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Human Genetics

, Volume 120, Issue 3, pp 396–409 | Cite as

Clinical and molecular genetic features of ARC syndrome

  • Paul GissenEmail author
  • Louise Tee
  • Colin A. Johnson
  • Emmanuelle Genin
  • Almuth Caliebe
  • David Chitayat
  • Carol Clericuzio
  • Jonas Denecke
  • Maja Di Rocco
  • Björn Fischler
  • David FitzPatrick
  • Angeles García-Cazorla
  • Delphine Guyot
  • Sebastien Jacquemont
  • Sibylle Koletzko
  • Bruno Leheup
  • Hanna Mandel
  • Maria Teresa Vieira Sanseverino
  • Roderick H. J. Houwen
  • Patrick J. McKiernan
  • Deirdre A. Kelly
  • Eamonn R. Maher
Original Investigation

Abstract

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900–1,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.

Keywords

Lamellar Body Recent Common Ancestor Renal Tubular Acidosis Nephrogenic Diabetes Insipidus Oligohydramnios 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors would like to thank all the families for their support for this research. This work has been supported by WellChild and CLIMB children’s charities. PG is a GSK Clinician Scientist Fellow. We are grateful to Dr Caillaux for collecting patient information.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Paul Gissen
    • 1
    • 2
    Email author
  • Louise Tee
    • 1
  • Colin A. Johnson
    • 1
  • Emmanuelle Genin
    • 3
  • Almuth Caliebe
    • 4
  • David Chitayat
    • 5
  • Carol Clericuzio
    • 6
  • Jonas Denecke
    • 7
  • Maja Di Rocco
    • 8
  • Björn Fischler
    • 9
  • David FitzPatrick
    • 10
  • Angeles García-Cazorla
    • 11
  • Delphine Guyot
    • 12
  • Sebastien Jacquemont
    • 13
  • Sibylle Koletzko
    • 14
  • Bruno Leheup
    • 15
  • Hanna Mandel
    • 16
  • Maria Teresa Vieira Sanseverino
    • 17
  • Roderick H. J. Houwen
    • 18
  • Patrick J. McKiernan
    • 19
  • Deirdre A. Kelly
    • 19
  • Eamonn R. Maher
    • 1
  1. 1.Section of Medical and Molecular Genetics, Norton Court, Birmingham Women’s HospitalUniversity of BirminghamEdgbaston, BirminghamUK
  2. 2.Inherited Metabolic Diseases UnitBirmingham Children’s HospitalBirminghamUK
  3. 3.Génétique Epidémiologique et Structure des Populations HumainesINSERM U535ParisFrance
  4. 4.Institut fuer HumangenetikUniversitaetsklinikum Schleswig-Holstein Campus Kiel SchwanenwegKielGermany
  5. 5.Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
  6. 6.Division of Genetics/Dysmorphology, Department of PediatricsUniversity of New Mexico AlbuquerqueAlbuquerqueUSA
  7. 7.Department of PaediatricsUniversity Hospital of MuensterMuensterGermany
  8. 8.II Pediatric UnitGaslini InstituteGenoaItaly
  9. 9.Children’s HospitalKarolinska University HospitalHuddingeSweden
  10. 10.MRC Human Genetics UnitEdinburghUK
  11. 11.Hospital Sant Joan de DéuBarcelonaSpain
  12. 12.NeonatologyPapeeteTahiti
  13. 13.Service de Genetique CHU de NantesNantesFrance
  14. 14.Department of Pediatric Gastroenterology, Dr. v. Haunersches KinderhospitalLudwig-Maximilians-University MunichMunichGermany
  15. 15.Genetique CliniqueHôpital d’Enfants et Faculte de Medicine de NancyNancyFrance
  16. 16.Metabolic unit, Meyer Children’s HospitalRambam Medical Center, Technion Faculty of MedicineHaifaIsrael
  17. 17.Servicio de Genetica MedicaHospital de Clinicas de Porto AllegroPorto AllegroBrazil
  18. 18.Department of Paediatric GastroenterologyUniversity Medical CentreUtrechtThe Netherlands
  19. 19.The Liver UnitBirmingham Children’s HospitalBirminghamUK

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