HESX1 – Septo-optic dysplasia

HESX1, a paired-like homeobox transcriptional repressor, is critically involved in forebrain and pituitary development. Biallelic and heterozygous HESX1 mutations have been reported in patients with septo-optic dysplasia (SOD), characterized by optic nerve hypoplasia and midline brain defects. Mouse Hesx1 knockout models recapitulate human SOD, supporting a causal role for HESX1 disruption in disease pathogenesis.

1 Clinical validity (ClinGen category: Strong)

The association between HESX1 and SOD is supported by at least seven unrelated probands ([PMID:10895039], [PMID:14561704]) harboring pathogenic HESX1 variants, including homozygous missense and splice-site changes, and de novo frameshifts with segregation in affected sibships (2 affected relatives). Concordant functional data from knockout mice and in vitro assays further reinforce causality.

2 Genetic evidence (ClinGen Tier: Strong)

Inheritance is primarily autosomal recessive, although heterozygous mutations with incomplete penetrance have been described. Segregation includes two siblings homozygous for c.158-1G>C leading to SOD. Case series report at least six distinct pathogenic alleles across >7 probands, including missense, frameshift, and splice-site variants. Variant spectrum: 4 missense (e.g., c.77T>C (p.Ile26Thr)), 2 splice-site, and multiple truncating alleles ([PMID:11136712], [PMID:12519827]). No founder or recurrent population-specific alleles have been established.

3 Functional evidence (ClinGen Tier: Moderate)

Hesx1-null mice display optic vesicle failure and Rathke’s pouch agenesis mirroring human SOD ([PMID:11748154]). Mutant HESX1 proteins demonstrate impaired DNA binding or altered corepressor interactions, including loss of Groucho recruitment and defective repression of PROP1 targets ([PMID:14561704], [PMID:17931718]). Rescue experiments and promoter assays confirm loss-of-function as the mechanism.

4 Conflicting evidence

Large screening of 724 patients with SOD and hypopituitarism identified HESX1 mutations in <1%, suggesting genetic heterogeneity and environmental contributions such as prenatal insults ([PMID:17148560]).

5 Integration & conclusion

Genetic and experimental data establish a strong causal link between HESX1 loss-of-function and septo-optic dysplasia. While rare, HESX1 testing is warranted in SOD cases with optic nerve hypoplasia and pituitary anomalies. Additional modifiers likely influence penetrance and expressivity. Key take-home: HESX1 mutation analysis informs molecular diagnosis and risk counseling in SOD.

References

• Hormone research • 2000 • Molecular genetics of septo-optic dysplasia. PMID:10895039
• The Journal of clinical investigation • 2003 • A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. PMID:14561704
• Human molecular genetics • 2001 • Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. PMID:11136712
• Development (Cambridge, England) • 2001 • Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. PMID:11748154
• Biochimica et biophysica acta • 2008 • DNMT1 interacts with the developmental transcriptional repressor HESX1. PMID:17931718
• The Journal of clinical endocrinology and metabolism • 2007 • HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. PMID:17148560

Evidence Based Scoring (AI generated)