Fryssira, H.

Hoffer, J.

Konstantinidou, A.

Ropers, H.

Tzschach, A.

MPG.PuRe

Novel WDR35 mutations in patients with cranioectodermal dysplasia (Sensenbrenner syndrome)

Clin Genet 2013: 83: 92–95Printed in Singapore. All rights reserved© 2012 John Wiley & Sons A/S.Published by Blackwell Publishing LtdCLINICAL GENETICSdoi: 10.1111/j.1399-0004.2012.01880.xLetter to the EditorNovel WDR35 mutations in patients withcranioectodermal dysplasia (Sensenbrennersyndrome)To the Editor :Cranioectodermal dysplasia (CED, Sensenbrennersyndrome, OMIM 218330) is a rare autosomal recessiveciliopathy characterized by craniosynostosis, dolicho-cephaly, narrow chest, sparse hair, epicanthal folds,microdontia, brachydactyly, joint laxity, ophthalmolog-ical problems (nystagmus, myopia, and retinal dystro-phy), nephronophthisis and cystic liver disease. CEDis a genetically heterogeneous disorder, and mutationshave been reported in IFT122, WDR35, C14orf179 andWDR19 (1–5). The products of all four genes are partof the intraflagellar transport complex A (IFT-A), amajor complex for dynein-driven retrograde flagellartransport in cilia (6).Here, we report on the detection of novel WDR35mutations in two unrelated CED patients.The clinical features of both patients are listed inTable 1.Patient 1 was born to remotely consanguineousGreek parents. She had short stature, short limbs,brachydactyly, dolichocephaly, frontal bossing, ptosis,micrognathia, high palate, low-set ears, fine sparsehair and dysplastic nails (Fig. 1a,b). Craniosynostosiswas surgically corrected at the age of 2 months.Psychomotor development was retarded (walking atage 16 months and talking at age 2 years). X-rayexaminations revealed narrow thorax with dysplasticribs, bowed femora with abnormal epiphyses, shortulnae, brachydactyly, short metacarpals, short andbowed tibiae, short metatarsals and a triphalangealhallux (Fig. 1c–e). Chronic renal failure was noticedin the first year of life. A brain magnetic resonanceimaging (MRI) scan at the age of 2 years revealed alarge cisterna magna and slight cortical atrophy.Patient 2 was born to non-consanguineous parents.She had dolichocephaly, craniosynostosis, bilateralnystagmus, short limbs, brachydactyly, fine sparsehair, frontal bossing, micrognathia, low-set ears andwidely spaced teeth (Fig. 1f,g). Renal dysfunction wasnoted at the age of 14 months. She received a kidneytransplant at the age of 5 years. Hepatic cystic diseasewas detected at the age of 4 years. Psychomotordevelopment was delayed (walking at the age of 3 yearsand no words at the age of 5 years). A brain MRI scanat the age of 4 years revealed no abnormalities.In patient 1, analysis of the 28 coding exons andflanking intronic regions of WDR35 revealed a homozy-gous missense mutation (c.A2912G; p.Tyr971Cys) inexon 25 (Fig. S1a). Tyrosine at position 971 is a highlyconserved amino acid with a PhyloP score of 0.996.Both parents were heterozygous carriers of the muta-tion.In patient 2, we detected a heterozygous missensemutation (c.T504A; p.Ser168Arg) in exon 6 whichwas inherited from the father and a heterozygous non-sense mutation in exon 18 (c.T1922G; p.Leu641X)which was inherited from the mother (Fig. S1b,c).Serine at position 168 is a highly conserved aminoacid with a PhyloP score of 0.407. We excluded thepresence of these mutations in 300 control chromo-somes.To date, WDR35 mutations have only been reportedin two other CED patients (2). Mutations in WDR35have recently also been identified in fetuses with shortrib-polydactyly syndrome (SRP) (5, 7). SRP affects thesame organs as CED, but with much greater severity(Table 1). The milder phenotype in CED might bedue to some residual function of the CED-associatedWDR35 alleles. Functional studies will be neededto elucidate the biological consequences of differentWDR35 mutations.Clinically, the two patients reported here sharenumerous features with those reported by Gilissenet al. (Table 1). Major clinical differences are devel-opmental delay and the renal problems which werenot reported in the Gilissen et al. patients. Additionalpatients with WDR35 mutations need to be identified toget more insight into the clinical variability of WDR35 -associated CED and to establish comprehensive geno-type–phenotype correlations.In conclusion, the patients reported here provideadditional evidence that mutations in WDR35 areassociated with CED, and they broaden the spectrumof clinical features. This will eventually also contributeto a better understanding of the function of the WDR35gene product and its role in intraflagellar transport.AcknowledgementsWe thank the parents of the patients for their support.92Letter to the EditorTable1.ClinicaldetailsofpatientsandfetuseswithWDR35mutationsPatientGilissenetal.,patient1Gilissenetal.,patient2Presentpatient1Presentpatient2Milletal.,familyofKannuetal.therein,fetus1Milletal.,familyofKannuetal.therein,fetus2Milletal.,sporadicfetusClinicaldiagnosisCEDCEDCEDCEDSRPSRPSRPSexMaleMaleFemaleFemaleMaleMaleN.A.Mutation(DNA)c.1877A>G;c.25-2A>Gc.2891delT;c.2623G>Ac.A2912Gc.T504A;c.T1922GGenomicdeletionof2847bpGenomicdeletionof2847bpc.1633C>T;c.781T>CMutation(Protein)p.E626G;p.I9TfsX7p.P964LfsX15;p.A875Tp.Y971Cp.S168R;p.L641XDeletionofexon5Deletionofexon5p.R545X;p.W261RAgeatexamination7years9years8years5yearsPregnancyterminatedat15weeksofgestationPregnancyterminatedat12weeksofgestationPregnancyterminatedat13weeksofgestationHeight<3rdcentile<3rdcentile<3rdcentile<3rdcentileN.A.N.A.N.A.Dolichocephaly++++N.A.N.A.N.A.CraniosynostosisSurgicallycorrectedatage1yearSurgicallycorrectedatage1yearSurgicallycorrectedatage2monthsSurgicallycorrectedatage1yearN.A.N.A.N.A.Frontalbossing++++N.A.N.A.N.A.Fine,sparsehair−+++N.A.N.A.N.A.Narrowpalpebralfissure++−+N.A.N.A.N.A.Hypermetropia+−−−N.A.N.A.N.A.Nystagmus−−−+N.A.N.A.N.A.PtosisUnilateral−+−N.A.N.A.N.A.Hypertelorism++++N.A.N.A.N.A.Strabismus+−−+N.A.N.A.N.A.Low-setears++++N.A.N.A.N.A.Simpleears+++−N.A.N.A.N.A.Evertedlowerlip+++−N.A.N.A.N.A.Micrognathia+−++N.A.N.A.N.A.Widelyspacedteeth++++N.A.N.A.N.A.Hypoplasticteeth++++N.A.N.A.N.A.Fusedteeth++−−N.A.N.A.N.A.Shortneck++++N.A.N.A.N.A.Narrowthorax/shortribs+++++++Pectusexcavatum++++N.A.N.A.N.A.Shortlimbs++++++ExtrememicromeliaBrachydactyly++++N.A.N.A.N.A.93Letter to the EditorTable1.ContinuedPatientGilissenetal.,patient1Gilissenetal.,patient2Presentpatient1Presentpatient2Milletal.,familyofKannuetal.therein,fetus1Milletal.,familyofKannuetal.therein,fetus2Milletal.,sporadicfetusWebbingoffingers++++N.A.N.A.N.A.Postaxialpolydactyly+−−−+++Triphalangealhallux−−+−N.A.N.A.N.A.Restrictedflexionoffingers+−−−N.A.N.A.N.A.Toesyndactyly+−−−N.A.N.A.N.A.Bilateralsandalgap−+−−N.A.N.A.N.A.Jointlaxity++++N.A.N.A.N.A.Inguinalhernia++−−N.A.N.A.N.A.Renaldisease−−+++N.A.N.A.Hepaticdisease−−−+N.A.N.A.N.A.Recurrentlunginfections+−+−FetusFetusFetusIntelligenceNormalNormalDevelopmentaldelayDevelopmentaldelayFetusFetusFetusBrainmalformation−−Slight cerebralatrophy−N.A.N.A.N.A.BehaviourHappy,friendlyHappy,friendlyHappy,friendlyHappy,friendlyFetusFetusFetusAdditionalfeatures−−−−Hypospadias,bowingoflimbsBowingoflimbs,cleftpalate,malrotationofthegut‘Facialabnormalities’(notspecified)CED,cranioectodermaldysplasia;N.A.,notavailable;SRP,shortrib-polydactylysyndrome.94Letter to the Editor(a) (f)(b) (d)(c)(e)(g)Fig. 1. Patient 1 at age 2 years. Note disproportionate short stature, frontal bossing, sparse hair, micrognathia and low-set ears (a, b). X-rays showtriphalangeal hallux (c), bowed femora and tibiae (d), and brachydactyly (e). Patient 2 at age 13 months (f) and 5 years (g). Note dolichocephaly,short limbs, sparse hair and low-set ears.Supporting InformationThe following Supporting information is available for this article:Fig.SI.Chromatograms showing the WDR35 missense mutationc.A2912G (p.Tyr971Cys) in the homozygous state in patient 1and in the heterozygous state in the parents (a); the heterozygousmissense mutation c.T504A (p.Ser168Arg) in patient 2 and hermother (b), and the heterozygous nonsense mutation c.T1922G(p.Leu641X) in patient 2 and her father (c).Additional Supporting information may be found in the onlineversion of this article.JL HofferaH FryssirabAE KonstantinidoucH -H RopersaA Tzschacha ,daDepartment of Human Molecular Genetics, Max PlanckInstitute for Molecular Genetics, Berlin, Germany,bAghia Sophia Children’s Hospital andcDepartment of Pathology, University of Athens MedicalSchool, Athens, Greece, anddInstitute of Human Genetics, University of Tuebingen,Tuebingen, GermanyReferences1. Walczak-Sztulpa J, Eggenschwiler J, Osborn D et al. CranioectodermalDysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutationsin the IFT122 gene. Am J Hum Genet 2010: 86: 949–956.2. Gilissen C, Arts H, Hoischen A et al. Exome sequencing identifiesWDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet2010: 87: 418–423.3. Arts H, Bongers E, Mans D et al. C14ORF179 encoding IFT43 ismutated in Sensenbrenner syndrome. J Med Genet 2011: 48: 390–395.4. Bredrup C, Saunier S, Oud M et al. Ciliopathies with skeletal anomaliesand renal insufficiency due to mutations in the IFT-A gene WDR19. AmJ Hum Genet 2011: 89: 634–643.5. Mill P, Lockhart P, Fitzpatrick E et al. Human and mouse mutationsin WDR35 cause short-rib polydactyly syndromes due to abnormalciliogenesis. Am J Hum Genet 2011: 88: 508–515.6. Ishikawa H, Marshall W. Ciliogenesis: building the cell’s antenna. NatRev Mol Cell Biol 2011: 12: 222–234.7. Kannu P, McFarlane J, Savarirayan R et al. An unclassifiable shortrib-polydactyly syndrome with acromesomelic hypomineralization andcampomelia in siblings. Am J Med Genet A 2007: 143A: 2607–2611.Correspondence:Andreas Tzschach, MDInstitute of Human GeneticsUniversity of TuebingenCalwerstr. 772076 TuebingenGermanyTel.: +49 7071 2972279Fax: +49 7071 295171e-mail: andreas.tzschach@med.uni-tuebingen.de95

Novel WDR35 mutations in patients with cranioectodermal dysplasia (Sensenbrenner syndrome)

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