title: Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO.
abstract: The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects.
  
  
  
  We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis.
  
  
  
  We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother.
  
  
  
  We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Hernandez-Garcia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Mahshid S
authors.initials: MS
authors.lastname: Azamian
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Valerie K
authors.initials: VK
authors.lastname: Jordan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Bum Jun
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Starkovich
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Jinglan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Darilek
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Breman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.|Texas Children's Hospital, Houston, Texas, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Amyn K
authors.initials: AK
authors.lastname: Jiwani
authors.affiliation: Department of Pediatrics, Children's Medical Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Das
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Columbia University, New York, New York, USA.
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Iglesias
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jill A
authors.identifier: 0000-0001-5664-7987
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Baylor Genetics, Houston, Texas, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
mesh_terms: D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology; D059472:Exome / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology*; D006801:Humans; D007223:Infant; D008297:Male; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics*; D050810:Octamer Transcription Factors / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C083214:NONO protein, human; D034521:Nuclear Matrix-Associated Proteins; D050810:Octamer Transcription Factors; D016601:RNA-Binding Proteins
keywords: NONO; X- linked; congenital heart defects; genetic syndrome; left ventricular non-compaction