Paediatric pseudo-obstruction syndrome

Gene: KIF26A

Green List (high evidence)

Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations - reported in all individuals. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.

Created: 31 Oct 2025, 1:46 p.m. | Last Modified: 31 Oct 2025, 1:49 p.m.

Panel Version: 2.4

At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

Note: several individuals died before certain clinical features could be assessed. The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/13 patients and corpus callosum agenesis / hypoplasia in 7/13 cases.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Post‐surgery, he had decreased stool frequency managed with macrogol; histopathological examination revealed features consistent with PIPO diagnosis. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).

Created: 31 Oct 2025, 11:43 a.m. | Last Modified: 31 Oct 2025, 12:02 p.m.

Panel Version: 2.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332

Publications

• 36228617
• 36564622
• 39305096

Green List (high evidence)

New patient with neurological impairment and paediatric intestinal pseudo-obstruction, has been found to be a carrier of KIF26A homozygous c.5111-2A>G LP variant.
Genetic diagnosis explains patient's history of developmental delay, brain abnormalities, hypertonia, and bowel issues.
AR inheritance, both parents confirmed to be carriers.
Consanguineous parents.

Another three patients published in 2024:
Nosrati MSS, Doustmohammadi A, Severino M, Romano F, Zafari M, Nemati AH, Velmans C, Netzer C, Breuer J, Broekaert IJ, Joachim A, Almasri N, Kruer MC, Skidmore P, Bisarad P, Hoque J, Bakhtiari S, Torella A, Nigro V, Buffelli F, Fulcheri E, Müller A, Zara F, Capra V, Scala M. Novel KIF26A variants associated with pediatric intestinal pseudo-obstruction (PIPO) and brain developmental defects. Clin Genet. 2025 Jan;107(1):83-90. doi: 10.1111/cge.14621.

Created: 14 Jul 2025, 10:11 a.m. | Last Modified: 14 Jul 2025, 10:11 a.m.

Panel Version: 2.1

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
KIF26A homozygous c.5111-2A>G LP varian

Red List (low evidence)

The rating of this gene has been updated to Red and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 7:44 a.m. | Last Modified: 1 Feb 2023, 7:44 a.m.

Panel Version: 0.216

Comment on rating: I do not find any cases in support of the implication of this gene in chronic megacolon and hence the rating should be RED. However, mouse models with Kif26a knockout developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities.

This gene has not yet been associated with megacolon or Hirschsprung disease in OMIM.

Created: 21 Dec 2022, 11:12 a.m. | Last Modified: 21 Dec 2022, 11:12 a.m.

Panel Version: 0.53

Publications

• 19914172
• 33542431

Review submitted on behalf of Dr. Anna Rybak and Dr. Osvaldo Borreli, Great Ormond Street Hospital for Children NHS Foundation Trust. Gene group: Genes involved in Hirschsprung disease (HSCR) in humans and models of megacolon. Protein function: kinesin family member 26A.

Created: 20 Dec 2022, 3:32 p.m. | Last Modified: 20 Dec 2022, 3:32 p.m.

Panel Version: 0.2

Mode of inheritance
Unknown

Phenotypes
GDNF-Ret in ENS development

Publications

• 30663199