Article Text

other Versions

PDF
Original article
Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO
  1. Daryl A Scott1,2,
  2. Andres Hernandez-Garcia1,
  3. Mahshid S Azamian1,
  4. Valerie K Jordan2,
  5. Bum Jun Kim1,
  6. Molly Starkovich1,
  7. Jinglan Zhang1,3,
  8. Lee-Jun Wong1,3,
  9. Sandra A Darilek1,
  10. Amy M Breman1,3,
  11. Yaping Yang1,3,
  12. James R Lupski1,4,5,6,
  13. Amyn K Jiwani7,
  14. Bibhuti Das8,
  15. Seema R Lalani1,
  16. Alejandro D Iglesias9,
  17. Jill A Rosenfeld1,
  18. Fan Xia1,3
  1. 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  2. 2Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA
  3. 3Baylor Genetics, Houston, Texas, USA
  4. 4Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA
  5. 5Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
  6. 6Texas Children's Hospital, Houston, Texas, USA
  7. 7University of Texas Medical Branch, Galveston, Texas, USA
  8. 8Department of Pediatrics, Children's Medical Center, UT Southwestern Medical Center, Dallas, Texas, USA
  9. 9Department of Pediatrics, Division of Medical Genetics, Columbia University, New York, New York, USA
  1. Correspondence to Dr Daryl A Scott, R813, One Baylor Plaza, BCM225, Houston TX 77030, USA; dscott{at}bcm.edu and Dr Fan Xia, One Baylor Plaza, NAB270C, Houston TX 77030, USA; fxia{at}bcm.edu

Abstract

Background 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.

Methods We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis.

Results 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.

Conclusions 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.

  • NONO
  • congenital heart defects
  • left ventricular non-compaction
  • genetic syndrome
  • X- linked

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.