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

Mohammad Sadegh Shams Nosrati1,2, Alireza Doustmohammadi3, Mariasavina Severino4

  • 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

Clinical Genetics
|September 21, 2024
PubMed

Insights

Newly identified KIF26A gene variants cause congenital hydrocephalus, neurodevelopmental issues, and intestinal obstruction in children. This expands the known spectrum of KIF26A-related disorders, offering insights into rare pediatric conditions.

Area of Science:

  • Genetics
  • Neuroscience
  • Pediatric Medicine

Background:

  • Pediatric intestinal pseudo-obstruction (PIPO) is a rare congenital disorder affecting the enteric nervous system, potentially causing intestinal obstruction.
  • Biallelic KIF26A variants have been linked to neurodevelopmental conditions with PIPO-like symptoms, but aganglionosis was not previously observed.

Purpose of the Study:

  • To investigate the genetic basis and phenotypic spectrum of KIF26A-related disorders in three subjects presenting with congenital hydrocephalus, neurodevelopmental impairment, and intestinal obstruction.

Main Methods:

  • Trio-exome sequencing (ES) was performed to identify genetic variants.
  • Brain MRI was used to assess cortical malformations.
  • Intestinal pathology confirmed aganglionosis and elevated acetylcholinesterase activity.
  • 3D protein modeling (Alphafold3, YASARA) analyzed the impact of missense variants.

Main Results:

  • Three subjects presented with congenital hydrocephalus, neurodevelopmental impairment, and intestinal obstruction with megacolon.
  • Brain MRI revealed cortical dysplasia spectrum malformations, including polymicrogyria and heterotopia.
  • Intestinal pathology showed aganglionosis and elevated acetylcholinesterase activity.
  • Four novel biallelic KIF26A variants (two missense, two truncating) were identified, predicted to be deleterious.
  • 3D protein modeling indicated structural destabilization for missense variants.

Conclusions:

  • This study expands the known genotype and phenotype spectrum of KIF26A-related disorders.
  • Novel KIF26A variants are associated with a complex phenotype including congenital hydrocephalus, neurodevelopmental impairment, and intestinal aganglionosis.
  • KIF26A plays a critical role in enteric neural crest cell development and its dysfunction leads to severe congenital anomalies.

Keywords:
KIF26Abrain malformationscongenital megacolonexome sequencingkinesinneurodevelopmental disorder

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