SIN3A – Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (MONDO:0005711) is a severe structural malformation characterized by pulmonary hypoplasia and hypertension. Despite its prevalence, the molecular underpinnings remain poorly understood.

Recent genomic analysis identified loss-of-function sequence variants in SIN3A in two unrelated patients with complex CDH (PMID:38295182). No segregation data are available, but both probands exhibited pulmonary hypoplasia (HP:0002089) and pulmonary arterial hypertension (HP:0002092).

Tissue-specific deletion of Sin3a in mouse diaphragm and lung mesenchyme recapitulated key CDH features including hypoplastic lung development and elevated pulmonary vascular resistance (PMID:38295182).

Treatment of embryonic Sin3a mutant mice with the histone acetyltransferase inhibitor anacardic acid reduced DNA damage, increased mesenchymal cell proliferation and differentiation, improved lung alveolarization, and attenuated pulmonary hypertension, demonstrating functional rescue (PMID:38295182).

Mechanistically, SIN3A haploinsufficiency disrupts histone deacetylation balance in lung mesenchyme, leading to impaired chromatin regulation, reduced proliferation, and increased genotoxic stress. Restoration of histone acetylation homeostasis offers a promising therapeutic avenue.

Together, these data support a Moderate clinical validity for SIN3A in congenital diaphragmatic hernia, with limited genetic evidence (2 probands) augmented by robust in vivo functional data. Key Take-home: SIN3A haploinsufficiency underpins a subset of CDH through epigenetic dysregulation, and histone acetylation inhibitors may offer targeted therapy.

References

• Science Translational Medicine • 2024 • Rescuing lung development through embryonic inhibition of histone acetylation. PMID:38295182

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