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Genet Med. 2018 Jul;20(7):728-736. doi: 10.1038/gim.2017.165. Epub 2017 Oct 26.

Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency.

Author information

1
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.
2
Division of Paediatric Endocrinology, Children's Hospital, Heidelberg University Hospital, Heidelberg, Germany.
3
Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
4
University of Heidelberg, Heidelberg, Germany.
5
Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
6
Bioinformatics and Omics Data Analytics, German Cancer Research Center, Heidelberg, Germany.
7
Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany.
8
Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany. gudrun.rappold@med.uni-heidelberg.de.

Abstract

PURPOSE:

Combined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases.

METHODS:

To identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed.

RESULTS:

We discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype.

CONCLUSION:

These data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD.

PMID:
29261175
DOI:
10.1038/gim.2017.165
[Indexed for MEDLINE]

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