PITX2 – Anterior Segment Dysgenesis 4

PITX2 encodes a paired-like homeodomain transcription factor essential for anterior segment development of the eye. Heterozygous variants in PITX2 underlie autosomal dominant anterior segment dysgenesis 4 (ASD4), characterized by iris stromal hypoplasia, an incomplete line of Schwalbe, and early‐onset glaucoma (PMID:14985297).

ClinGen categorizes the PITX2–ASD4 association as Definitive based on identification of ~64 unrelated probands with ASD4 phenotypes harboring diverse PITX2 point mutations and microdeletions, segregation in a multigenerational kindred, and extensive functional concordance. Segregation analysis demonstrated cosegregation of a 4q25 microdeletion with ASD4 in an extended family (PMID:14985297).

Genetically, ASD4 follows an autosomal dominant inheritance pattern. Across cohorts, at least 23 distinct missense and truncating variants have been reported in ~64 probands, including c.350C>G (p.Pro117Arg) in the homeodomain, with no evidence of biallelic occurrence in unaffected individuals (PMID:14985297).

Functional assays demonstrate that ASD4‐associated PITX2 missense variants (e.g., p.Thr30Pro, p.Arg31His) exhibit graded reductions in DNA binding and transactivation proportional to phenotypic severity, supporting a hypomorphic mechanism (PMID:10958652). In vivo overexpression of PITX2A in mouse corneal mesenchyme induces corneal opacification and irido‐corneal adhesions mirroring human ASD4, confirming dosage sensitivity (PMID:15509533).

No pathogenic PITX2 variants have been identified in large cohorts of patients with isolated transposition of the great arteries, ruling out a common role in cardiac laterality defects and supporting eye‐specific pathogenicity (PMID:15890066).

In summary, heterozygous loss‐ and gain-of-function PITX2 variants cause ASD4 via a dominant mechanism, with robust genetic and experimental evidence. Clinical testing for PITX2 variants informs diagnosis, risk of glaucoma, and genetic counseling.

References

• Invest Ophthalmol Vis Sci • 2004 • Characterization and prevalence of PITX2 microdeletions and mutations in Axenfeld-Rieger malformations. PMID:14985297
• Hum Mol Genet • 2000 • Variation in residual PITX2 activity underlies the phenotypic spectrum of anterior segment developmental disorders. PMID:10958652
• Am J Pathol • 2004 • PITX2 gain-of-function in Rieger syndrome eye model. PMID:15509533
• BMC Med Genet • 2005 • Mutational analysis of the PITX2 coding region revealed no common cause for transposition of the great arteries (dTGA). PMID:15890066

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