Human genetics and molecular genomics of Chiari malformation type 1

Kedous Y. Mekbib, William Muñoz, Garrett Allington, Stephen McGee, Neel H. Mehta, John P. Shofi, Carla Fortes, Hao Thi Le, Carol Nelson-Williams, Pranav Nanda, Evan Dennis, Adam J. Kundishora, Arjun Khanna, Hannah Smith, Jack Ocken, Ana B.W. Greenberg, Rui Wu, Andres Moreno-De-Luca, Tyrone DeSpenza, Shujuan ZhaoArnaud Marlier, Sheng Chih Jin, Seth L. Alper, William E. Butler, Kristopher T. Kahle

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations


Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a ‘one-size-fits-all’ surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes.

Original languageEnglish
Pages (from-to)1059-1075
Number of pages17
JournalTrends in Molecular Medicine
Issue number12
StatePublished - Dec 2023


  • Chiari malformation type 1
  • cranio-cervical junction
  • craniometric measurements
  • neurodevelopmental disorders
  • whole-exome sequencing


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