DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for familial thyroid dyshormonogenesis — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleFamilial thyroid dyshormonogenesis maps to a 5-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for familial thyroid dyshormonogenesis is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
thyroglobulin (TG) — TG is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7B75 · 3.2 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
From a French national screening programme covering 14,416,428 neonates over 19 years, 4049 cases of congenital hypothyroidism were detected, of which 2863 were due to thyroid dysgenesis. Among those, 67 patients from 32 multiplex families were identified, meaning families with at least two affected members. The distribution of ectopic gland and athyreosis in familial cases was similar to sporadic cases, but the female-to-male ratio was significantly lower in familial cases (1.4 versus 2.7). Extrathyroidal congenital malformations occurred at similarly elevated rates in both familial and isolated cases (9% and 8.2% respectively, versus 2.5% in the general population). The authors concluded that familial clustering was more than 15-fold higher than expected by chance, suggesting genetic factors are involved in thyroid dysgenesis.
In a separate study of 104 patients with thyroid dyshormonogenesis from consanguineous or multi-case families, TPO mutations were the most common identifiable cause. Twenty-one TPO mutations were found in 28 cases, including four novel mutations (A5T, Y55X, E596X, D633N). The authors proposed comprehensive mutation screening by new sequencing technology for all newly diagnosed primary congenital hypothyroidism cases. Another study of three unrelated patients with goitrous congenital hypothyroidism and low serum thyroglobulin identified four inactivating mutations in the TG gene, three of which were novel (c.548G>A, p.C164Y; c.759-760insA, p.L234fsX237; c.6701C>A, p.A2215D) and one previously reported (c.886C>T, p.R277X). One patient was homozygous for p.R277X, and two were compound heterozygotes. This was the first report of a nucleotide insertion mutation in the TG gene.
A 2018 review states that thyroid dyshormonogenesis accounts for 10–15% of congenital hypothyroidism and is associated with seven genes: SLC5A5, SLC26A4, TG, TPO, DUOX2, DUOXA2, and IYD. Inheritance is usually autosomal recessive, though autosomal dominant cases occur. The review advocates targeted exome sequencing as an updated diagnostic approach. A 1981 report described a family with four siblings, three of whom had hypothyroidism due to thyroid aplasia, and noted ten previously reported families with familial thyroid aplasia or dysplasia without other malformations, arguing that autosomal recessive inheritance occurs rather frequently.
What remains missing is a systematic, prospective trial that tests whether early genetic diagnosis of specific dyshormonogenesis mutations leads to better long-term outcomes than standard neonatal screening and levothyroxine replacement alone. No data exist on whether identifying the precise genetic defect changes management or prognosis in a way that justifies routine sequencing. The cost-effectiveness and feasibility of targeted exome sequencing in all newborns with congenital hypothyroidism has not been established, and patient stratification by mutation type has not been prospectively linked to treatment response or developmental outcomes.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Journal of Clinical Endocrinology & Metabolism · 2001 · 232 citations · open access
Nineteen Years of National Screening for Congenital Hypothyroidism: Familial Cases with Thyroid Dysgenesis Suggest the Involvement of Genetic Factors
AbstractAlthough a few familial forms of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD) have been reported, this disorder is usually considered to be sporadic. Recently, we reported that 2% of CH patients with TD have a positive familial history. The aim of this study was to describe the clinical characteristics of these familial cases and to compare them with sporadic cases. We used the French national population-based registry of the first 19-yr screening program, which included 14,416,428 screened neonates with a 100% recovery rate. Familial history of CH with TD was investigated by means of a questionnaire sent to the pediatricians (n = 592) who provided ongoing clinical care for the 4049 CH patients detected during this period, including 2863 CH cases due to TD. Information was obtained from 73% of these pediatricians who were following up 2472 CH patients with TD (86%). In all, 67 patients with a positive family history of CH with TD were referred, belonging to 32 multiplex families (i.e. including at least 2 affected members). Families were identified with ectopic gland (n = 12), athyreosis (n = 7), or both (n = 13). Comparison of familial with isolated cases showed a similar etiological diagnosis distribution of CH (40% vs. 33% for athyreosis and 60% vs. 67% for ectopic thyroid gland, respectively), whereas a significantly lower predominance of females was found in familial than in isolated cases (1.4 vs. 2.7; P < 0.03). Extrathyroidal congenital malformations were found with a similarly higher incidence in familial and isolated CH populations compared with the general population (respectively, 9% and 8.2% vs. 2.5%). In conclusion, although familial cases represent a minority of cases of congenital hypothyroidism caused by thyroid dysgenesis, they were observed in a significantly higher proportion (>15-fold) than would be expected from chance alone. This familial clustering, including athyreosis and ectopic thyroid gland, strongly suggests that genetic factors could be involved in thyroid dysgenesis with a common underlying mechanism for both etiological groups. Moreover, the high proportion of extrathyroidal congenital malformations in a population affected by CH due to TD suggests that the potential genetic factors involved in thyroid gland organogenesis are also involved in the development of other organs.
Thyroid dyshormonogenesis is mainly caused by <i><scp>TPO</scp></i> mutations in consanguineous community
AbstractOBJECTIVE: In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH). CONTEXT: Thyroid dyshormonogenesis comprises 10-15% of all cases of congenital hypothyroidism (CH), which is the most common neonatal endocrine disorder, and might result from disruptions at any stage of thyroid hormone biosynthesis. Currently seven genes (NIS, TPO, PDS, TG, IYD, DUOX2 and DUOXA2) have been implicated in the aetiology of the disease. DESIGN: As TDH is mostly inherited in an autosomal recessive manner, we planned to conduct the study in consanguineous/multi-case families. PATIENTS: One hundred and four patients with congenital TDH all coming from consanguineous and/or multi-case families. MEASUREMENTS: Initially, we performed potential linkage analysis of cases to all seven causative-TDH loci as well as direct sequencing of the TPO gene in cases we could not exclude linkage to this locus. In addition, in silico analyses of novel missense mutations were carried out. RESULTS: TPO had the highest potential for linkage and we identified 21 TPO mutations in 28 TDH cases showing potential linkage to this locus. Four of 10 distinct TPO mutations detected in this study were novel (A5T, Y55X, E596X, D633N). CONCLUSIONS: This study underlines the importance of molecular genetic studies in diagnosis, classification and prognosis of CH and proposes a comprehensive mutation screening by new sequencing technology in all newly diagnosed primary CH cases.
Congenital hypothyroidism with goitre caused by new mutations in the thyroglobulin gene
AbstractCONTEXT: Thyroid dyshormonogenesis is associated with mutations in the thyroglobulin (TG) gene and characterized by normal organification of iodide and low serum TG. These mutations give rise to congenital goitrous hypothyroidism, transmitted in an autosomal recessive mode. OBJECTIVES: The aim of this study was to identify new mutations in the TG gene in an attempt to increase the understanding of the molecular basis of this disorder. Three unrelated patients with marked impairment of TG synthesis were studied. METHODS: The promoter and the complete coding regions of the TG gene, along with the flanking intronic regions, were analysed by direct DNA sequencing. RESULTS: Four different inactivating TG mutations, three novel mutations (c.548G>A, p.C164Y; c.759-760insA, p.L234fsX237; c.6701C>A, p.A2215D) and one previously identified mutation (c.886C>T, p.R277X) were identified. Multiple sequence alignment study revealed that the wild-type cysteine residue at position 164 is strictly conserved in the TG of all the species analysed, whereas the wild-type alanine residue at position 2215 is well conserved in the TG and acetylcholinesterase (AChE) of all the species analysed except in rabbit AChE, in which it is substituted by glutamic acid. CONCLUSIONS: We report three patients with congenital hypothyroidism with goitre caused by two compound heterozygous mutations, p.C164Y/p.L234fsX237 and p.R277X/p.A2215D, and one homozygous mutation, p.R277X, in the TG gene. To our knowledge this is the first report of the presence of a nucleotide insertion mutation in the TG gene.
Annals of Pediatric Endocrinology & Metabolism · 2018 · 30 citations · open access
Clinical genetics of defects in thyroid hormone synthesis
AbstractThyroid dyshormonogenesis is characterized by impairment in one of the several stages of thyroid hormone synthesis and accounts for 10%-15% of congenital hypothyroidism (CH). Seven genes are known to be associated with thyroid dyshormonogenesis: SLC5A5 (NIS), SCL26A4 (PDS), TG, TPO, DUOX2, DUOXA2, and IYD (DHEAL1). Depending on the underlying mechanism, CH can be permanent or transient. Inheritance is usually autosomal recessive, but there are also cases of autosomal dominant inheritance. In this review, we describe the molecular basis, clinical presentation, and genetic diagnosis of CH due to thyroid dyshormonogenesis, with an emphasis on the benefits of targeted exome sequencing as an updated diagnostic approach.
European Journal of Endocrinology · 1981 · 10 citations
Congenital familial thyroid aplasia
AbstractA family with 4 siblings, 3 of which have hypothyroidism due to thyroid aplasia is described. A review of the literature revealed 10 families with familial occurrence of this disorder without other malformations. Therefore, thyroid aplasia or dysplasia should no longer be called "sporadic cretinism" since autosomal recessive inheritance of this disorder appears to occur rather frequently.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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