2023.01.24
A novel NONO variant that causes developmental delay and cardiac phenotypes
Sci Rep. 2023 Jan 18;13(1):975. doi: 10.1038/s41598-023-27770-6.
Itai T1, Sugie A2, Nitta Y2, Maki R3, Suzuki T3, Shinkai Y4, Watanabe Y5, Nakano Y6, Ichikawa K7, Okamoto N8, Utsuno Y1, Koshimizu E1, Fujita A1, Hamanaka K1, Uchiyama Y1,9, Tsuchida N1,9, Miyake N10, Misawa K1,11, Mizuguchi T1, Miyatake S1,12, Matsumoto N1.
1Department of Human Genetics, Yokohama City University Graduate School of Medicine.
2Brain Research Institute, Niigata University.
3School of Life Science and Technology, Tokyo Institute of Technology.
4Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST).
5Children's Medical Center, Yokohama City University Medical Center.
6Department of Pediatric Cardiology, Yokohama City University Hospital.
7Department of Pediatrics, Fujisawa City Hospital.
8Department of Medical Genetics, Osaka Women's and Children's Hospital.
9Department of Rare Disease Genomics, Yokohama City University Hospital.
10Department of Human Genetics, Research Institute, National Center for Global Health and Medicine.
11RIKEN Center for Advanced Intelligence Project.
12Clinical Genetics Department, Yokohama City University Hospital.
Abstract
The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g., distinctive facial features, cardiac symptoms, and skeletal symptoms) in an X-linked recessive manner. Most of the reported variants have been LoF variants, and two missense variants have been reported as likely deleterious but with no functional validation. We report three individuals from two families harboring an identical missense variant that is located in the nuclear localization signal, NONO: NM_001145408.2:c.1375C > G p.(Pro459Ala). All of them were male and the variant was inherited from their asymptomatic mothers. Individual 1 was diagnosed with developmental delay and cardiac phenotypes (ventricular tachycardia and dilated cardiomyopathy), which overlapped with the features of reported individuals having NONO LoF variants. Individuals 2 and 3 were monozygotic twins. Unlike in Individual 1, developmental delay with autistic features was the only symptom found in them. A fly experiment and cell localization experiment showed that the NONO variant impaired its proper intranuclear localization, leading to mild LoF. Our findings suggest that deleterious NONO missense variants should be taken into consideration when whole-exome sequencing is performed on male individuals with developmental delay with or without cardiac symptoms.
*Reprinted under the terms of the Creative Commons Attribution License (CC BY).
