SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD).

Background:The mutation frequencies of pituitary transcription factors genes in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. However, apart fromPROP1the mutation rate of other genes is low and for almost half of the patients with CPHD the routine sequencing of known genes is unsuccessful in the identification of genetic causes. Methods:A cohort of 66 sporadic and nine familial CPHD cases (80 patients in total) were subjected to initial testing of the genesPROP1, POU1F1, LHX3, LHX4, andHESX1using a targeted gene panel and MLPA. In patients who tested negative, a whole exome sequencing approach was employed. Results:In nine of the familial cases and 32 of the sporadic patients mutations in thePROP1gene were found (the common pathogenic variants included c.301_302delAG and c.150delA). Mutations were also found in genes so far not related directly to CPHD. A unique homozygous and clinically relevant variant was identified in theSEMA3Agene, which may contribute to neural development and his phenotypic spectrum including short stature and isolated hypogonadotropic hypogonadism (IHH). Another pathogenic variant p.A1672T was found in theIGSF10gene reported to be responsible for delayed puberty and neuronal migration during embryogenesis. Several suspected novel but predicted benign variants were also identified for theCHD7, WDR11andFGF17genes. Conclusion:AlthoughPROP1defects account for a majority of CPHD patients, identification of rare, less frequent variants constitutes a big challenge. Multiple genetic factors responsible for CPHD are still awaiting discovery and therefore the usage of efficient genomic tools (i.e., whole exome sequencing) will further broaden our knowledge regarding pituitary development and function.