PT  - JOURNAL ARTICLE
AU  - Daryl A Scott
AU  - Andres Hernandez-Garcia
AU  - Mahshid S Azamian
AU  - Valerie K Jordan
AU  - Bum Jun Kim
AU  - Molly Starkovich
AU  - Jinglan Zhang
AU  - Lee-Jun Wong
AU  - Sandra A Darilek
AU  - Amy M Breman
AU  - Yaping Yang
AU  - James R Lupski
AU  - Amyn K Jiwani
AU  - Bibhuti Das
AU  - Seema R Lalani
AU  - Alejandro D Iglesias
AU  - Jill A Rosenfeld
AU  - Fan Xia
TI  - Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in <em>NONO</em>
AID  - 10.1136/jmedgenet-2016-104039
DP  - 2017 Jan 01
TA  - Journal of Medical Genetics
PG  - 47--53
VI  - 54
IP  - 1
4099  - http://jmg.bmj.com/content/54/1/47.short
4100  - http://jmg.bmj.com/content/54/1/47.full
SO  - J Med Genet2017 Jan 01; 54
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-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.