602 - Genomic Insights into Congenital Portosystemic Shunt: Enrichment of Variants in Cilia-Related Genes

Publication Number: 4590.602

Ryohei Matsuoka, Kyushu University, Fukuoka, Fukuoka, Japan; Kiyoshi Uike, The Hospital for Sick Children, Toronto, ON, Canada; Hazumu Nagata, Fukuoka Children's Hospital, Fukuoka, Fukuoka, Japan; Eiko Terashi, Kyushu university, Fukuoka, Fukuoka, Japan; Yusaku Nagatomo, Kyushu University Hospital, Fukuoka, Fukuoka, Japan; Yuichiro Hirata, Kyushu University, Fukuoka, Fukuoka, Japan; Motoshi Sonoda, Kyushu University, Fukuoka, Fukuoka, Japan; Kanako Kojima-Ishii, Fukuoka Children's Hospital, Fukuoka, Fukuoka, Japan; Toshiharu Matsuura, Kyushu University, Fukuoka, Fukuoka, Japan; Tatsuro Tajiri, Kyushi University, Fukuoka, Fukuoka, Japan; Kohtaro Abe, Kyushu University Hospital, Fukuoka, Fukuoka, Japan; Yasunari Sakai, Kyushu University, Fukuoka, Fukuoka, Japan; Kenichiro Yamamura, Kyushu University Hospital, Fukuoka, Fukuoka, Japan; Shouichi Ohga, Kyushu University, Fukuoka, Fukuoka, Japan

Background: Congenital portosystemic shunt (CPSS) is a rare vascular malformation where the portal blood bypasses hepatic metabolism, and enters the systemic circulation directly, leading to systemic complications. Many patients often present with syndromic manifestations involving multiple organs beyond shunt-related complications.

Objective: This study aimed to elucidate the genetic basis underlying these complex CPSS phenotypes.

Design/Methods: Whole-exome sequencing (WES) was performed on 15 probands specifically selected for their syndromic features from a cohort of 46 CPSS patients in Kyushu University Hospital. Given the absence of definitively established CPSS-associated genes, rare and predicted deleterious variants remaining after a stringent filtering strategy were prioritized. Candidate variants were further examined using family-based and recurrent variant analyses, followed by functional enrichment and oligogenic inheritance analyses.

Results: The 15 WES probands exhibited central nervous system disorders (60.0%), cardiovascular disorders (53.3%), facial dysmorphism (46.7%), and low birth weight (46.7%). No single gene harbored recurrent variants across multiple probands. However, both the family-based and recurrent variant analyses revealed a significant enrichment of variants in cilia-related genes. Overall, potentially pathogenic variants in cilia-related genes were identified in 86.7% (13/15) of the syndromic CPSS probands, including variants in C2CD3, SFI1, PTPN11, SYNE1, MYO9A, MYO15A, GPR173, CNGA2, RP1L1, RSPH1, DNAH11, and DNAH1. Most end-to-side portocaval shunt (ESPC) type CPSS probands were diagnosed during infancy and predominantly carried sensory cilia-related gene variants. Motile cilia-related gene variants were detected in some probands with other types of CPSS, including a patient with heterotaxy. Bioinformatic analyses indicated potential oligogenic contributions to syndromic CPSS pathogenesis, involving combinations of ciliary and non-ciliary gene variants. The identified cilia-related genes were expressed in murine embryonic tissues during stages of portal vein development, according to a public database.

Conclusion(s): The enrichment of cilia-related gene variants indicates that CPSS likely reflects the condition of impaired remodeling of embryonic veins. This genetic burden supports the involvement of ciliary dysfunction in failure of complete separation between the developing portal and systemic circulations.

Filtering strategy for the candidate genes responsible for syndromic CPSS
Schematic overview of the filtering strategy used to identify candidate gene variants for congenital portosystemic shunt (CPSS) from whole-exome sequencing data of 15 probands. CPSS, congenital portosystemic shunt; MAF, minor allele frequency; CADD, combined annotation-dependent depletion; P, pathogenic; LP, likely pathogenic; CNV, copy number variant; CGH, comparative genomic hybridization.

Demographics and characteristics of patients with CPSS
Values are expressed as No. (%) or median (range). CPSS, Congenital portosystemic shunt; WES, Whole-exome sequencing.

Genotype and phenotype of individuals with candidate genes for syndromic CPSS
Clinical characteristics and candidate gene variants identified in each of the 15 probands who underwent WES are summarized. Probands 1-12 (above the dashed line) had parental data available, allowing for family-based analysis (or duo-based analysis as specified in Figure 1) in addition to recurrent variant analysis. Probands 13-15 (below the dashed line) were singletons, and thus only recurrent variant analysis was performed for candidate gene identification. The heatmap section illustrates the number of specific abnormalities within each affected organ system, as indicated by the key at the bottom. Candidate genes identified through family-based analysis and recurrent variant analysis are listed for each proband. Genes highlighted in bold are those classified as cilia-related according to our defined criteria. *Age at diagnosis. ESPC, end-to-side portocaval shunt; EHPS, extrahepatic portosystemic shunt; SSPC, side-to-side portocaval shunt; PDV, patent ductus venosus; PAH, pulmonary arterial hypertension; CNS, central nervous system; ORL, otorhinolaryngological; NA, not applicable.