Novel <i>KIF26A</i> variants associated with pediatric intestinal pseudo‐obstruction ( <scp>PIPO</scp> ) and brain developmental defects
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.
Authors
- Alexander Joachim (ORCID: https://orcid.org/0000-0001-6724-0015)
- Annette Müller (ORCID: https://orcid.org/0000-0002-7368-5018)
- Ezio Fulcheri (ORCID: https://orcid.org/0000-0002-9041-4981)
- Francesca Buffelli (ORCID: https://orcid.org/0000-0003-1086-2651)
- Marcello Scala (ORCID: https://orcid.org/0000-0003-2194-7239)
- Valeria Capra (ORCID: https://orcid.org/0000-0002-3097-0388)
- Nihad A. Almasri (ORCID: https://orcid.org/0000-0002-3079-7327)
- Amir Hesam Nemati
- Michael C. Kruer (ORCID: https://orcid.org/0000-0002-1373-7891)
- Mohammad Sadegh Shams Nosrati (ORCID: https://orcid.org/0000-0002-5762-0601)
- Ferruccio Romano (ORCID: https://orcid.org/0009-0005-3933-0597)
- Peter T. Skidmore (ORCID: https://orcid.org/0000-0003-1051-5051)
- Federico Zara (ORCID: https://orcid.org/0000-0001-9744-5222)
- Mariasavina Severino (ORCID: https://orcid.org/0000-0003-4730-5322)
- Mahdi Zafari (ORCID: https://orcid.org/0000-0001-9906-1556)
- Christian Netzer (ORCID: https://orcid.org/0000-0002-9416-0712)
- Clara Velmans (ORCID: https://orcid.org/0000-0002-3352-1035)
- Pritha Bisarad (ORCID: https://orcid.org/0000-0002-2677-9847)
- Ilse Julia Broekaert
- Jonas Breuer
- Vincenzo Nigro
- Alireza Doustmohammadi
- Jumana Hoque
- Somayeh Bakhtiari
- Annalaura Torella
Institutions
- University of Jordan (JO)
- Northeastern University (US)
- Pasteur Institute of Iran (IR)
- Barrow Neurological Institute (US)
- University of Arizona (US)
- Witten/Herdecke University (DE)
- University of Cologne (DE)
- University of Campania "Luigi Vanvitelli" (IT)
- Istituto Giannina Gaslini (IT)
- Phoenix Children's Hospital (US)
- Telethon Institute Of Genetics And Medicine (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University Hospital Cologne (DE)
- Arizona State University (US)
- Qatar University (QA)
- University of Duisburg-Essen (DE)
- University of Genoa (IT)
Publication Details
- Journal
- Clinical Genetics
- Published
- 2024-09-21
- DOI
- https://doi.org/10.1111/cge.14621
- Citations
- 4
- Primary Topic
- Congenital gastrointestinal and neural anomalies
- Type
- article
- Field-Weighted Citation Impact
- 2.29
Funders
- Regione Liguria