Familial Central Hypothyroidism Caused by a Novel <i>IGSF1</i> Gene Mutation
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".