Abstract
The immunoglobulin superfamily member 1 (IGSF1) gene encodes a plasma membrane glycoprotein mainly expressed in pituitary and testes. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism (CeH), macroorchidism, and delayed puberty (delayed rise of testosterone, but normal timing of testicular growth). As this syndrome was discovered in patients with CeH, it is unknown whether IGSF1 mutations might also cause delayed puberty without CeH. We therefore determined the prevalence of IGSF1 sequence variants in 30 patients with an apparent X-linked form of constitutional delay of growth and puberty (CDGP). 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 CDGP, all three VUCSs showed normal plasma membrane expression in transfected HEK293 cells, and no other features of the IGSF1 deficiency syndrome were observed in family members carrying the VUCSs. The observation of hyperprolactinemia in two carriers remains unexplained.
Conclusion: There is insufficient evidence to conclude that the three observed VUCSs in IGSF1 are associated with CDGP, making it unlikely that IGSF1 mutations are a prevalent cause of CDGP.
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Abbreviations
- BMI:
-
Body mass index
- CDGP:
-
Constitutional delay of growth and puberty
- CeH:
-
Central hypothyroidism
- IGSF1:
-
Immunoglobulin superfamily, member 1
- IHH:
-
Isolated hypogonadotropic hypogonadism
- MAC:
-
Minor allele count
- MAF:
-
Minor allele frequency
- SD:
-
Standard deviation
- VUCS:
-
Variant of unknown clinical significance
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Conflict of interest
Daniel J. Bernard was funded by the Canadian Institutes of Health Operating Grant MOP-133557; Wilma Oostdijk received an unrestricted research grant from Ipsen Farmaceutica BV. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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Communicated by Beat Steinmann
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Joustra, S.D., Wehkalampi, K., Oostdijk, W. et al. IGSF1 variants in boys with familial delayed puberty. Eur J Pediatr 174, 687–692 (2015). https://doi.org/10.1007/s00431-014-2445-9
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DOI: https://doi.org/10.1007/s00431-014-2445-9