Abstract
IntroductionGrowth hormone is secreted by the pituitary gland, which forms part of the craniofacial midline. IRF6 encodes a transcription factor involved in the development of the craniofacial midline and mutations in IRF6 are known to disturb craniofacial development. Craniofacial and pituitary development are closely related. After whole exome sequencing revealed a new mutation in IRF6 in a family with Idiopathic Growth Hormone Deficiency (IGHD), we screened the remainder of our IGHD cohort for mutations in this gene and related their genotypes to pituitary and craniofacial morphology.Materials and methodsWe sequenced all coding exons and exon–intron boundaries of IRF6 in 81 patients with IGHD. We performed a multiplex ligation-dependent probe amplification (MLPA) in order to exclude copy number variations in IRF6. We analyzed facial measurements taken from standardized digital pictures of 48 patients.ResultsWe found two new variants and eleven polymorphisms. Apart from the new mutation found in the index family (p.Arg233Cys), we found one other new heterozygous missense mutation in IRF6 (Pro456Ser). p.Arg233Cys was reported as extremely rare in exome databases (1 allele out of 120.852 alleles sequenced), strictly conserved among species and was predicted deleterious by all variant predictor programs. Pro456Ser was predicted to be benign. MLPA did not reveal any exon deletions or duplications in any of the patients.ConclusionThis is the first report of IRF6 analysis in an IGHD cohort. We found one new mutation which, based on in silico analysis, could be of functional relevance. However, we did not find any mutations in the other patients. Therefore, we conclude that IRF6 defects are rare in IGHD patients and further research should focus on new candidate genes.
Highlights
Growth hormone is secreted by the pituitary gland, which forms part of the craniofacial midline
Since IRF6 mutations are known to disturb craniofacial development, which is related to pituitary development, we considered IRF6 a possible candidate gene for Idiopathic Growth Hormone Deficiency (IGHD)
We studied 81 patients with IGHD participating in the Dutch HYPOPIT study, which investigates the genetic causes of idiopathic Growth hormone (GH) deficiency
Summary
Growth hormone (GH) is secreted by the pituitary gland, which forms part of the craniofacial midline. In patients with Isolated GH Deficiency (IGHD), a broad range of craniofacial midline abnormalities have been described, like hypertelorism, cleft lip and palate and single median maxillary central incisor [22, 23]. The mechanism underlying this association between isolated GH deficiency and craniofacial midline defects is still poorly understood. Mutations in IRF6 are associated with Van der Woude Syndrome (VWS, OMIM #119300) and Popliteal Pterygium Syndrome (PPS, OMIM #119500) Both syndromes are characterized by a cleft lip and/or cleft palate, which are due to defective craniofacial development. The relation between IRF6 and pituitary function, pituitary morphology and craniofacial features has not been studied before
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