講演情報
[II-TKIS-OR-6]Genomic Insights into Congenital Portosystemic Shunt: Enrichment of Variants in Cilia-Related Genes
○Ryohei Matsuoka1,2, Kiyoshi Uike1,3, Hazumu Nagata1, Eiko Terashi1, Yusaku Nagatomo1, Yuichiro Hirata1, Yasunari Sakai1, Kenichiro Yamamura1, Chikara Meno2, Shouichi Ohga1 (1.Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 2.Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 3.Department of Cardiology, The Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada)
キーワード：
Congenital Portosystemic Shunt、whole-exome sequencing、vascular development
Objective
Congenital portosystemic shunt (CPSS) is a developmental vascular malformation often accompanied by multisystem features, including heterotaxy syndrome. We aimed to identify genetic contributors to syndromic CPSS and provide developmental support for candidate pathways.
Methods
Whole-exome sequencing was performed in 15 syndromic probands from a 46-patient CPSS cohort. Rare predicted deleterious variants were prioritized and evaluated by family-based and recurrent-variant analyses with gene-set permutation testing. Mouse embryos were immunostained for ARL13B and gamma-tubulin, and embryonic hepatic vasculature in Cryptic (right isomerism) and Lefty1 (left isomerism) mutants was imaged by light-sheet microscopy.
Results
Variants in cilia-related genes were significantly enriched (11/38 variants; empirical P = 0.0001). Primary cilia-related variants were frequent in infant-diagnosed end-to-side portocaval shunts, whereas motile cilia-related variants appeared in other subtypes, including heterotaxy. Bioinformatic analyses suggested possible oligogenic patterns involving combinations of ciliary and non-ciliary variants. ARL13B/gamma-tubulin-positive cilia were more prominent adjacent to venous than arterial structures (by anatomical landmarks) and were stronger at E9.5 than at E10.5. Light-sheet imaging revealed abnormal hepatic vascular connections in Lefty1-/- embryos.
Conclusion
Cilia-related variants are a major genetic signature of syndromic CPSS, and embryologic findings support links between ciliary pathways, laterality, and portal/hepatic vascular connectivity.
Congenital portosystemic shunt (CPSS) is a developmental vascular malformation often accompanied by multisystem features, including heterotaxy syndrome. We aimed to identify genetic contributors to syndromic CPSS and provide developmental support for candidate pathways.
Methods
Whole-exome sequencing was performed in 15 syndromic probands from a 46-patient CPSS cohort. Rare predicted deleterious variants were prioritized and evaluated by family-based and recurrent-variant analyses with gene-set permutation testing. Mouse embryos were immunostained for ARL13B and gamma-tubulin, and embryonic hepatic vasculature in Cryptic (right isomerism) and Lefty1 (left isomerism) mutants was imaged by light-sheet microscopy.
Results
Variants in cilia-related genes were significantly enriched (11/38 variants; empirical P = 0.0001). Primary cilia-related variants were frequent in infant-diagnosed end-to-side portocaval shunts, whereas motile cilia-related variants appeared in other subtypes, including heterotaxy. Bioinformatic analyses suggested possible oligogenic patterns involving combinations of ciliary and non-ciliary variants. ARL13B/gamma-tubulin-positive cilia were more prominent adjacent to venous than arterial structures (by anatomical landmarks) and were stronger at E9.5 than at E10.5. Light-sheet imaging revealed abnormal hepatic vascular connections in Lefty1-/- embryos.
Conclusion
Cilia-related variants are a major genetic signature of syndromic CPSS, and embryologic findings support links between ciliary pathways, laterality, and portal/hepatic vascular connectivity.
