A patient with a mild holoprosencephaly spectrum phenotype and heterotaxy and a 1.3 Mb deletion encompassing GLI2

Authors

  • Sietske H.G. Kevelam,

    Corresponding author
    1. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
    • Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.
    Search for more papers by this author
  • Jeske J.T. van Harssel,

    1. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
    Search for more papers by this author
  • Bert van der Zwaag,

    1. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
    Search for more papers by this author
  • Hubertus J.M. Smeets,

    1. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
    2. School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands
    Search for more papers by this author
  • Aimee D.C. Paulussen,

    1. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
    2. School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands
    Search for more papers by this author
  • Klaske D. Lichtenbelt

    1. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
    Search for more papers by this author

  • How to cite this article: Kevelam SHG, van Harssel JJT, van der Zwaag B, Smeets HJM, Paulussen ADC, Lichtenbelt KD. 2012. A patient with a mild holoprosencephaly spectrum phenotype and heterotaxy and a 1.3 Mb deletion encompassing GLI2. Am J Med Genet Part A 158A:166–173.

Abstract

Loss-of-function mutations of GLI2 are associated with features at the mild end of the holoprosencephaly spectrum, including abnormal pituitary gland formation and/or function, and craniofacial abnormalities. In addition patients may have branchial arch anomalies and polydactyly. Large, microscopically visible, interstitial deletions spanning 2q14.2 have been reported in patients with multiple congenital anomalies and intellectual disability. We report here on a patient with a mild holoprosencephaly spectrum phenotype (bilateral cleft lip and palate and abnormal pituitary gland formation with panhypopituitarism) and normal psychomotor development, who was found to carry a 1.3 Mb submicroscopic heterozygous deletion in 2q14.2, encompassing the GLI2 gene. We review the genotype and phenotype of previously published probands with GLI2 aberrations. Our findings confirm the association of haploinsufficiency of GLI2 and mild HPE spectrum features. Consistent with prior reports, we observed incomplete penetrance of the deletion in the family, illustrating the multifactorial etiology of holoprosencephaly spectrum features. In addition to the holoprosencephaly spectrum features, the proband had heterotaxy of the abdominal organs. Mutations in the known heterotaxy genes (NODAL, ZIC3 and CFC1) were excluded. The deletion contains five genes, in addition to GLI2, including the EPB4.1l5 gene. Based on findings in Epb4.1l5 mutant mice we hypothesize that Epb4.1l5 is a candidate gene for the heterotaxy observed in the proband. © 2011 Wiley Periodicals, Inc.

Ancillary