Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO

Daryl A. Scott, Andres Hernandez-Garcia, Mahshid S. Azamian, Valerie K. Jordan, Bum Jun Kim, Molly Starkovich, Jinglan Zhang, Lee Jun Wong, Sandra A. Darilek, Amy M. Breman, Yaping Yang, James R. Lupski, Amyn Jiwani, Bibhuti Das, Seema R. Lalani, Alejandro D. Iglesias, Jill A. Rosenfeld, Fan Xia

Research output: Contribution to journalArticle

2 Citations (Scopus)

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-offunction 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.

Original languageEnglish (US)
JournalJournal of Medical Genetics
DOIs
StateAccepted/In press - Aug 22 2016

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Congenital Heart Defects
Intellectual Disability
Developmental Disabilities
Megalencephaly
RNA
Exome
Atrial Heart Septal Defects
Penetrance
Corpus Callosum
Ventricular Heart Septal Defects
Gene Deletion
DNA-Binding Proteins
Heart Transplantation
Cardiomyopathies
Epigenomics
Neuroimaging
DNA Repair
Chromosomes
Mothers
Databases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Scott, D. A., Hernandez-Garcia, A., Azamian, M. S., Jordan, V. K., Kim, B. J., Starkovich, M., ... Xia, F. (Accepted/In press). Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO. Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2016-104039

Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO. / Scott, Daryl A.; Hernandez-Garcia, Andres; Azamian, Mahshid S.; Jordan, Valerie K.; Kim, Bum Jun; Starkovich, Molly; Zhang, Jinglan; Wong, Lee Jun; Darilek, Sandra A.; Breman, Amy M.; Yang, Yaping; Lupski, James R.; Jiwani, Amyn; Das, Bibhuti; Lalani, Seema R.; Iglesias, Alejandro D.; Rosenfeld, Jill A.; Xia, Fan.

In: Journal of Medical Genetics, 22.08.2016.

Research output: Contribution to journalArticle

Scott, DA, Hernandez-Garcia, A, Azamian, MS, Jordan, VK, Kim, BJ, Starkovich, M, Zhang, J, Wong, LJ, Darilek, SA, Breman, AM, Yang, Y, Lupski, JR, Jiwani, A, Das, B, Lalani, SR, Iglesias, AD, Rosenfeld, JA & Xia, F 2016, 'Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO', Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2016-104039
Scott, Daryl A. ; Hernandez-Garcia, Andres ; Azamian, Mahshid S. ; Jordan, Valerie K. ; Kim, Bum Jun ; Starkovich, Molly ; Zhang, Jinglan ; Wong, Lee Jun ; Darilek, Sandra A. ; Breman, Amy M. ; Yang, Yaping ; Lupski, James R. ; Jiwani, Amyn ; Das, Bibhuti ; Lalani, Seema R. ; Iglesias, Alejandro D. ; Rosenfeld, Jill A. ; Xia, Fan. / Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO. In: Journal of Medical Genetics. 2016.
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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-offunction 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.",
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T1 - Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO

AU - Scott, Daryl A.

AU - Hernandez-Garcia, Andres

AU - Azamian, Mahshid S.

AU - Jordan, Valerie K.

AU - Kim, Bum Jun

AU - Starkovich, Molly

AU - Zhang, Jinglan

AU - Wong, Lee Jun

AU - Darilek, Sandra A.

AU - Breman, Amy M.

AU - Yang, Yaping

AU - Lupski, James R.

AU - Jiwani, Amyn

AU - Das, Bibhuti

AU - Lalani, Seema R.

AU - Iglesias, Alejandro D.

AU - Rosenfeld, Jill A.

AU - Xia, Fan

PY - 2016/8/22

Y1 - 2016/8/22

N2 - 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-offunction 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.

AB - 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-offunction 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.

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