2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-<em>KIF26A</em> is mutated in the syndrome of congenital hydrocephalus with megacolon

Pdf Summary

KIF26A is a gene that has been found to be mutated in individuals with congenital hydrocephalus (a condition characterized by an accumulation of cerebrospinal fluid in the brain) and megacolon (a condition characterized by an abnormally large colon). The enteric nervous system (ENS), which consists of neurons and glial cells along the gastrointestinal tract, plays a crucial role in the development of the ENS. Glial cell-derived neurotrophic factor (GDNF) signaling is important in this process. Pathogenic variants in the RET gene, which reduce GDNF/Ret-GFRα1 signaling, are known to cause Hirschsprung's disease. <br /><br />Studies on mice have shown that KIF26A deficiency leads to abnormal GDNF-Ret signaling and the failure to establish normal neuronal networks. In humans, loss of KIF26A has been found to cause abnormal brain development and severe ENS dysfunction. <br /><br />In this study, five individuals from two families with a homozygous truncating variant in the KIF26A gene were found to have profound ENS dysfunction similar to Hirschsprung's disease, despite normal ganglionosis. These individuals also had brain malformations ranging from ventriculomegaly to severe hydrocephalus. They displayed developmental delay and, in one case, spastic paraplegia. Similar intestinal and neurological phenotypes were observed in mice deficient in KIF26A.<br /><br />The study suggests that KIF26A deficiency should be considered in the diagnosis of patients with severe ENS dysfunction who do not show aganglionosis on biopsy. Future research should identify milder variants of KIF26A and further explore the phenotypic spectrum of this disorder.

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Presenting Author - Mohammed Almannai, MD; Co-Author - Lama AlAbdi, PhD; Co-Author - Sateesh Maddirevula, PhD; Co-Author - Maha Alotaibi, MD; Co-Author - Bader AlSaleem, MD; Co-Author - Yaser Aljadhai, MD; Co-Author - Hessa Alsaif, PhD; Co-Author - Mussad Abu Khalid, PhD; Co-Author - Fowzan S. Alkuraya, MD, FACMG;

Meta Tag

Brain/Nervous System

Congenital Anomaly

Delineation of Diseases

Exome sequencing

Gastrointestinal System

Identification of Disease Genes

Co-Author Lama AlAbdi, PhD

Co-Author Sateesh Maddirevula, PhD

Co-Author Maha Alotaibi, MD

Co-Author Bader AlSaleem, MD

Co-Author Yaser Aljadhai, MD

Co-Author Hessa Alsaif, PhD

Co-Author Mussad Abu Khalid, PhD

Co-Author Fowzan S. Alkuraya, MD, FACMG

Presenting Author Mohammed Almannai, MD

Keywords

KIF26A

gene mutation

congenital hydrocephalus

megacolon

enteric nervous system

glial cell-derived neurotrophic factor

GDNF signaling

RET gene

Hirschsprung's disease

abnormal brain development