Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy
Yu‐Ri Lee, Kamal Khan, Kim Armfield-Uhas, Sujata Srikanth, Nicola Thompson, Mercedes Pardo, Lu Yu, Joy Norris, Yunhui Peng, Karen W. Gripp, Kirk Aleck, Chumei Li, Ed Spence, Tae‐Ik Choi, Soo Jeong Kwon, Hee‐Moon Park, Daseuli Yu, Won Do Heo, Marie R. Mooney, Shahid Mahmood 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, Charles E. Schwartz
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.