Human Genetics

, Volume 133, Issue 5, pp 625–638 | Cite as

X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome

  • R. S. Møller
  • L. R. Jensen
  • S. M. Maas
  • J. Filmus
  • M. Capurro
  • C. Hansen
  • C. L. M. Marcelis
  • K. Ravn
  • J. Andrieux
  • M. Mathieu
  • M. Kirchhoff
  • O. K. Rødningen
  • N. de Leeuw
  • H. G. Yntema
  • G. Froyen
  • J. Vandewalle
  • K. Ballon
  • E. Klopocki
  • S. Joss
  • J. Tolmie
  • A. C. Knegt
  • A. M. Lund
  • H. Hjalgrim
  • A. W. Kuss
  • N. Tommerup
  • R. Ullmann
  • A. P. M. de Brouwer
  • P. Strømme
  • S. Kjaergaard
  • Z. Tümer
  • T. Kleefstra
Original Investigation

Abstract

Submicroscopic duplications along the long arm of the X-chromosome with known phenotypic consequences are relatively rare events. The clinical features resulting from such duplications are various, though they often include intellectual disability, microcephaly, short stature, hypotonia, hypogonadism and feeding difficulties. Female carriers are often phenotypically normal or show a similar but milder phenotype, as in most cases the X-chromosome harbouring the duplication is subject to inactivation. Xq28, which includes MECP2 is the major locus for submicroscopic X-chromosome duplications, whereas duplications in Xq25 and Xq26 have been reported in only a few cases. Using genome-wide array platforms we identified overlapping interstitial Xq25q26 duplications ranging from 0.2 to 4.76 Mb in eight unrelated families with in total five affected males and seven affected females. All affected males shared a common phenotype with intrauterine- and postnatal growth retardation and feeding difficulties in childhood. Three had microcephaly and two out of five suffered from epilepsy. In addition, three males had a distinct facial appearance with congenital bilateral ptosis and large protruding ears and two of them showed a cleft palate. The affected females had various clinical symptoms similar to that of the males with congenital bilateral ptosis in three families as most remarkable feature. Comparison of the gene content of the individual duplications with the respective phenotypes suggested three critical regions with candidate genes (AIFM1,RAB33A, GPC3 and IGSF1) for the common phenotypes, including candidate loci for congenital bilateral ptosis, small head circumference, short stature, genital and digital defects.

Supplementary material

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Supplementary material 1 (DOCX 21 kb)
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Supplementary material 2 (DOC 77 kb)
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Supplementary material 3 (PPT 1031 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • R. S. Møller
    • 1
    • 2
    • 18
  • L. R. Jensen
    • 3
    • 22
  • S. M. Maas
    • 4
    • 5
  • J. Filmus
    • 6
  • M. Capurro
    • 6
  • C. Hansen
    • 2
  • C. L. M. Marcelis
    • 7
  • K. Ravn
    • 8
  • J. Andrieux
    • 9
  • M. Mathieu
    • 10
  • M. Kirchhoff
    • 11
  • O. K. Rødningen
    • 12
  • N. de Leeuw
    • 7
  • H. G. Yntema
    • 7
  • G. Froyen
    • 13
  • J. Vandewalle
    • 13
  • K. Ballon
    • 14
  • E. Klopocki
    • 15
    • 16
  • S. Joss
    • 17
  • J. Tolmie
    • 17
  • A. C. Knegt
    • 4
  • A. M. Lund
    • 11
  • H. Hjalgrim
    • 1
    • 18
  • A. W. Kuss
    • 3
    • 22
  • N. Tommerup
    • 2
  • R. Ullmann
    • 19
  • A. P. M. de Brouwer
    • 7
    • 20
  • P. Strømme
    • 21
  • S. Kjaergaard
    • 11
  • Z. Tümer
    • 8
  • T. Kleefstra
    • 7
  1. 1.Danish Epilepsy CentreDianalundDenmark
  2. 2.Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular MedicineUniversity of CopenhagenCopenhagenDenmark
  3. 3.Institute for Human GeneticsUniversity Medicine GreifswaldGreifswaldGermany
  4. 4.Department of Clinical GeneticsAcademic Medical CenterAmsterdamThe Netherlands
  5. 5.Department of PaediatricsAcademic Medical CenterAmsterdamThe Netherlands
  6. 6.Sunnybrook Research InstituteUniversity of TorontoTorontoCanada
  7. 7.Department of Human GeneticsRadboud University Medical CentreNijmegenThe Netherlands
  8. 8.Applied Human Molecular Genetics, Kennedy CenterCopenhagen University HospitalGlostrupDenmark
  9. 9.Institut de Génétique MédicaleHopital Jeanne de Flandre, CHRULilleFrance
  10. 10.Service de Génétique Clinique, CHU d’AmiensAmiensFrance
  11. 11.Department of Clinical Genetics, RigshospitaletUniversity Hospital of CopenhagenCopenhagenDenmark
  12. 12.Department of Medical GeneticsOslo University HospitalUllevaalNorway
  13. 13.Human Genome Laboratory, Department of Human GeneticsVIB Center for the Biology of Disease, KU LeuvenLeuvenBelgium
  14. 14.Department of PaediatricsUniversity Hospitals LeuvenLouvainBelgium
  15. 15.Institute for Medical and Human GeneticsCharité Universitätsmedizin BerlinBerlinGermany
  16. 16.Institute for Human GeneticsUniversity of WürzburgWürzburgGermany
  17. 17.Ferguson-Smith Department of Clinical GeneticsYorkhill HospitalGlasgowUK
  18. 18.Institute for Regional Health ServicesUniversity of Southern DenmarkOdenseDenmark
  19. 19.Max Planck Institute for Molecular GeneticsBerlinGermany
  20. 20.Department of Cognitive NeurosciencesDonders Institute for Brain Cognition and Behaviour, Radboud UniversityNijmegenThe Netherlands
  21. 21.Women and Children’s Division, Department of Clinical Neurosciences for ChildrenUniversity Hospital and University of OsloOsloNorway
  22. 22.Interfaculty Institute for Genetics and Functional GenomicsErnst Moritz Arndt UniversityGreifswaldGermany

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