Familial Central Hypothyroidism Caused by a Novel IGSF1 Gene Mutation

Background: Congenital hypothyroidism of central origin (CH-C) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin stimulation of a normal thyroid gland. A recently described syndrome of isolated CH-C and macroorchidism was attributed to loss-of-function mutations of the immunoglobulin superfamily, member 1 gene (IGSF1).

Patients and methods: CH-C was diagnosed in three siblings. The TRH, TRHR, and TSHB genes were sequenced followed by whole-exome sequencing in the proband. A mutation identified in IGSF1 was analyzed by direct PCR sequencing in family members. The effects of the mutation were assessed by in vitro studies in HEK293 cells.

Results: The index case was negative for mutations in TRH, TRHR, and TSHB. Whole-exome sequencing revealed a novel insertion mutation in IGSF1, c.2284_2285insA, p.R762QfsX7, which was confirmed by direct PCR sequencing and was identified in six additional family members. The mutation introduces a frame-shift and premature stop codon in the seventh Ig loop, thereby truncating IGSF1. In vitro studies revealed that the mutated IGSF1-R762QfsX7 migrates as a doublet at ∼28 kDa, which is far smaller than the wild type protein (130-140 kDa). Both bands were endonuclease H sensitive, indicating immature glycosylation and failure of the protein to traffic out of the endoplasmic reticulum to the plasma membrane. Further phenotypic findings in the family included macroorchidism and infertility in the uncle and mild neurological phenotypes in the affected males, such as hypotonia, delayed psychomotor development, clumsy behavior, and attention deficit disorder.

Conclusions: We identified a novel insertion mutation in the IGSF1 gene and further delineated the phenotype of the IGSF1-deficiency syndrome. Our findings indicate a possible association between an IGSF1 mutation and neurological phenotypes.