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Background <p>Persistent cloaca (PC), the most severe subtype of congenital anorectal malformations (ARMs) in female infants with an incidence of 1/50,000 live births, has poorly understood etiology.</p> Methods <p>The study enrolled 12 Chinese PC patients (4 trio families, 8 unrelated individuals), performed whole exome sequencing (WES) via the CG Black Bird platform, extracted genomic DNA from peripheral blood and cryopreserved surgical specimens, annotated variants using databases (dbSNP, gnomAD) and tools (SIFT/PolyPhen2), assessed pathogenicity by 2015 ACMG/AMP Guidelines, and validated via Sanger sequencing. We generated Dnah2⁻/⁻ mice and silenced DNAH2 in human mesenchymal stem cells (hMSCs) to detect SHH pathway proteins.</p> Results <p>A novel DNAH2 compound heterozygous variant (p.Ser312Thr, p.Arg573Cys, inherited from asymptomatic parents) was identified in one trio, both classified as Variants of Unknown Significance (VUS). Dnah2⁻/⁻ mice showed vaginal atresia and features consistent with ciliary dysfunction; DNAH2 silencing in hMSCs reduced Smo (53.1%), Gli2 (66.4%).</p> Conclusion <p>The first report of the DNAH2 compound heterozygous variant in Chinese PC patients suggests DNAH2 should be considered a candidate susceptibility gene for PC (limited by small sample, conflicting evidence, model flaws), providing a preliminary basis for cilia-associated gene research in PC.</p>

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A novel compound heterozygous variant in DNAH2: preliminary evidence of a potential genetic modifier for persistent cloaca in a Chinese family

  • 期刊论文

  • 发表日期：

    2026年6月2日

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  • Chen Wang,
  • Hongsong Wu,
  • Liyan Wang,
  • Tao Liu,
  • Lei Wu,
  • Yongqiang Ye,
  • Yongqi Yan,
  • Li Long,
  • Sen Li,
  • Zhen Chen

摘要

Background

Persistent cloaca (PC), the most severe subtype of congenital anorectal malformations (ARMs) in female infants with an incidence of 1/50,000 live births, has poorly understood etiology.

Methods

The study enrolled 12 Chinese PC patients (4 trio families, 8 unrelated individuals), performed whole exome sequencing (WES) via the CG Black Bird platform, extracted genomic DNA from peripheral blood and cryopreserved surgical specimens, annotated variants using databases (dbSNP, gnomAD) and tools (SIFT/PolyPhen2), assessed pathogenicity by 2015 ACMG/AMP Guidelines, and validated via Sanger sequencing. We generated Dnah2⁻/⁻ mice and silenced DNAH2 in human mesenchymal stem cells (hMSCs) to detect SHH pathway proteins.

Results

A novel DNAH2 compound heterozygous variant (p.Ser312Thr, p.Arg573Cys, inherited from asymptomatic parents) was identified in one trio, both classified as Variants of Unknown Significance (VUS). Dnah2⁻/⁻ mice showed vaginal atresia and features consistent with ciliary dysfunction; DNAH2 silencing in hMSCs reduced Smo (53.1%), Gli2 (66.4%).

Conclusion

The first report of the DNAH2 compound heterozygous variant in Chinese PC patients suggests DNAH2 should be considered a candidate susceptibility gene for PC (limited by small sample, conflicting evidence, model flaws), providing a preliminary basis for cilia-associated gene research in PC.