Cross-Species Functional Analysis of a De Novo DCLK1 Variant Associated With a Neurodevelopmental Disorder

Authors

• David F Butler
• Weimin Yuan
• Hirokazu Hashimoto
• Hieu Hoang
• Jonathan H Sheehan
• Vanessa Gomez
• Jill A Rosenfeld
• Lindsay C Burrage
• Gary A Silverman
• Patricia Dickson
• Karen K Moeller
• Lisa Emrick
• Mythily Ganapathi
• Dustin Baldridge
• Oguz Kanca
• Carlos Bacino
• Brendan Lee
• Hugo J Bellen
• Shinya Yamamoto
• Wendy K Chung
• Tim Schedl
• Michael Wangler
• Andrew Yoo
• Stephen C Pak

Language

English

Publication Date

7-23-2026

Journal

Research Square

DOI

10.21203/rs.3.rs-10425123/v1

PMID

42539103

PMCID

PMC13419596

PubMedCentral® Posted Date

7-23-2026

PubMedCentral® Full Text Version

Pre-Print

Abstract

Neurodevelopmental disorders are genetically heterogeneous and often remain unresolved despite extensive clinical evaluation and genomic testing. Here, we report a proband with a progressive neurodevelopmental disorder evaluated through the Undiagnosed Diseases Network who harbored heterozygous de novo missense variants in two genes, DCLK1 (p.(S228L)) and SFPQ (p.(P623R)). To determine the clinical significance of these candidate variants, we employed an integrative pipeline combining structural modeling, cross-species functional genomics, and patient-derived neuronal analyses. While the SFPQ variant yielded no detectable phenotype in Drosophila melanogaster, modeling the DCLK1 p.S228L variant in Caenorhabditis elegans induced severe locomotor deficits and aberrant neuronal morphology, including neurite blebbing. Parallel analyses of directly reprogrammed patient-derived neurons recapitulated these neurite defects, characterized by neurite beading, swelling and fragmentation, and elevated apoptosis. Transcriptomic profiling revealed dysregulation of neurodevelopmental and axon-guidance pathways alongside molecular signatures of neurodegeneration. Crucially, exogenous expression of wild-type DCLK1 or pharmacological targeting of a downstream dysregulated pathway partially rescued the neurite defects. Collectively, our findings implicate DCLK1 in a previously unrecognized progressive neurodevelopmental disorder and demonstrate the power of integrative cross-species functional genomics in resolving ultra-rare disease variants.

Keywords

DCLK1, neurodevelopmental disorder, undiagnosed diseases, functional genomics, Caenorhabditis elegans, patient-derived neurons, neurite degeneration

Published Open-Access

yes

Recommended Citation

Butler, David F; Yuan, Weimin; Hashimoto, Hirokazu; et al., "Cross-Species Functional Analysis of a De Novo DCLK1 Variant Associated With a Neurodevelopmental Disorder" (2026). Faculty, Staff and Students Publications. 8366.
https://digitalcommons.library.tmc.edu/baylor_docs/8366