615 - De novo variants in KIF26B, encoding kinesin family member 26B, are associated with neurological disorders

Publication Number: 4602.615

Qifei Li, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL, United States; Tzofia Drori, University of Miami Leonard M. Miller School of Medicine, MIAMI, FL, United States; Erin Torti, GeneDx, Gaithersburg, MD, United States; Casie A. Genetti, Boston Children's Hospital, Boston, MA, United States; Shiyu Luo, University of Miami Leonard M. Miller School of Medicine, Miami, FL, United States; Monica Wojcik, Boston Children's Hospital, Boston, MA, United States; Klaus Schmitz-Abe, University of Miami, Miami, FL, United States; Alan H.. Beggs, Boston Children's Hospital, Boston, MA, United States; Pankaj Agrawal, Holtz Children's Hospital Jackson Memorial Hospital, Miami, FL, United States

Background: Kinesin proteins are a family of motor proteins that play a critical role in intracellular transport and cell division. Abnormalities in kinesin function have been associated with a range of diseases, including neurodegenerative and developmental disorders and cancer. The kinesin family member 26B (KIF26B) belongs to an unconventional member of the kinesin superfamily that plays a role in regulating microtubule dynamics and organization, rather than participating in active transport. Mouse data suggests that Kif26b may be linked to kidney defects, but the few patients that have been reported with KIF26B mutations suggest its role in brain development.

Objective: This study assesses the role of KIF26B in human neurological development by reporting three unrelated individuals with de novo monoallelic variants and overlapping neurologic abnormalities, supported by complementary in silico, mouse model, and expression analyses.

Design/Methods: We report three unrelated individuals, each with a de novo monoallelic variant in KIF26B. We evaluated the clinical presentation in those patients, analyzed their variants using both supervised and unsupervised in silico prediction tools, examined phenotypes in more recent Kif26b-deficient mouse models, and assessed KIF26B mRNA expression in the human fetal brain using both single-cell and spatial transcriptomic data. Additionally, fetal brain tissue was stained with KIF26B antibody for immunohistochemical analysis.

Results: The three unrelated individuals share several neurologic abnormalities, including microcephaly (3/3), hypotonia (3/3), and developmental delay (2/3). Their variants are evaluated using both supervised and unsupervised in silico prediction tools. Additionally, analysis of Kif26b-deficient mice revealed that while homozygous mutants exhibit perinatal lethality, heterozygous ones develop neurological impairments in early adulthood. Furthermore, KIF26B mRNA is highly expressed in the developing human brain, particularly in the fetal cortex, with enrichment in the subventricular zone and upper cortical plate. This expression corresponds to the presence of KIF26B in outer radial glia, intermediate progenitor cells, and upper layer cortical neurons.

Conclusion(s): We present three cases with neurologic abnormalities associated with monoallelic KIF26B variants, further linking KIF26B to neurological disorders in humans.

Figure 1
Fig. 1. Loss-of-function and missense tolerance in the KIF superfamily. (A) Relationship between the missense and LOEUF scores. Genes linked to dominant diseases are shown in red, those linked to recessive are shown in blue, and those linked to mixed dominant and recessive are shown in orange. (B) Disease and inheritance distribution of 19 Known KIF genes cataloged in OMIM. (C) Relationship between the missense and LOEUF constraints among all 44 KIF genes. KIF26B is indicated by a purple triangle. (D) Heatmap of the transcription levels of all 44 KIF genes in various tissues.

Figure 2
Fig. 2. Three de novo KIF26B variants. (A) KIF26B variant tolerance analysis with MetaDome.2 The corresponding amino acids of KIF26B variants (arrows) are evolutionally conserved in orthologous species. Green: non-polar amino acids; Orange: polar amino acids; Pink: positive charge; Yellow: negative charge. (B) Variants are evaluated using in silico prediction tools. Red colors indicate pathogenic effects and blue colors for benign.

Figure 3
Fig. 3. Human KIF26B mRNA expression in brain. (A) KIF26B mRNA expression during brain development.3 (B) KIF26B mRNA throughout human embryonic and postnatal brain development adapted from Lin et al.'s study.4 (C) Cell-type clusters (left) and feature plot showing KIF26B mRNA expression (right) in GW17-18 fetal cortex. The dataset were obtained from Polioudakis et al.5 (D) Spatial z-score plot for KIF26B expression in the prefrontal cortex (PFC) at GW20 analyzed by MERFISH. M(E) Immunostaining image showing KIF26B expression in fetal PFC at GW 22. KIF26B expression is enriched in the SVZ and upper layer of the CP. Scale bar, 500µm.