Common genetic causes across motor neuron diseases identified

The researchers found significant overlap in the burden of ultrarare variants between ALS and HSP, including genetic variants newly identified to contribute to disease risk for both conditions. This included the canonical HSP gene AP4S1, which was found to be significantly enriched in ultrarare variants in ALS patients with European ancestry.

“One of the foundational principles underlying establishment of the CReATe Consortium was the idea that we should study multiple related disorders, with the expectation that we could leverage knowledge from one, to understand another,” said co-corresponding author Michael Benatar, MD, PhD, in the Department of Neurology at the University of Miami Miller School of Medicine. “The work published today underscores the value of this approach.” 

The study calls for more investigation into motor neuron disease-associated genes in an unbiased fashion, along with an open-minded approach to interpreting genetic mutations linked to specific diseases. This will ultimately help clinicians provide more personalized care for patients.

“Extensive progress has been made over the past decade to decode the genetic landscape of motor neuron diseases such as ALS and HSP,” said co-author J. Paul Taylor, MD, PhD, St. Jude Executive Vice President, Scientific Director, and Department of Cell and Molecular Biology chair. “This study furthers that cause by showing the overlapping contributions of canonically distinct genes, offering a clear path forward to more accurate diagnosis and care.”

Authors and funding

The study’s other authors are Wenan Chen, St. Jude and Mayo Clinic; Joanne Wuu, Volkan Granit, Jacob McCauley and Stephan Zuchner, University of Miami Miller School of Medicine; Angita Jain, Matthew Baker and Marka van Blitterswijk, Mayo Clinic; Isabell Cordts, Mayo Clinic and Technical University of Munich; Jeannine Heckmann and Melissa Nel, University of Cape Town; Jeffrey Statland, University of Kansas Medical Center; Andrea Swenson, University of Iowa Carver College of Medicine; John Ravits, University of California, San Diego; Corey McMillan and Lauren Elman, University of Pennsylvania Perelman School of Medicine; James Caress, Wake Forest School of Medicine; Ted Burns, University of Virginia School of Medicine; Erik Pioro, University of British Columbia; Jaya Trivedi, UT Southwestern Medical Center; Jonathan Katz, California Pacific Medical Center; Carlayne Jackson, University of Texas Health Science Center; Samuel Maiser and David Walk, University of Minnesota; Yuen So, Stanford University School of Medicine; Rosa Rademakers, Mayo Clinic, University of Antwerp and Vlaams Instituut voor Biotechnologie; and Jason Myers, and Evadnie Rampersaud St. Jude.

The study was supported by the National Institutes of Health (U54NS092091), the National Cancer Institute (P30CA021765), the ALS Association (17-LGCA-331 and 16-TACL-242), the Wellcome Trust (226519/Z/22/Z) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.