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

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.

journal_name

J Med Genet

journal_title

Journal of medical genetics

authors

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 AK,Das B,Lalani SR,Iglesias AD,Rosenfeld JA,Xia F

doi

10.1136/jmedgenet-2016-104039

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

47-53

issue

eissn

0022-2593

issn

1468-6244

pii

jmedgenet-2016-104039

journal_volume

pub_type

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