Downloaded from jmg.bmj.com on January 18, 2012 - Published by group.bmj.com Genotype-phenotype correlations ORIGINAL ARTICLE Genotypeephenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures Ruxandra Bachmann-Gagescu,1 Gisele E Ishak,2 Jennifer C Dempsey,1 Jonathan Adkins,1 Diana O’Day,1 Ian G Phelps,1 Meral Gunay-Aygun,3 Antonie D Kline,4 Krzysztof Szczaluba,5 Loreto Martorell,6 Abdulrahman Alswaid,7 Shatha Alrasheed,7 Shashidhar Pai,8 Louise Izatt,9 Anne Ronan,10 Melissa A Parisi,11 Heather Mefford,1 Ian Glass,1 Dan Doherty1,12 For numbered affiliations see ABSTRACT junction.1 2 Patients with JS manifest hypotonia, end of article. Background Joubert syndrome (JS) is a ciliopathy ataxia, developmental delay, abnormal eye move- characterised by a distinctive brain malformation (the ments and abnormal respiratory control.34In Correspondence to Dr Dan Doherty, Associate ‘molar tooth sign’), developmental delay, abnormal eye addition to the core neurological features, subsets Professor, Divisions of Genetic movements and abnormal breathing pattern. Retinal of patients with JS also display abnormalities in Medicine and Developmental dystrophy, cystic kidney disease, liver fibrosis and other organ systems, including retinal dystrophy, Medicine, University of polydactyly are variably present, resulting in significant chorioretinal coloboma, cystic kidney disease, liver Washington, Box 356320, phenotypic heterogeneity and overlap with other fi 5 RR-249, 1959 NE Pacific Street, brosis and polydactyly. Given this pleiotropic Seattle, WA 98195-6320, USA; ciliopathies. JS is also genetically heterogeneous, phenotypic presentation, substantial overlap with [email protected] resulting from mutations in 13 genes. These factors other disorders is observed, including Meckel, render clinical/molecular diagnosis and management SenioreLøken and BardeteBiedl syndromes, as well Received 5 October 2011 challenging. CC2D2A mutations are a relatively common as Leber congenital amaurosis and isolated neph- Revised 7 December 2011 fi Accepted 8 December 2011 cause of JS and also cause Meckel syndrome. The ronophthisis. These disorders have been classi ed as clinical consequences of CC2D2A mutations in patients ciliopathies, since their causative genes all encode with JS have been incompletely reported. proteins involved in function of primary cilia, Methods Subjects with JS from 209 families were ubiquitous organelles essential in mechanical, evaluated to identify mutations in CC2D2A. Clinical and chemical and light transduction, as well as specific imaging features in subjects with CC2D2A mutations signalling pathways.6 were compared with those in subjects without CC2D2A JS, like most ciliopathies, is characterised by mutations and reports in the literature. significant genetic heterogeneity, since 13 causative Results 10 novel CC2D2A mutations in 20 subjects genes have been identified to date: AHI1, ARL13B, were identified; a summary is provided of all published CC2D2A, CEP290, INPP5E, KIF7, NPHP1, OFD1, CC2D2A mutations. Subjects with CC2D2A-related JS RPGRIP1L, TCTN1, TCTN2, TMEM67 (MKS3) and e were more likely to have ventriculomegaly (p<0.0001) TMEM216.7 20 These account individually for up and seizures (p¼0.024) than subjects without CC2D2A to 10% and collectively for w50% of patients with mutations. No mutation-specific genotypeephenotype JS, indicating that many genes are yet to be iden- correlations could be identified, but the findings confirm tified. In addition to the phenotypic overlap the observation that mutations that cause CC2D2A- between ciliopathies, significant genetic overlap is related JS are predicted to be less deleterious than observed, particularly between JS and Meckel mutations that cause CC2D2A-related Meckel syndrome. syndrome (MKS), which is characterised by ence- Missense variants in the coiled-coil and C2 domains, as phalocele, cystic/dysplastic kidney disease, ductal well as the C-terminal region, identify these regions as plate malformation of the liver, polydactyly and, important for the biological mechanisms underlying JS. typically, fetal or neonatal lethality.21 Of the 13 Conclusions CC2D2A testing should be prioritised in genes responsible for JS, six also cause MKS patients with JS and ventriculomegaly and/or seizures. (CC2D2A,21 CEP290,22 RPGRIP1L,23 TCTN2,24 Patients with CC2D2A-related JS should be monitored TMEM6712 and TMEM21614), leading to the for hydrocephalus and seizures. concept that some forms of JS and MKS represent mild and severe presentations of the same biological disorder. Consistent with this concept, patients with MKS more often have truncating mutations INTRODUCTION in CC2D2A, and patients with JS more often have Joubert syndrome (JS) is a recessive disorder char- at least one missense mutation.21 Of note, no other acterised by cerebellar vermis hypoplasia, thick- genotypeephenotype correlations have been ened, mis-oriented superior cerebellar peduncles reported in patients with CC2D2A mutations. and an abnormally deep interpeduncular fossa CC2D2A mutations represent a major cause of resulting in the pathognomonic ‘molar tooth sign’ both JS and MKS since they are responsible for (MTS) on axial imaging of the mid-hind brain w10% of each disorder.4 721CC2D2A encodes 126 J Med Genet 2012;49:126e137. doi:10.1136/jmedgenet-2011-100552 J Med Genet Table 1 Summary of phenotypic information in subjects with CC2D2A mutations, single heterozygous variants, and variants of unclear functional significance identified in this cohort CC2D2A CC2D2A P2 score, Ctrl allele % Age Identification no mutations, cDNA mutations, protein Div/Var EU/AA (years) MTS EC DD/ ID Sz A/T Nyst, OMA RD Kidney Liver PD Other 2012; CC2D2A mutations and phenotypic summary UW36-37 c.3364C>T homM,P p.P1122S 1.0/0.99 0 8 + e + e + eeeee 49 UW41-37 c.2848C>T homM,P p.R950X hom 04+e + ee ++eeeCortic vis imp :126 UW46-1 N c.3289 delGP p.V1097Ffs*1 ND 19 + e + ee + ee e e e c.4289T>CM p.V1430A 1.0/0.86 0 137. doi:10.1136/jmedgenet-2011-100552 UW46-2 N c.3289 delGP p.V1097Ffs*1 ND 22 + e + ee + ee e eScoliosis c.4289T>CM p.V1430A 1.0/0.86 0 UW47-37 c.3055C>TM p.R1019X 0 19 + e ++++ ee e e Downloaded from c.3288G>CP p.Q1096H 0.64/0.12 0 UW48-37 c.3364C>T homM,P p.P1122S 1.0/0.99 0 7* + e + e + + + + (ESRF/TXPT) eeScoliosis UW49-330 c.3289 delGM p.V1097Ffs*1 ND 24 + e ++++ e + + (TXPT) e Coloboma c.4582C>TP p.R1528C 1.0/0.97 0 COACH UW50-37 c.4582C>T homM,P p.R1528C hom 1.0/0.97 0 12 + e + ee e ee e eSibling w/ EC UW50-67 c.4582C>T homM,P p.R1528C hom 1.0/0.97 0 8 + + + ee e ee e e jmg.bmj.com UW67-330 c.3145C>T p.R1049X 0 7+e + e ++ e + + fibrosis e c.3347C>T p.T1116M 1.0/0.97 0.03/0 UW75-3N c.1676T>CM p.L559P 1.0/0.99 0 18 + e + e ++ ee e e c.3892_3 del(GT)P p.V1298Ffs*16 ND N P UW76-3 c.3134T>C p.V1045A 0.98/0.6 0 3+e + e + eeeee onJanuary18,2012-Publishedby c.3850C>TM p.R1284C 1.0/1.0 0 UW78-3 N c.3055C>TM p.R1019X 0 1+e + ee + e ND ND e c.4667A>TP p.D1556V 0.98/0.74 0.03/0.03 UW79-3 N c.(1263_4InsGGCATGT p.S423Gfs*19 ND 26 + e + e ++ ee e e TTTGGC; c.1268G>A)P p.V1151A 1.0/0.39 0 c.3452T>CM 0 UW79-4 N c.(1263_4InsGGCATGT p.S423Gfs*19 ND 24 + e ++++ ee e e TTTGGC; 1268G>A)P p.V1151A 1.0/0.39 0 c.3452T>CM 0 UW80-3 c.3289 delG p.V1097Ffs*1 ND 1+e +++ND e + (cysts) ND e c.3347C>T p.T1116M 1.0/0.97 0.03/0 UW81-3 N c.4179+1delG p.E1393Efs*1 ND 11 + e + ee + ee e e c.4667A>T p.D1556V 0.98/0.74 0.03/0.03 N P Genotype-phenotype correlations UW82-3 c.3976-3C>A p.IVS30(-3) 0 8+e ++++ ee e e group.bmj.com c.4844_4847delCTCTM p.S1615Lfs*15 ND UW102-3 N c.3772-1G>TP p.IVS29(-1) 0 4+e + e + eeeeND Cortic vis imp c.4582C>TM p.R1528C 1.0/0.97 0 UW103-3 N c.3289delG p.V1097Ffs*1 ND 3+e + ee e ee e eSibling w/ MKS c.3851G>A p.R1284H 1.0/1.0 0 n¼20 subjects from 17 families 20/20 1/20 20/20 5/20 12/20 13/19 2/20 4/19 2/18 0/19 Single heterozygous changes and variants of unclear significance UW06-3 N c.351T>G p.S117R 0.84/0.36 0.2/0.07 14 + e + +F + + + + (ESRF, TXPT) eeVPI UW54-3 c.1519A>G p.K507E 0.99/0.70 0.8/0.08 10 + e + e ++ e + (ESRF, TXPT) + (TXPT) e Coloboma TMEM67 UW88-3 N c.3989G>A p.R1330Q 1.0/0.94 0 10 + e + ee + ee e e UW88-4 N c.3989G>A p.R1330Q 1.0/0.94 0 13 + e + ee e ee e e UW106-3 c.4667A>T p.D1556V 0.98/0.74 0.03/0.03 4 + e + ee e ee e e 127 Continued 128 Table 1 Continued Genotype-phenotype correlations CC2D2A CC2D2A P2 score, Ctrl allele % Age Identification no mutations, cDNA mutations, protein Div/Var EU/AA (years) MTS EC DD/ ID Sz A/T Nyst, OMA RD Kidney Liver PD Other UW107-3 c.1519A>G p.K507E 0.99/0.70 0.8/0.08 2 + e + ee + ee e eTwins UW107-4 c.1519A>G p.K507E 0.99/0.70 0.8/0.08 2 + e + ee + ee e e UW108-3 N c.3055C>T p.R1019X 01NDe + e ND + + ND ND ND Sibling with MTS UW109-3 ND c.3347C>T p.T1116M 1.0/0.97 0.03/0 2 + e + ee +NDNDNDe ND UW110-3N c.2101C>G p.L701V 0.05/0.02 0 <1* + e + e + ND ND + ND + UW111-3N c.351T>G p.S117R 0.84/0.36 0.2/0.07 2 + e + e ++ ee ND + Coloboma TCTN2 Downloaded from UW77-3 N c.1978G>A p.V660I 0.004/0.005 0.01/2.4 13 + e ++++ ee e e c.2050T>A p.L684I 0.003/0.004 0/0.5 UW104-3 N c.685_687delGAA p.E229del 3/ND <1+e + e +NDNDeeeDextro-cardia c.1017+1G>A p.IVS11(+1) 0/0.03 UW105-3 c.685_687delGAA p.E229del 3/ND 6+e + +NN + + ee e e c.4667A>T p.D1556V 0.98/0.74 0.03/0.03 Nonsense or frameshift mutations are in bold.