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Phenotypes
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

https://doi.org/10.1136/jmedgenet-2016-104039

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    Footnotes

    • Contributors DAS, AH-G, VKJ, BJK, MS, JZ, L-JW, AMB, YY, SRL and FX planned and conducted experiments and/or analysed experimental data. DAS, AKJ, BD and ADI performed clinical evaluations. DAS, MSA, VKJ, SAD, YY, JRL, BD, ADI and JAR aided in subject accrual. DAS was the primary author of the article with all co-authors contributing to the content. DAS and FX are responsible for the overall content as guarantors.

    • Funding This work was supported by the National Institutes of Health/National Institute of General Medical Sciences Initiative for Maximizing Student Development [R25 GM056929-16], the United States National Human Genome Research Institute/National Heart, Lung, and Blood Institute [U54 HG006542] to the Baylor-Hopkins Center for Mendelian Genomics. This project was also supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development [U54 HD083092] to the Intellectual and Developmental Disabilities Research Center through the use of the Clinical Translational Core.

    • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health.

    • Competing interests JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc., is a member of the Scientific Advisory Board of Baylor Genetics and is a co-inventor on US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered by Baylor Genetics. The other authors declare no conflict of interest.

    • Ethics approval Institutional Review Board of Baylor College of Medicine.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Requests for access to any unpublished data generated in this study may be made to the corresponding authors.