Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy PMID: 32703943

GLP-1 and Obesity Research

2026-08-18

Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Nat Commun. 2020 Jul 23;11(1):3698. doi: 10.1038/s41467-020-17452-6.

Yu-Ri Lee ^# ¹ , Kamal Khan ^# ² ³ ⁴ ⁵ , Kim Armfield-Uhas ^# ⁶ , Sujata Srikanth ^# ⁷ , Nicola A Thompson ⁸ , Mercedes Pardo ⁹ , Lu Yu ⁹ , Joy W Norris ⁷ , Yunhui Peng ¹⁰ , Karen W Gripp ¹¹ , Kirk A Aleck ¹² , Chumei Li ¹³ , Ed Spence ¹⁴ , Tae-Ik Choi ¹ , Soo Jeong Kwon ¹⁵ , Hee-Moon Park ¹⁵ , Daseuli Yu ¹⁶ , Won Do Heo ¹⁶ , Marie R Mooney ² ³ , Shahid M Baig ⁴ , Ingrid M Wentzensen ¹⁷ , Aida Telegrafi ¹⁷ , Kirsty McWalter ¹⁷ , Trevor Moreland ⁷ , Chelsea Roadhouse ¹³ , Keri Ramsey ¹⁸ , Michael J Lyons ⁷ , Cindy Skinner ⁷ , Emil Alexov ¹⁰ , Nicholas Katsanis ² ³ ¹⁹ , Roger E Stevenson ⁷ , Jyoti S Choudhary ⁹ , David J Adams ⁸ , Cheol-Hee Kim ²⁰ , Erica E Davis ²¹ ²² ²³ , Charles E Schwartz ²⁴

Affiliations

1. Department of Biology, Chungnam National University, Daejeon, Korea.
2. Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA.
3. Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
4. Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
5. Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad, Pakistan.
6. Children's Healthcare of Atlanta, Atlanta, GA, USA.
7. Greenwood Genetic Center, Greenwood, SC, USA.
8. Wellcome Sanger Institute, Hinxton, Cambridge, UK.
9. Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
10. Department of Physics, Clemson University, Clemson, SC, USA.
11. Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, DE, USA.
12. Genetics and Metabolism, Phoenix Children's Medical Group, Phoenix, AZ, USA.
13. Clinical Genetics Program, McMaster University Medical Center, Hamilton, ON, Canada.
14. Division of Pediatric Genetics and Metabolism, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
15. Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, Korea.
16. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
17. GeneDx Inc, Gaithersburg, MD, USA.
18. Center for Rare Childhood Disorders, TGen, Phoenix, AZ, USA.
19. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
20. Department of Biology, Chungnam National University, Daejeon, Korea. [email protected].
21. Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA. [email protected].
22. Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA. [email protected].
23. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
24. Greenwood Genetic Center, Greenwood, SC, USA. [email protected].
# Contributed equally.

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.