Curation XLID SOX3

Gene SOX3

Disease XLID, PHPX

Inheritance XR

Score

3 + 2 = 5 / 18

Genetic + experimental = total

Classification

Limited

Refuted

Moderate

Definitive

Last Updated 05/14/2026

Pubs Reviewed 4

Publication Span 0.88 years

Publication Interval 0.88 years

Curator(s) Laurel Hiatt, Macayla Weiner, Harriet Dashnow

Description

Patients have been reported with SOX3 polyalanine repeat mutations associated with X-linked pituitary hormone deficiency with or without intellectual disability, with functional studies showing altered transactivation, protein aggregation in overexpression systems, and reduced SOX3 protein levels in a mouse expansion model. 5 total patients across 2 papers and a mouse model. SOX3 has previously been curated by the ClinGen Syndromic Disorders GCEP (08/02/2023) for SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder.

All criTRia Curations Locus Page

Genetic evidence

Total: 3

Per page

Category	Type	Citation	Score	Details
Singular Evidence	Probands	PMID:24346842	1.5	One male proband with molecularly confirmed Kabuki syndrome and CPHD carried a hemizygous 21-bp SOX3 polyalanine-tract deletion (p.Ala239_245del7A); the SOX3 deletion was maternally inherited, while a separate MLL2 variant was de novo.
Collective Evidence	Segregation	PMID:19654509	1.5	One family with three affected males carrying a 21-bp in-frame SOX3 polyalanine expansion (+7 alanines) segregating with GH deficiency through carrier females; LOD = 2.68 and the expansion was absent from 100 control females.

Experimental evidence

Total: 2

Per page

Category	Type	Citation	Score	Details
Function	Regulatory impact	PMID:17127446	0.5	SOX3 polyalanine expansion mutants showed impaired transcriptional activation and reduced repression of β-catenin/TCF-mediated transcription in reporter assays.
Function	Biochemical function	PMID:17127446	0.5	SOX3 +7 and +11 alanine expansion proteins formed cytoplasmic and nuclear aggregates, including aggresome-like perinuclear aggregates, in transfected cell systems and chick neural explants.
Models	Non-human model organism	PMID:23505376	1	Sox3-26ala mouse/ES-cell model showed markedly reduced nuclear SOX3 protein, pituitary-region developmental abnormalities, no detectable in vivo aggregates, and a partial loss-of-function mechanism.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.