Human Genetics

, Volume 132, Issue 8, pp 885–898

Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome

  • J. C. Czeschik
  • C. Voigt
  • Y. Alanay
  • B. Albrecht
  • S. Avci
  • D. FitzPatrick
  • D. R. Goudie
  • U. Hehr
  • A. J. Hoogeboom
  • H. Kayserili
  • P. O. Simsek-Kiper
  • L. Klein-Hitpass
  • A. Kuechler
  • V. López-González
  • M. Martin
  • S. Rahmann
  • B. Schweiger
  • M. Splitt
  • B. Wollnik
  • H. -J. Lüdecke
  • M. Zeschnigk
  • D. Wieczorek
Original Investigation

DOI: 10.1007/s00439-013-1295-2

Cite this article as:
Czeschik, J.C., Voigt, C., Alanay, Y. et al. Hum Genet (2013) 132: 885. doi:10.1007/s00439-013-1295-2

Abstract

Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.

Keywords

Acrofacial dysostosis Preaxial limb defect Thumb hypoplasia Radial hypoplasia SF3B4 EFTUD2 Exome sequencing 

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • J. C. Czeschik
    • 1
  • C. Voigt
    • 1
  • Y. Alanay
    • 2
  • B. Albrecht
    • 1
  • S. Avci
    • 3
  • D. FitzPatrick
    • 4
  • D. R. Goudie
    • 5
  • U. Hehr
    • 6
  • A. J. Hoogeboom
    • 7
  • H. Kayserili
    • 3
  • P. O. Simsek-Kiper
    • 8
  • L. Klein-Hitpass
    • 9
  • A. Kuechler
    • 1
  • V. López-González
    • 10
  • M. Martin
    • 11
  • S. Rahmann
    • 12
  • B. Schweiger
    • 13
  • M. Splitt
    • 14
  • B. Wollnik
    • 15
  • H. -J. Lüdecke
    • 1
  • M. Zeschnigk
    • 1
  • D. Wieczorek
    • 1
  1. 1.Institut für HumangenetikUniversitätsklinikum Essen, Universität Duisburg-EssenEssenGermany
  2. 2.Pediatric Genetics, Department of PediatricsAcibadem University School of MedicineIstanbulTurkey
  3. 3.Medical Genetics DepartmentIstanbul Medical Faculty, Istanbul UniversityIstanbulTurkey
  4. 4.MRC Human Genetics Unit, Institute of Genetic and Molecular MedicineWestern General HospitalEdinburghUK
  5. 5.Clinical GeneticsTayside University Hospitals NHS Trust, Ninewells Hospital and Medical SchoolDundeeUK
  6. 6.Zentrum für Humangenetik und Institut für Humangenetik Universität RegensburgRegensburgGermany
  7. 7.Department of Clinical GeneticsErasmus Medical Center RotterdamRotterdamThe Netherlands
  8. 8.Ihsan Dogramaci Children’s HospitalClinical Genetics UnitAnkaraTurkey
  9. 9.Institut für Zellbiologie (Tumorforschung)Universitätsklinikum Essen, Universität Duisburg-EssenEssenGermany
  10. 10.Unidad de Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de La ArrixacaMurciaSpain
  11. 11.Bioinformatics, Computer Science XITU DortmundGermany
  12. 12.Genominformatik, Institut für HumangenetikUniversität Duisburg-EssenEssenGermany
  13. 13.Institut für Diagnostische und Interventionelle Radiologie und NeuroradiologieUniversität Duisburg-EssenEssenGermany
  14. 14.Institute of Genetic MedicineInternational Centre for LifeNewcastle upon TyneUK
  15. 15.Institut für HumangenetikUniversität zu KölnKölnGermany

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