A Patient With a Mild Holoprosencephaly Spectrum Phenotype and Heterotaxy and a 1.3 Mb Deletion EncompassingGLI2

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Abstract

Loss–of–function mutations ofGLI2are 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 theGLI2gene. We review the genotype and phenotype of previously published probands withGLI2aberrations. Our findings confirm the association of haploinsufficiency ofGLI2and 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, ZIC3andCFC1) were excluded. The deletion contains five genes, in addition toGLI2, including theEPB4.1l5gene. Based on findings inEpb4.1l5mutant mice we hypothesize thatEpb4.1l5is a candidate gene for the heterotaxy observed in the proband. © 2011 Wiley Periodicals, Inc.

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