Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic

Abstract

PurposeCongenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown.MethodsWe studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups.ResultsFirst, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband’s condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01).ConclusionOur findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency

“…In this study, each patient was found to harbor three possible causative gene variants, after WES. Although to date numerous studies have shown that CPHD as well as PSIS have an oligogenic rather than a monogenic etiology [11,12,[63][64][65], such a conclusion could not be reached in this work.…”

“…However, the etiology of approximately 85% of the cases still remains unknown [3]. Furthermore, various studies demonstrated that the genetic causes of CPHD and pituitary stalk interruption syndrome (PSIS) are oligogenic rather than monogenic [11][12][13]. Similarly, congenital hypogonadotropic hypogonadism (CHH) is now considered as an oligogenic disease, and it has been shown by various studies that mutations in genes associated with CHH may also be related with CPHD, PSIS and holoprosencephaly, indicating a genetic overlap between these syndromes [14][15][16].…”

POU1F1/Pou1f1 c.143-83A > G Variant Disrupts the Branch Site in Pre-mRNA and Leads to Dwarfism

“…Furthermore, some family members with the variants, which lead to an abnormal pattern of transcripts, showed no phenotype or attenuated phenotype ( 34 , 45 ). In congenital hypopituitarism, previous studies suggested oligogenic inheritance ( 59 , 60 ), which may also apply to these POU1F1 variant carriers.…”