PAX8

Chr 2AD

paired box 8

Also known as: PAX-8

NCBI Gene: 7849 ENSG00000125618 UniProt: Q06710

This gene encodes a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins that contain a paired box domain, an octapeptide, and a paired-type homeodomain. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

Primary Disease Associations & Inheritance

Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasiaMIM #218700

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

0.8

Missense Z

0.20

LOEUF· LoF intolerant

Clinical Summary— PAX8

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

8 Pathogenic / Likely Pathogenic· 59 VUS of 82 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — PAX8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.20LOEUF

pLI 0.999

Z-score 4.32

OE 0.04 (0.01–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.79Z-score

OE missense 0.87 (0.78–0.96)

239 obs / 275.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.20)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.78–0.96)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10

0≤1.21.6

LoF obs/exp: 1 / 23.7Missense obs/exp: 239 / 275.7Syn Z: -0.83

0.5771th %ile

GOF

0.3491th %ile

LOF

0.78top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 38% of P/LP variants are LoF · LOEUF 0.20

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNThese functional characteristics result in a dominant negative effect of PAX8-S48F on coexpressed wild-type PAX8 activity, which is not observed in paired domain mutations with DNA binding defect.PMID:15718293

GOFAutosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis.PMID:10102047

LOFFunctional characterization of four novel PAX8 mutations causing congenital hypothyroidism: new evidence for haploinsufficiency as a disease mechanism.PMID:22898500

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.