On this page
IGSF1
immunoglobulin superfamily member 1
IGSF1 is located on the long (q) arm of chromosome X, at band Xq26.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome X in the library →Available at Jeen Health
Clinical tests that include this
Overview
IGSF1 (immunoglobulin superfamily member 1) is located on the X chromosome and encodes a large cell-surface glycoprotein. The protein is predominantly expressed in the pituitary gland and Sertoli cells of the testes, where it contributes to endocrine signalling pathways. Because the gene resides on the X chromosome, pathogenic variants primarily affect males, who have only one copy of the gene. Females carrying a single pathogenic variant are typically unaffected or show milder features. IGSF1 variants are recognised as a cause of central hypothyroidism, a condition in which the pituitary gland does not produce sufficient thyroid-stimulating hormone, leading to low thyroid hormone levels despite a structurally normal thyroid gland.
What the gene does
The IGSF1 protein functions as a transmembrane receptor or co-receptor that modulates hormone signalling in neuroendocrine tissues. Research suggests that it interacts with other membrane proteins to regulate the secretion of thyroid-stimulating hormone from pituitary thyrotroph cells. The protein also appears to influence the maturation and function of Sertoli cells in the testes, which support developing sperm cells and contribute to male reproductive hormone balance. At the cellular level, IGSF1 is thought to participate in intracellular signalling cascades that respond to hormonal cues, coordinating the body's metabolic and reproductive responses. Loss of functional IGSF1 disrupts these regulatory pathways, leading to reduced thyroid-stimulating hormone secretion and altered testicular function. The precise molecular partners and downstream signalling mechanisms remain areas of active investigation.
Video: Genetics 101
Chromosome location
IGSF1 is located on the long arm of the X chromosome at position Xq26.1. This chromosomal region contains numerous genes involved in neurological and endocrine functions. The gene spans multiple exons encoding a 1,336-amino-acid protein. Its X-linked position means that males inherit only one copy from their mother, whilst females inherit one copy from each parent. This inheritance pattern accounts for the predominantly male presentation of IGSF1-related conditions, as males lack a second gene copy to compensate for pathogenic variants.
Protein structure
The IGSF1 protein comprises 1,336 amino acids and features an extracellular region containing twelve immunoglobulin-like C2-type domains. These domains span Ig-like C2-type 1 (amino acids 38-122), Ig-like C2-type 2 (amino acids 137-222), Ig-like C2-type 3 (amino acids 226-312), Ig-like C2-type 4 (amino acids 321-408), Ig-like C2-type 5 (amino acids 419-500), Ig-like C2-type 6 (amino acids 589-677), Ig-like C2-type 7 (amino acids 686-760), Ig-like C2-type 8 (amino acids 777-869), Ig-like C2-type 9 (amino acids 873-958), Ig-like C2-type 10 (amino acids 965-1060), Ig-like C2-type 11 (amino acids 1065-1150), and Ig-like C2-type 12 (amino acids 1161-1242). This tandem arrangement of immunoglobulin-like domains is characteristic of cell-adhesion molecules and receptors that mediate protein-protein interactions at the cell surface. A disordered region extends from amino acids 1,308 to 1,336 at the C-terminus, which may provide flexibility for regulatory interactions.
Key variants
Pathogenic variants in IGSF1 include nonsense mutations, frameshift deletions, and missense changes that disrupt protein structure or stability. Whole-gene deletions affecting IGSF1 have also been reported. Most documented variants lead to loss of protein function, either through premature termination of translation or through structural disruption of the immunoglobulin-like domains. Males with pathogenic variants typically present with central hypothyroidism, often accompanied by macroorchidism and delayed pubertal testosterone rise.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1814_1836dup | p.Arg613delinsGlyArgThrTer | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2407dup | p.His803fs | Pathogenic/Likely pathogenic | ★★☆☆ | X-linked central congenital hypothyroidism with late-onset testicular enlargement |
c.3550C>T | p.Arg1184Ter | Pathogenic | ★★☆☆ | X-linked central congenital hypothyroidism with late-onset testicular enlargement |
c.1785G>A | p.Trp595Ter | Pathogenic | ★☆☆☆ | not provided |
c.2145T>A | p.Tyr715Ter | Pathogenic | ★☆☆☆ | X-linked central congenital hypothyroidism with late-onset testicular enlargement |
c.2175del | p.Gln725fs | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.2333dup | p.Pro779fs | Pathogenic | ★☆☆☆ | Paediatric disorders |
c.2380C>T | p.Arg794Ter | Pathogenic | ★☆☆☆ | IGSF1-related disorder |
c.257_264dup | p.Val89fs | Pathogenic | ★☆☆☆ | Pituitary hormone deficiency |
c.2974C>T | p.Arg992Ter | Pathogenic | ★☆☆☆ | Pituitary hormone deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in IGSF1 cause X-linked central hypothyroidism, an endocrine disorder characterised by low thyroid hormone levels due to insufficient pituitary thyroid-stimulating hormone secretion. Affected males often exhibit normal growth but may have subtle metabolic abnormalities and delayed bone maturation. Some individuals also experience macroorchidism, an enlargement of the testes, and a delayed rise in testosterone during puberty. Females who carry a single pathogenic variant are generally asymptomatic, though mild thyroid function abnormalities have occasionally been observed. The condition is usually identified through newborn screening programmes or clinical evaluation of unexplained hypothyroidism in childhood.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic IGSF1 variants typically follow X-linked inheritance.
Carrier frequency by population How common is heterozygous IGSF1 carrier status across ancestry groups?UK clinical status
Within the NHS Genomic Medicine Service, IGSF1 appears on the Congenital hypothyroidism panel (green classification, R145) and the Pituitary hormone deficiency panel (green classification, R159). Green classification indicates strong evidence linking the gene to the specified condition, supporting its use in clinical diagnostic testing. IGSF1 is also listed in the Developmental Disorders Genotype-to-Phenotype database. These panel memberships reflect the gene's established role in inherited endocrine disorders and support its inclusion in targeted genetic testing for individuals with central hypothyroidism or pituitary hormone abnormalities.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
Why do IGSF1 variants mainly affect males?
IGSF1 is located on the X chromosome. Males have only one X chromosome, so a pathogenic variant in their single copy of IGSF1 results in loss of protein function. Females have two X chromosomes, and the normal copy typically compensates, meaning most female carriers show no symptoms.
What is central hypothyroidism?
Central hypothyroidism is a condition in which the pituitary gland does not produce enough thyroid-stimulating hormone, leading to low thyroid hormone levels despite a normally structured thyroid gland. This differs from primary hypothyroidism, where the thyroid itself is impaired.
Can IGSF1-related hypothyroidism be treated?
Central hypothyroidism associated with IGSF1 variants is typically managed with thyroid hormone replacement therapy under endocrinologist supervision. Treatment aims to maintain normal thyroid hormone levels and support healthy growth and metabolism. Specific dosing and monitoring require individualised clinical assessment.