Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Yu-Ri Lee, Kamal Khan, Kim Armfield-Uhas, Sujata Srikanth, Nicola A. Thompson, Mercedes Pardo, Lu Yu, Joy W. Norris, Yunhui Peng, Karen W. Gripp, Kirk A. Aleck, Chumei Li, Ed Spence, Tae-Ik Choi, Soo Jeong Kwon, Hee-Moon Park, Daseuli Yu, Won Do Heo, Marie R. Mooney, Shahid M. Baig, Ingrid M. Wentzensen, Aida Telegrafi, Kirsty McWalter, Trevor Moreland, Chelsea Roadhouse, Keri Ramsey, Michael J. Lyons, Cindy Skinner, Emil Alexov, Nicholas Katsanis, Roger E. Stevenson, Jyoti S. Choudhary, David J. Adams, Cheol-Hee Kim (), Erica E. Davis () and Charles E. Schwartz ()
Additional contact information
Yu-Ri Lee: Chungnam National University
Kamal Khan: Duke University Medical Center
Kim Armfield-Uhas: Children’s Healthcare of Atlanta
Sujata Srikanth: Greenwood Genetic Center
Nicola A. Thompson: Wellcome Sanger Institute
Mercedes Pardo: Institute of Cancer Research
Lu Yu: Institute of Cancer Research
Joy W. Norris: Greenwood Genetic Center
Yunhui Peng: Clemson University
Karen W. Gripp: A. I. duPont Hospital for Children
Kirk A. Aleck: Phoenix Children’s Medical Group
Chumei Li: McMaster University Medical Center
Ed Spence: University of North Carolina School of Medicine
Tae-Ik Choi: Chungnam National University
Soo Jeong Kwon: Chungnam National University
Hee-Moon Park: Chungnam National University
Daseuli Yu: Korea Advanced Institute of Science and Technology
Won Do Heo: Korea Advanced Institute of Science and Technology
Marie R. Mooney: Duke University Medical Center
Shahid M. Baig: National Institute for Biotechnology and Genetic Engineering (NIBGE)
Ingrid M. Wentzensen: GeneDx Inc
Aida Telegrafi: GeneDx Inc
Kirsty McWalter: GeneDx Inc
Trevor Moreland: Greenwood Genetic Center
Chelsea Roadhouse: McMaster University Medical Center
Keri Ramsey: Center for Rare Childhood Disorders, TGen
Michael J. Lyons: Greenwood Genetic Center
Cindy Skinner: Greenwood Genetic Center
Emil Alexov: Clemson University
Nicholas Katsanis: Duke University Medical Center
Roger E. Stevenson: Greenwood Genetic Center
Jyoti S. Choudhary: Institute of Cancer Research
David J. Adams: Wellcome Sanger Institute
Cheol-Hee Kim: Chungnam National University
Erica E. Davis: Duke University Medical Center
Charles E. Schwartz: Greenwood Genetic Center

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). We report rare FAM50A missense variants in the original Armfield XLID syndrome family localized in Xq28 and four additional unrelated males with overlapping features. Our fam50a knockout (KO) zebrafish model exhibits abnormal neurogenesis and craniofacial patterning, and in vivo complementation assays indicate that the patient-derived variants are hypomorphic. RNA sequencing analysis from fam50a KO zebrafish show dysregulation of the transcriptome, with augmented spliceosome mRNAs and depletion of transcripts involved in neurodevelopment. Zebrafish RNA-seq datasets show a preponderance of 3′ alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex. These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. In sum, Armfield XLID syndrome is a spliceosomopathy associated with aberrant mRNA processing during development.

Date: 2020
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DOI: 10.1038/s41467-020-17452-6

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