Novel KIF26A variants associated with pediatric intestinal pseudo‐obstruction (PIPO) and brain developmental defects

• Published in: Clinical genetics Vol. 107; no. 1; pp. 83 - 90
• Main Authors: Nosrati, Mohammad Sadegh Shams, Doustmohammadi, Alireza, Severino, Mariasavina, Romano, Ferruccio, Zafari, Mahdi, Nemati, Amir Hesam, Velmans, Clara, Netzer, Christian, Breuer, Jonas, Broekaert, Ilse Julia, Joachim, Alexander, Almasri, Nihad, Kruer, Michael C., Skidmore, Peter, Bisarad, Pritha, Hoque, Jumana, Bakhtiari, Somayeh, Torella, Annalaura, Nigro, Vincenzo, Buffelli, Francesca, Fulcheri, Ezio, Müller, Annette, Zara, Federico, Capra, Valeria, Scala, Marcello
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2025
• Subjects: Acetylcholinesterase; Brain - diagnostic imaging; Brain - pathology; brain malformations; Cell differentiation; Cell migration; Child; Child, Preschool; Congenital defects; Congenital diseases; congenital megacolon; Dysplasia; Enteric nervous system; Exome Sequencing; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotypes; Humans; Hydrocephalus; Infant; Intestinal obstruction; Intestinal Pseudo-Obstruction - genetics; Intestinal Pseudo-Obstruction - pathology; Intestine; KIF26A; kinesin; Kinesins - genetics; Magnetic Resonance Imaging; Male; Mutation; Mutation, Missense - genetics; Neural coding; Neural crest; neurodevelopmental disorder; Neurodevelopmental disorders; Parasympathetic nervous system; Pediatrics; Phenotype; Phenotypes; Polymicrogyria; Proteins; Short Report; Whole genome sequencing; exome sequencing; congenital megacolon; KIF26A; neurodevelopmental disorder; brain malformations; kinesin
• DOI: 10.1111/cge.14621
• ISSN: 0009-9163; 1399-0004

Pediatric intestinal pseudo‐obstruction (PIPO) is a rare congenital disorder of the enteric nervous system with distal colon aganglionosis potentially leading to intestinal obstruction. Recently, biallelic variants in KIF26A, encoding a crucial motor protein for the migration and differentiation of enteric neural crest cells, have been associated with a neurodevelopmental condition featuring cortical defects and PIPO‐like features, though in absence of aganglionosis. So far, only 10 patients have been reported. In this study, we investigated three subjects with congenital hydrocephalus, neurodevelopmental impairment, and intestinal obstruction megacolon syndrome. Brain MRI revealed malformations within cortical dysplasia spectrum, including polymicrogyria and heterotopia. Pathology study of the intestine revealed aganglionosis and elevated acetylcholinesterase activity in parasympathetic nerve fibers. Through trio‐exome sequencing (ES), we detected four novel biallelic KIF26A variants, including two missense changes (#1) and two distinct homozygous truncating variants in (#2 and #3). All variants are rare and predicted to be deleterious according to in silico tools. To characterize the impact of the missense variants, we performed 3D protein modeling using Alphafold3 and YASARA. Mutants exhibited increased energy scores compared to wild‐type protein, supporting a significant structural destabilization of the protein. Our study expands the genotype and phenotype spectrum of the emerging KIF26A‐related disorder. This study identifies novel biallelic KIF26A variants in three patients with congenital hydrocephalus and intestinal obstruction. Using 3D protein modeling, we reveal that missense variants cause significant structural destabilization of the KIF26A protein. Additionally, histopathology data show aganglionosis and elevated acetylcholinesterase activity, expanding the genotype–phenotype spectrum of this emerging disorder.