.FORGE Canada ConsortiumMutations in TMEM231 cause Joubert syndrome in French Canadians.J. Med. Genet. 2012; 49: 636-641Crossref PubMed Scopus (58) Google Scholar Thus, we used Sanger sequencing to screen all unexplained JBTS-affected families (n = 19) for the seven known recurrent FC mutations. Five individuals (fetus 474, 1673.590, 1951.677, HSJ-JBTS-3, and HSJ-JBTS-4) were found to have homozygous or compound-heterozygous mutations in C5orf42, and two individuals (1342.488 and 1343.488) showed compound-heterozygous mutations in CC2D2A (Table 1). In addition, screening identified a single heterozygous mutation in C5orf42 in one individual (2049.708) and single heterozygous mutations in CC2D2A in two individuals (1610.572 and 1123.415). Sequencing the remaining exons of C5orf42 in individual 2049.708 revealed a heterozygous truncating variant (c.6354dupT [p.Ile2119Tyrfs∗2] [GenBank: NM_023073.3]), whereas sequencing the remaining exons of CC2D2A in individuals 1610.572 and 1123.415 identified a heterozygous canonical splice-site variant (c.2181+1G>A [GenBank: NM_001080522.2]) in the former and a heterozygous missense variant (c.3544T>C [p.Trp1182Arg]) in the latter (Table 1). The c.3544T>C (p.Trp1182Arg) variant has been previously reported as pathogenic in an individual with nephronophthisis.11Otto E.A. Ramaswami G. Janssen S. Chaki M. Allen S.J. Zhou W. Airik R. Hurd T.W. Ghosh A.K. Wolf M.T. et al.GPN Study GroupMutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy.J. Med. Genet. 2011; 48: 105-116Crossref PubMed Scopus (107) Google Scholar These three individuals are compound heterozygous for their respective mutations.Table 1Clinical Characteristics of Previously Unpublished JBTS-Affected Individuals Included in This StudyIndividualGeneMutationsGenderAgeMTSOMARetinal InvolvementRenal InvolvementLiver InvolvementLimb AnomaliesDevelopmental DelayCognitionRespiratory AbnormalityHypotoniaAtaxiaOtherFetus 474C5orf42c.[4006C>T];[6407del], p.[Arg1336Trp];[Pro2136Hisfs∗31]aThe genotype of the fetus was not tested but was assumed on the basis of the genotype of similarly affected sibling 1304.474 (Table S1).F22 weeks+NA−−−−NANANANANA−HSJ-JBTS-3C5orf42homozygous c.4006C>T (p.Arg1336Trp)F28 years++−f−h−h−−borderline−++strabismusHSJ-JBTS-4C5orf42homozygous c.4006C>T (p.Arg1336Trp)F3 years+++f−u−u++NA−NANAbifid epiglottis, strabismus, central polydactyly on the right, bilateral preaxial poldaytyly in feet1712.604NPHP1homozygous deletion of NPHP1F2 years++−e−u−u−−NA−−+−1915.669NPHP1homozygous c.555delA (p.Lys185Asnfs∗7)F3 years++−f−u−u−+NA−+NA−HSJ-JBTS-1TMEM67homozygous c.2132A>C (p.Asp711Ala)F3.5 years++−f−u−u−+mild ID−++−1123.415CC2D2Ac.[3544T>C];[4667A>T], p.[Trp1182Arg];[Asp1556Val]F4 years++−f−u−u−+NA−++−1673.590C5orf42homozygous c.4006C>T (p.Arg1336Trp)F12 years++−f−u−u−+mild ID−++ADHD, motor apraxia1951.677C5orf42c.[4006C>T];[7400+1G>A], p.[Arg1336Trp];[?]F1 years+++e−u−u−+NA++NAswallowing difficulties1342.488CC2D2Ac.[4667A>T];[3376G>A], p.[Asp1556Val];[Glu1126Lys]M28 years++−f−h−h−+moderate ID−++autism, ADHD1343.488M31 years++−f−h−h−+normal(university)−++−2049.708C5orf42c.[4690G>A];[6354dupT], p.[Ala1564Thr];[Ile2119Tyrfs∗2]F1.5 years+−−f−u−u++NA+++oromotor apraxia, swallowing difficulties, tongue and hypothalamic hamartomas, neonatal seizures1610.572CC2D2Ac.[4667A>T];[2181+1G>A], p.[Asp1556Val];[?]F2 years++−e−u−u−+NA−++−1310.476NPHP1hemizygous c.555delA (p.Lys185Asnfs∗7),NPHP1 deletionM18 years++−f+u−u−+mild ID+++renal failure, renal transplant, severe dysphasiaHSJ-JBTS-2TCTN1c.[342−2A>C];[898C>T], p.[?];[Arg300∗]M27 weeks+NANA−u−u+NANANANANAabnormal gyration of the frontal lobes1639.581B9D1c.[493C>T];[151T>C], p.[Gln165∗];[Ser51Pro]M22 years++−f−h−h−−normal−++congenital club feet, dysphasia1767.621CEP290c.[6401T>C];[4195−1G>A], p.[Ile2134Thr];[?]F21 weeks+NANA+ u−u+NANANANANAoccipital encephalocele, olfactory bulb agenesis, bifid uterus, renal cystsFetus2 621F20 weeks+NANA+ u−u−NANANANANArenal cysts1686.595OFD1hemizygous c.920T>A (p.Val307Asp)M15 years+++fbHypertensive retinopathy.+u−u−+severe ID+++autism, end-stage renal failure, swallowing difficulties, abdominal situs inversus1299.472C2CD3c.[5929C>T];[5227G>T], p.[Arg1977∗];[Gly1743Cys]M7 years+−−f−u−u−+NA−++−1294.472M4 years++−e−u−u−+NA+++swallowing difficulties, oromotor apraxia, gastrostomy, fundoplication1763.618CEP104homozygous c.735+2T>CF2 years+++e−u−u−+NA+++−GeneDx01CEP104c.[2572−2A>G];[496C>T], p.[?];[Arg166∗]F2.5 years++−f−u−u−+NA−−−−842629CEP104homozygous c.1328_1329insT (p.Tyr444fs∗3)M3.5 years++−−−u−+severe ID−++self-mutilationAll individuals, except for GeneDx01 and 842629, are of French Canadian ancestry. Individuals 1342.488 and 1343.288 are siblings, as are 1299.472 and 1294.47. The following abbreviations are used: ADHD, attention deficit and hyperactivity disorder; e, electroretinogram; F, female; f, fundoscopy; h, history; ID, intellectual disability; M, male; MTS, molar tooth sign; NA, not available or not applicable; OMA, oculomotor apraxia; u, ultrasound.a The genotype of the fetus was not tested but was assumed on the basis of the genotype of similarly affected sibling 1304.474 (Table S1).b Hypertensive retinopathy. Open table in a new tab All individuals, except for GeneDx01 and 842629, are of French Canadian ancestry. Individuals 1342.488 and 1343.288 are siblings, as are 1299.472 and 1294.47. The following abbreviations are used: ADHD, attention deficit and hyperactivity disorder; e, electroretinogram; F, female; f, fundoscopy; h, history; ID, intellectual disability; M, male; MTS, molar tooth sign; NA, not available or not applicable; OMA, oculomotor apraxia; u, ultrasound. In parallel, disease in three individuals was elucidated on a clinical basis. Two affected individuals were found to have mutations in NPHP1 (MIM: 607100): individual 1712.604 showed a 0.152 Mb homozygous deletion encompassing NPHP1 on chromosomal microarray in region 2q13 (110,826,262–110,978,224; UCSC Genome Browser hg19 assembly), and individual 1915.669 showed a homozygous frameshift (c.555delA [p.Lys185Asnfs∗7] [GenBank: NM_207181.2]) in NPHP1. Parents were confirmed to be heterozygous carriers of the mutations. Individual HSJ-JBTS-1 showed a homozygous mutation (c.2132A>C [p.Asp711Ala] [GenBank: NM_153704.5]) in TMEM67 (MIM: 609884). This mutation has been previously identified in a French individual with JBTS.12Baala L. Romano S. Khaddour R. Saunier S. Smith U.M. Audollent S. Ozilou C. Faivre L. Laurent N. Foliguet B. et al.The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.Am. J. Hum. Genet. 2007; 80: 186-194Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar We then performed WES in the remaining eight individuals (from seven families) in whom disease had not been explained. Genomic DNA from each sample was captured with the Agilent SureSelect 50 Mb exome capture oligonucleotide library and sequenced with paired-end 100 bp reads on an Illumina HiSeq 2000, resulting in an average of 12.8 Gb of raw sequence for each sample. Exome capture and sequencing were performed at the McGill University and Génome Québec Innovation Center (MUGQIC). Data were analyzed as previously described.13Majewski J. Schwartzentruber J.A. Caqueret A. Patry L. Marcadier J. Fryns J.P. Boycott K.M. Ste-Marie L.G. McKiernan F.E. Marik I. et al.FORGE Canada ConsortiumMutations in NOTCH2 in families with Hajdu-Cheney syndrome.Hum. Mutat. 2011; 32: 1114-1117Crossref PubMed Scopus (82) Google Scholar We aligned reads to human genome assembly hg19 by using the Burrows-Wheeler Aligner (BWA v.0.5.9) and then used Picard (v.1.48) to remove putative PCR-generated duplicate reads. The median read depth of bases in consensus coding sequence (CCDS) exons was 102× (determined with Genome Analysis Toolkit v.1.6.7).14McKenna A. Hanna M. Banks E. Sivachenko A. Cibulskis K. Kernytsky A. Garimella K. Altshuler D. Gabriel S. Daly M. DePristo M.A. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.Genome Res. 2010; 20: 1297-1303Crossref PubMed Scopus (14763) Google Scholar On average, 91% (±3%) of bases in CCDS exons were covered by at least 20 reads. We used SAMtools (v.0.1.17) mpileup and bcftools to call sequence variants and required at least three variant reads and ≥20% variant reads for each called position, as well as Phred-like quality scores of at least 20 for single-nucleotide variants (SNVs) and at least 50 for small insertions or deletions (indels). We used ANNOVAR15Wang K. Li M. Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res. 2010; 38: e164Crossref PubMed Scopus (7866) Google Scholar and custom scripts to annotate variants according to the type of mutation, occurrence in dbSNP, 1000 Genomes minor allele frequencies, and NHLBI Exome Sequencing Project (ESP) Exome Variant Server (EVS) minor allele frequencies. To identify potentially pathogenic variants, we filtered out (1) synonymous variants or intronic variants other than those affecting the consensus splice sites, (2) variants seen in more than 5 of 1,128 exomes (sequenced at the MUGQIC) from individuals with rare, monogenic diseases unrelated to JBTS, and (3) variants with a minor allele frequency greater than 0.5% in either the 1000 Genomes or the NHLBI ESP exome datasets. We first looked at the exome datasets for rare variants in the 23 genes already associated with JBTS (INPP5E [MIM: 613037], TMEM216 [MIM: 613277], AHI1 [MIM: 608894], NPHP1, CEP290 [MIM: 610142], TMEM67, RPGRIP1L [MIM: 610937], ARL13B [MIM: 608922], CC2D2A, CXORF5 [OFD1; MIM: 300170], KIF7 [MIM: 611254], TCTN1 [MIM: 609863], TCTN2 [MIM: 613885], TMEM237 [MIM: 614424], CEP41 [MIM: 610523], TMEM138 [MIM: 614459], C5orf42, TMEM231, TCTN3 [MIM: 613847], ZNF423 [MIM: 604557], CSPP1 [MIM: 611654], B9D1 [MIM: 614209], KIAA0586 [MIM: 610178], MKS1 [MIM: 609883], B9D2 [MIM: 611951] and C2CD3 [MIM: 615944]9Srour M. Schwartzentruber J. Hamdan F.F. Ospina L.H. Patry L. Labuda D. Massicotte C. Dobrzeniecka S. Capo-Chichi J.M. Papillon-Cavanagh S. et al.FORGE Canada ConsortiumMutations in C5ORF42 cause Joubert syndrome in the French Canadian population.Am. J. Hum. Genet. 2012; 90: 693-700Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 10Srour M. Hamdan F.F. Schwartzentruber J.A. Patry L. Ospina L.H. Shevell M.I. Désilets V. Dobrzeniecka S. Mathonnet G. Lemyre E. et al.FORGE Canada ConsortiumMutations in TMEM231 cause Joubert syndrome in French Canadians.J. Med. Genet. 2012; 49: 636-641Crossref PubMed Scopus (58) Google Scholar, 12Baala L. Romano S. Khaddour R. Saunier S. Smith U.M. Audollent S. Ozilou C. Faivre L. Laurent N. Foliguet B. et al.The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.Am. J. Hum. Genet. 2007; 80: 186-194Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 16Bielas S.L. Silhavy J.L. Brancati F. Kisseleva M.V. Al-Gazali L. Sztriha L. Bayoumi R.A. Zaki M.S. Abdel-Aleem A. Rosti R.O. et al.Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies.Nat. Genet. 2009; 41: 1032-1036Crossref PubMed Scopus (309) Google Scholar, 17Edvardson S. Shaag A. Zenvirt S. Erlich Y. Hannon G.J. Shanske A.L. Gomori J.M. Ekstein J. Elpeleg O. Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation.Am. J. Hum. Genet. 2010; 86: 93-97Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 18Valente E.M. Logan C.V. Mougou-Zerelli S. Lee J.H. Silhavy J.L. Brancati F. Iannicelli M. Travaglini L. Romani S. Illi B. et al.Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.Nat. Genet. 2010; 42: 619-625Crossref PubMed Scopus (215) Google Scholar, 19Dixon-Salazar T. Silhavy J.L. Marsh S.E. Louie C.M. Scott L.C. Gururaj A. Al-Gazali L. Al-Tawari A.A. Kayserili H. Sztriha L. Gleeson J.G. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria.Am. J. Hum. Genet. 2004; 75: 979-987Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 20Parisi M.A. Bennett C.L. Eckert M.L. Dobyns W.B. Gleeson J.G. Shaw D.W. McDonald R. Eddy A. Chance P.F. Glass I.A. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome.Am. J. Hum. Genet. 2004; 75: 82-91Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 21Valente E.M. Silhavy J.L. Brancati F. Barrano G. Krishnaswami S.R. Castori M. Lancaster M.A. Boltshauser E. Boccone L. Al-Gazali L. et al.International Joubert Syndrome Related Disorders Study GroupMutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome.Nat. Genet. 2006; 38: 623-625Crossref PubMed Scopus (316) Google Scholar, 22Sayer J.A. Otto E.A. O'Toole J.F. Nurnberg G. Kennedy M.A. Becker C. Hennies H.C. Helou J. Attanasio M. Fausett B.V. et al.The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.Nat. Genet. 2006; 38: 674-681Crossref PubMed Scopus (451) Google Scholar, 23Arts H.H. Doherty D. van Beersum S.E. Parisi M.A. Letteboer S.J. Gorden N.T. Peters T.A. Märker T. Voesenek K. Kartono A. et al.Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.Nat. Genet. 2007; 39: 882-888Crossref PubMed Scopus (256) Google Scholar, 24Delous M. Baala L. Salomon R. Laclef C. Vierkotten J. Tory K. Golzio C. Lacoste T. Besse L. Ozilou C. et al.The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.Nat. Genet. 2007; 39: 875-881Crossref PubMed Scopus (366) Google Scholar, 25Cantagrel V. Silhavy J.L. Bielas S.L. Swistun D. Marsh S.E. Bertrand J.Y. Audollent S. Attié-Bitach T. Holden K.R. Dobyns W.B. et al.International Joubert Syndrome Related Disorders Study GroupMutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome.Am. J. Hum. Genet. 2008; 83: 170-179Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 26Noor A. Windpassinger C. Patel M. Stachowiak B. Mikhailov A. Azam M. Irfan M. Siddiqui Z.K. Naeem F. Paterson A.D. et al.CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa.Am. J. Hum. Genet. 2008; 82: 1011-1018Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 27Gorden N.T. Arts H.H. Parisi M.A. Coene K.L. Letteboer S.J. van Beersum S.E. Mans D.A. Hikida A. Eckert M. Knutzen D. et al.CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290.Am. J. Hum. Genet. 2008; 83: 559-571Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 28Dafinger C. Liebau M.C. Elsayed S.M. Hellenbroich Y. Boltshauser E. Korenke G.C. Fabretti F. Janecke A.R. Ebermann I. Nürnberg G. et al.Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics.J. Clin. Invest. 2011; 121: 2662-2667Crossref PubMed Scopus (147) Google Scholar, 29Sang L. Miller J.J. Corbit K.C. Giles R.H. Brauer M.J. Otto E.A. Baye L.M. Wen X. Scales S.J. Kwong M. et al.Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways.Cell. 2011; 145: 513-528Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar, 30Huang L. Szymanska K. Jensen V.L. Janecke A.R. Innes A.M. Davis E.E. Frosk P. Li C. Willer J.R. Chodirker B.N. et al.TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone.Am. J. Hum. Genet. 2011; 89: 713-730Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 31Lee J.E. Silhavy J.L. Zaki M.S. Schroth J. Bielas S.L. Marsh S.E. Olvera J. Brancati F. Iannicelli M. Ikegami K. et al.CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium.Nat. Genet. 2012; 44: 193-199Crossref PubMed Scopus (129) Google Scholar, 32Lee J.H. Silhavy J.L. Lee J.E. Al-Gazali L. Thomas S. Davis E.E. Bielas S.L. Hill K.J. Iannicelli M. Brancati F. et al.Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.Science. 2012; 335: 966-969Crossref PubMed Scopus (62) Google Scholar, 33Tuz K. Bachmann-Gagescu R. O'Day D.R. Hua K. Isabella C.R. Phelps I.G. Stolarski A.E. O'Roak B.J. Dempsey J.C. Lourenco C. et al.Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy.Am. J. Hum. Genet. 2014; 94: 62-72Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 34Shaheen R. Shamseldin H.E. Loucks C.M. Seidahmed M.Z. Ansari S. Ibrahim Khalil M. Al-Yacoub N. Davis E.E. Mola N.A. Szymanska K. et al.Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans.Am. J. Hum. Genet. 2014; 94: 73-79Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 35Akizu N. Silhavy J.L. Rosti R.O. Scott E. Fenstermaker A.G. Schroth J. Zaki M.S. Sanchez H. Gupta N. Kabra M. et al.Mutations in CSPP1 lead to classical Joubert syndrome.Am. J. Hum. Genet. 2014; 94: 80-86Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 36Thauvin-Robinet C. Lee J.S. Lopez E. Herranz-Pérez V. Shida T. Franco B. Jego L. Ye F. Pasquier L. Loget P. et al.The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.Nat. Genet. 2014; 46: 905-911Crossref PubMed Scopus (88) Google Scholar, 37Romani M. Micalizzi A. Kraoua I. Dotti M.T. Cavallin M. Sztriha L. Ruta R. Mancini F. Mazza T. Castellana S. et al.Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome.Orphanet J. Rare Dis. 2014; 9: 72Crossref PubMed Scopus (44) Google Scholar, 38Roosing S. Hofree M. Kim S. Scott E. Copeland B. Romani M. Silhavy J.L. Rosti R.O. Schroth J. Mazza T. et al.Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome.eLife. 2015; 4: e06602Crossref Scopus (53) Google Scholar, 39Bachmann-Gagescu R. Phelps I.G. Dempsey J.C. Sharma V.A. Ishak G.E. Boyle E.A. Wilson M. Marques Lourenço C. Arslan M. Shendure J. Doherty D. University of Washington Center for Mendelian GenomicsKIAA0586 is Mutated in Joubert Syndrome.Hum. Mutat. 2015; 36: 831-835Crossref PubMed Scopus (50) Google Scholar), as well as the JBTS candidate gene TTC21B (MIM: 612014).40Davis E.E. Zhang Q. Liu Q. Diplas B.H. Davey L.M. Hartley J. Stoetzel C. Szymanska K. Ramaswami G. Logan C.V. et al.NISC Comparative Sequencing ProgramTTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.Nat. Genet. 2011; 43: 189-196Crossref PubMed Scopus (266) Google Scholar In one individual (1310.476), we identified homozygous frameshift mutation c.555delA (p.Lys185Asnfs∗7) (GenBank: NM_207181.2) in NPHP1; this is the same mutation that was identified in individual 1915.669. However, array genomic hybridization showed that this individual is also heterozygous for a 116 kb deletion encompassing NPHP1 in chromosomal region 2q13 (110,862,369–110,978,000; hg19 genome assembly). This deletion is similar to that found in subject 1712.604. The mother is heterozygous for the frameshift mutation, but paternal DNA was unavailable. It thus appears that the proband
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