Human Genetics

, Volume 133, Issue 7, pp 939–949

Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations

  • Lina Basel-Vanagaite
  • Rüstem Yilmaz
  • Sha Tang
  • Miriam S. Reuter
  • Nils Rahner
  • Dorothy K. Grange
  • Megan Mortenson
  • Patrick Koty
  • Heather Feenstra
  • Kelly D. Farwell Gonzalez
  • Heinrich Sticht
  • Nathalie Boddaert
  • Julie Désir
  • Kwame Anyane-Yeboa
  • Christiane Zweier
  • André Reis
  • Christian Kubisch
  • Tamison Jewett
  • Wenqi Zeng
  • Guntram Borck
Original Investigation

DOI: 10.1007/s00439-014-1436-2

Cite this article as:
Basel-Vanagaite, L., Yilmaz, R., Tang, S. et al. Hum Genet (2014) 133: 939. doi:10.1007/s00439-014-1436-2

Abstract

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis–ptosis–intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello–Carey syndrome as well as the patient reported to have a “new” syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello–Carey syndrome, and suggest the single designation “Kaufman oculocerebrofacial syndrome”.

Supplementary material

439_2014_1436_MOESM1_ESM.tif (7.5 mb)
Supplementary Figure 1 MRI scans of six individuals with biallelic UBE3B mutations. Patient 1 (MRI performed at the age of 32 years): moderate dilatation of the lateral ventricles; Patient 2 (14 months): slightly dilated lateral ventricles and thin corpus callosum; Patient 3 (newborn period): frontal lipoma, short corpus callosum; Patient 4 (7 years): no gross anomalies; Patient 5 (8 years): severe dilatation of the lateral ventricles, Chiari type 1 malformation; Patient 10 (10 days): severe hypoplasia (or agenesis) of the corpus callosum (TIFF 7663 kb)
439_2014_1436_MOESM2_ESM.tif (1.4 mb)
Supplementary Fig. 2 UBE3B mutations. Sequence chromatograms showing UBE3B mutations. (TIFF 1421 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Lina Basel-Vanagaite
    • 1
    • 2
    • 3
  • Rüstem Yilmaz
    • 4
  • Sha Tang
    • 5
  • Miriam S. Reuter
    • 6
  • Nils Rahner
    • 7
  • Dorothy K. Grange
    • 8
  • Megan Mortenson
    • 9
  • Patrick Koty
    • 9
  • Heather Feenstra
    • 10
  • Kelly D. Farwell Gonzalez
    • 5
  • Heinrich Sticht
    • 11
  • Nathalie Boddaert
    • 12
  • Julie Désir
    • 13
  • Kwame Anyane-Yeboa
    • 14
  • Christiane Zweier
    • 6
  • André Reis
    • 6
  • Christian Kubisch
    • 4
  • Tamison Jewett
    • 9
  • Wenqi Zeng
    • 5
  • Guntram Borck
    • 4
  1. 1.Raphael Recanati Genetic Institute and Felsenstein Medical Research CenterRabin Medical CenterPetah TikvaIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Pediatric Genetics, Schneider Children’s Medical Center of IsraelPetah TikvaIsrael
  4. 4.Institute of Human GeneticsUniversity of UlmUlmGermany
  5. 5.Ambry GeneticsAliso ViejoUSA
  6. 6.Institute of Human GeneticsFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  7. 7.Medical Faculty, Institute of Human GeneticsUniversity of DusseldorfDusseldorfGermany
  8. 8.Division of Genetics and Genomic Medicine, Department of PediatricsWashington University School of Medicine, St. Louis Children’s HospitalSt. LouisUSA
  9. 9.Department of Pediatrics, Section on Medical GeneticsWake Forest School of MedicineWinston-SalemUSA
  10. 10.Roosevelt HospitalNew YorkUSA
  11. 11.Institute of BiochemistryFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  12. 12.Department of Pediatric Radiology, Hôpital Necker, Enfants Malades and Medical FacultyUniversité Paris DescartesParisFrance
  13. 13.Institut de Pathologie et de GénétiqueGosseliesBelgium
  14. 14.Columbia University Medical CenterNew YorkUSA

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