Genetic and phenotypic spectrum in the NONO‐associated syndromic disorder

• Published in: American journal of medical genetics. Part A Vol. 191; no. 2; pp. 469 - 478
• Main Authors: Roessler, Franziska, Beck, Anita E., Susie, Ball, Tobias, Bartolomaeus, Begtrup, Amber, Biskup, Saskia, Caluseriu, Oana, Delanty, Norman, Fröhlich, Christine, Greally, Marie T., Karnstedt, Maike, Klöckner, Chiara, Kurtzberg, Joanne, Schubert, Susanna, Schulze, Martin, Weidenbach, Michael, Westphal, Dominik S., White, Maire, Wolf, Cordula M., Zyskind, Jacob, Popp, Bernt, Strehlow, Vincent
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.02.2023; Wiley Subscription Services, Inc
• Subjects: Cardiomyopathies - genetics; Cardiomyopathy; Corpus callosum; corpus callosum anomalies; DNA repair; DNA-Binding Proteins - genetics; Epilepsy; Gene regulation; Genes, X-Linked; Heart Defects, Congenital - diagnosis; Heart Defects, Congenital - genetics; Humans; in‐frame splice deletion; Macrocephaly; Male; neurodevelopmental delay; non‐compaction cardiomyopathy; RNA; RNA expression analysis; RNA-Binding Proteins - genetics; X‐linked inheritance; in-frame splice deletion; neurodevelopmental delay; RNA expression analysis; corpus callosum anomalies; X-linked inheritance; non-compaction cardiomyopathy
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.63044

The non‐POU domain‐containing octamer‐binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene were confirmed to cause a rare X‐linked syndromic disorder. Through our in‐house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO‐associated disorder. The combined cohort consists of 16 live‐born males showing developmental delay, corpus callosum anomalies, non‐compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in‐frame splice deletion, we reinforce loss‐of‐function as the pathomechanism for the NONO‐associated syndromic disorder.