ESPE Abstracts (2014) 82 P-D-1-2-216

IGSF1 Variants in Boys with Familial Delayed Puberty

Sjoerd Joustraa, Karoliina Wehkalampib, Wilma Oostdijka, Nienke Biermasza, Sasha Howardsc, Daniel Bernardd, Jan Maarten Wita, Leo Dunkelc & Monique Losekoota


aLeiden University Medical Center, Leiden, The Netherlands; bHelsinki University Central Hospital, Helsinki, Finland; cQueen Mary University of London, London, UK; dMcGill University, Montréal, Canada


Background: The immunoglobulin superfamily member 1 (IGSF1) gene encodes a plasma membrane glycoprotein enriched in pituitary and testes. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism (CeH), macroorchidism, and delayed pubertal rise of testosterone despite normal timing of testicular growth. This syndrome was discovered in patients with CeH; therefore, it is presently unknown whether IGSF1 mutations also cause delayed puberty without CeH.

Methods: We determined the prevalence of IGSF1 sequence variants in 30 patients with familial constitutional delay of growth and puberty (CDGP) in an apparent maternally transmitted pattern of inheritance (pubertal delay in the index patient’s siblings, mother, and/or siblings of mother). Isolated DNA was screened for mutations in IGSF1 using Sanger sequence analysis. Functional effects of variants with unknown clinical significance were assessed by: i) in silico prediction of pathogenicity, and ii) transfecting heterologous HEK293 cells with expression vectors specific for each IGSF1 variant, followed by cell surface biotinylation and immunofluorescence to determine plasma membrane expression of the resulting IGSF1 proteins.

Results: In four families, we discovered three novel variants of unknown clinical significance (VUCSs) with possible pathogenicity predicted by in silico analysis. However, the genotype did not fully cosegregate with delayed puberty. All three VUCSs showed normal plasma membrane localization in transfected HEK293 cells. Besides delayed puberty, no other features of the IGSF1 deficiency syndrome were observed in family members carrying the VUCSs. Hyperprolactinemia was observed in one family.

Conclusion: There is insufficient evidence that the three newly discovered VUCSs in IGSF1 in 30 patients with maternally transmitted CDGP are associated with delayed puberty. Thus, it is unlikely that IGSF1 mutations are a prevalent cause of CDGP. However, the limited size of the study group does not completely rule out such an association.

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