Hypothyroidism: genes and variants

Genes linked to Hypothyroidism

• TPO: Thyroid peroxidase

  It oxidizes iodide and catalyzes iodination and coupling reactions on thyroglobulin that generate thyroid hormones. Biallelic loss-of-function variants cause thyroid dyshormonogenesis and congenital hypothyroidism, usually with goiter if untreated.

  3 disease-causing and 2 uncertain variants in TPO are linked to Hypothyroidism.

• PAX8: Paired box protein Pax-8

  It controls developmental and adult gene programs in the thyroid, kidney, and Mullerian-derived tissues. Heterozygous pathogenic variants can cause congenital hypothyroidism through thyroid dysgenesis or impaired thyroid-specific transcription.

  3 disease-causing and 0 uncertain variants in PAX8 are linked to Hypothyroidism.

• TSHR: Thyrotropin receptor

  TSH signaling through this pathway drives thyroid-hormone synthesis, iodine handling, and thyroid growth. Activating variants can cause autonomous hyperthyroidism, whereas loss-of-function variants can cause TSH resistance and congenital hypothyroidism.

  1 disease-causing and 1 uncertain variants in TSHR are linked to Hypothyroidism.

• TG: Thyroglobulin

  It provides the large iodinated scaffold on which thyroid hormones are synthesized and stored within thyroid follicles. Biallelic or dominant pathogenic variants can impair hormone production and cause congenital hypothyroidism, often with goiter.

  0 disease-causing and 5 uncertain variants in TG are linked to Hypothyroidism.

• BACH2: Transcription regulator protein BACH2

  It controls transcriptional programs that balance lymphocyte differentiation, immune tolerance, and effector-cell development. Haploinsufficiency can cause immunodeficiency with autoimmunity, and common variation influences susceptibility to several autoimmune diseases.

  0 disease-causing and 0 uncertain variants in BACH2 are linked to Hypothyroidism.

• CTLA4: Cytotoxic T-lymphocyte protein 4

  It restrains T-cell activation by competing with CD28 for CD80 and CD86 and by delivering inhibitory signals after immune activation. Haploinsufficiency causes immune dysregulation with autoimmunity and lymphoproliferation, while therapeutic blockade enhances antitumor immunity.

  0 disease-causing and 0 uncertain variants in CTLA4 are linked to Hypothyroidism.

• FLT3: Receptor-type tyrosine-protein kinase FLT3

  Its signaling supports survival and expansion of early hematopoietic progenitors. Internal tandem duplications and kinase-domain mutations produce constitutive activity in acute myeloid leukemia and are important prognostic markers and therapeutic targets.

  0 disease-causing and 0 uncertain variants in FLT3 are linked to Hypothyroidism.

• IL7R: Interleukin-7 receptor subunit alpha

  It transmits survival and developmental signals required for T-cell and lymphoid homeostasis. Biallelic loss-of-function variants cause T-cell-negative, B-cell-positive severe combined immunodeficiency, while somatic activating alterations occur in acute lymphoblastic leukemia.

  0 disease-causing and 0 uncertain variants in IL7R are linked to Hypothyroidism.

• IRF4: Interferon regulatory factor 4

  It controls differentiation and function of B cells, plasma cells, T cells, and other immune lineages in a context-dependent manner. Germline variants can cause immunodeficiency, while rearrangements or abnormal expression drive several lymphoid malignancies.

  0 disease-causing and 0 uncertain variants in IRF4 are linked to Hypothyroidism.

• JAK1: Tyrosine-protein kinase JAK1

  It couples many cytokine receptors to STAT transcription factors and is essential for interferon, interleukin, and growth-factor signaling. Loss-of-function can cause immunodeficiency, whereas activating alterations contribute to inflammatory disease and some malignancies.

  0 disease-causing and 0 uncertain variants in JAK1 are linked to Hypothyroidism.

• PTPN22: Tyrosine-protein phosphatase non-receptor type 22

  It tunes antigen-receptor signaling thresholds in T and B cells and helps maintain immune tolerance. The common R620W variant is a major non-HLA genetic risk factor for several autoimmune diseases, including type 1 diabetes and rheumatoid arthritis.

  0 disease-causing and 0 uncertain variants in PTPN22 are linked to Hypothyroidism.

• SH2B3: SH2B adapter protein 3

  It restrains cytokine and growth-factor signaling in hematopoietic cells, including JAK-STAT pathways controlling blood-cell production. Loss-of-function variants can increase blood-cell proliferation and predispose to myeloproliferative neoplasms, while common variants influence autoimmune and hematologic traits.

  0 disease-causing and 0 uncertain variants in SH2B3 are linked to Hypothyroidism.

• THRB: Thyroid hormone receptor beta

  0 disease-causing and 0 uncertain variants in THRB are linked to Hypothyroidism.

• TLR3: Toll-like receptor 3

  It detects double-stranded RNA in endosomes and activates interferon and inflammatory programs important for antiviral defense. Loss-of-function variants can impair intrinsic immunity to herpes simplex virus in the central nervous system and predispose to herpes simplex encephalitis.

  0 disease-causing and 0 uncertain variants in TLR3 are linked to Hypothyroidism.

• TYK2: Non-receptor tyrosine-protein kinase TYK2

  It transmits signals from type I interferon, IL-12, IL-23, and related cytokine receptors. Severe loss-of-function can cause immunodeficiency, common variants influence autoimmune susceptibility, and partial pharmacologic inhibition is effective in inflammatory disease.

  0 disease-causing and 0 uncertain variants in TYK2 are linked to Hypothyroidism.

Weakly linked (only a few uncertain records): ADNP and SLC26A4.

Known disease-causing variants in Hypothyroidism

Same protein, different disease

• Deficiency of iodide peroxidase is also caused by TPO variants; they fall mostly in different places as the Hypothyroidism variants (20 disease-causing).
• Hypothyroidism, congenital, nongoitrous, 2 is also caused by PAX8 variants; they fall mostly in different places as the Hypothyroidism variants (11 disease-causing).
• Hypothyroidism due to TSH receptor mutations is also caused by TSHR variants; they fall mostly in different places as the Hypothyroidism variants (24 disease-causing).
• Familial hyperthyroidism due to mutations in TSH receptor is also caused by TSHR variants; they fall mostly in different places as the Hypothyroidism variants (18 disease-causing).
• Familial gestational hyperthyroidism is also caused by TSHR variants; they fall mostly in different places as the Hypothyroidism variants (13 disease-causing).
• Thyroid adenoma, hyperfunctioning, somatic is also caused by TSHR variants; they fall mostly in different places as the Hypothyroidism variants (5 disease-causing).
• Ovarian cancer is also caused by TSHR variants; they fall mostly in different places as the Hypothyroidism variants (4 disease-causing).

Diseases related to Hypothyroidism

• Type 1 diabetes mellitus, also linked to BACH2, CTLA4, PTPN22, SH2B3 and 1 more
• Hyperthyroidism, also linked to CTLA4, THRB, TPO and TSHR
• Primary myelofibrosis, also linked to FLT3, JAK1 and SH2B3
• Systemic lupus erythematosus, also linked to CTLA4, PTPN22 and TYK2
• Basal cell carcinoma, also linked to BACH2, CTLA4 and IRF4
• Acquired polycythemia vera, also linked to FLT3, JAK1 and TYK2
• Hepatocellular carcinoma, also linked to CTLA4 and FLT3
• Renal cell carcinoma, also linked to CTLA4 and FLT3
• Melanoma, also linked to CTLA4 and IRF4
• Gastrointestinal stromal tumor, also linked to FLT3
• Ovarian cancer, also linked to TSHR
• Severe combined immunodeficiency disease, also linked to IL7R

Frequently asked questions

Which genes are linked to Hypothyroidism?

In CATVariant, Hypothyroidism is linked to 15 analyzed proteins: TPO (Thyroid peroxidase), PAX8 (Paired box protein Pax-8), TSHR (Thyrotropin receptor), TG (Thyroglobulin), BACH2 (Transcription regulator protein BACH2), CTLA4 (Cytotoxic T-lymphocyte protein 4) and 9 more.

How many genetic variants are linked to Hypothyroidism?

30 variants: 7 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 8 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hypothyroidism look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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