Unique near-complete deletion of GLI2 in a patient with combined pituitary hormone deficiency and post-axial polydactyly.

Introduction: Combined pituitary hormone deficiency (CPHD) can cause a broad spectrum of health problems, ranging from short stature only, to convulsions or even death. In the majority of patients, the cause is unknown.

Methods: The idex case had unexplained CPHD, pituitary anomalies on MRI and polydactyly. In the patients and her unaffected parents, we performed SNP array analysis and Whole Exome Sequencing, after candidate gene analysis turned out negative.

Results: We found a unique de novo heterozygous 229.9 kb deletion in the index case on chr. 2q14.2. This deletion covered 12 out of the 13 coding exons of the GLI2 gene, a transcription factor involved in midline formation and previously associated with CPHD. As reported GLI2 deletions and mutations show a large phenotypic variability, we performed a genotype-phenotype analysis. This revealed that GLI2 missense mutations usually present with a 'ppp-only' phenotype (pituitary anomalies ± postaxial polydactyly without brain phenotype), whereas the 'ppp-plus' phenotype (with major brain malformations and/or intellectual disabilities) is more frequent in patients with larger deletions, and those with frameshift mutations/point mutations or splice variants resulting in a stop codon (p < .001).

Conclusion: The present case shows that a deletion of the GLI2 gene only (not affecting any of the adjacent genes) causes pituitary anomalies without brain phenotype. This suggests that brain phenotype only occurs when additional genes adjacent to GLI2 are deleted, or when mutations result in truncated GLI2 mRNA/protein. However, due to the lack of functional data for many GLI2 mutations and based on the available information regarding variable penetrance, phenotype-genotype correlations need to be made with caution.