Expanding the genetic and clinical spectrum of the NONO‐associated X‐linked intellectual disability syndrome

Abstract

The NONO gene encodes a nuclear protein involved in RNA metabolism. Hemizygous loss-offunction NONO variants have been associated with syndromic intellectual disability and with left ventricular noncompaction (LVNC). A two-year-old boy presented to the University of Utah's Penelope Undiagnosed Disease Program with developmental delay, nonfamilial features, relative macrocephaly, and dilated cardiomyopathy with LVNC and Ebstein anomaly. Brain MRI showed a thick corpus callosum, mild Chiari I malformation, and a flattened pituitary. Exome sequencing identified a novel intronic deletion (c.154+5_154+6delGT) in the NONO gene. Splicing studies demonstrated intron 4 read-through and the use of an alternative donor causing the frameshift p.Asn52Serfs*6.Family segregation analysis showed that the variant occurred de novo in the boy's unaffected mother. MRI and endocrine findings suggest that hypopituitarism may contribute to growth failure, abnormal thyroid hormone levels, cryptorchidism, or delayed puberty in patients with NONOassociated disease. Also, including this case LVNC has been observed in five out of eight patients, and this report also confirms an association between loss of NONO and Ebstein anomaly. In some cases, unrelated individuals share the same pathogenic NONO variants but do not all have clinically significant LVNC, suggesting that additional modifiers may contribute to cardiac phenotypes. K E Y W O R D S Ebstein anomaly, left ventricular noncompaction, NONO, splicing variant, syndromic intellectual disability 1 | INTRODUCTION The nonoctamer-containing, POU-domain DNA-binding protein (NONO) is a highly conserved, member of the Drosophila behavior/human splicing (DBHS) protein family thought to be involved in various aspects of RNA metabolism (Shav-Tal and Zipori, 2002). Mice lacking NONO have small cerebellums, spatial memory impairment, and changes at inhibitory synapses (Mircsof et al., 2015). Immunohistochemistry indicates that NONO is broadly expressed in mouse tissues, including in neurons and granule cells of the cortex and hippocampus (Mircsof et al., 2015) as well as in the heart (Scott et al., 2017). Hemizygous loss-of-function variants in the Xq13.1-located NONO gene in patients were initially associated with an intellectual disability syndrome (MIM: 300967), with findings including macrocephaly, nonfamilial features, and thickened corpus callosum (Mircsof et al., 2015). Subsequently, four additional patients were described with these features and with left ventricular noncompaction (LVNC) cardiomyopathy (Reinstein et al., 2016; Scott et al., 2017). To date, five pathogenic NONO alterations have been reported, two of which were observed twice in unrelated patients.Notably, identical NONO variants were variably associated with LVNC. Here we report a patient with shared as well as additional features that confirm and expand the physical, functional, and cardiovascular phenotypes associated with NONO loss. | CLINICAL REPORTThis two-year-old boy at the time of testing was the first-born child of ...

Further delineation of the phenotypic spectrum associated with hemizygous loss‐of‐function variants in NONO

“…Developmental delay and/or intellectual disability have been described in all living males carrying pathogenic variants in NONO . One individual was diagnosed with autism spectrum disorder, and another individual had mild pseudo‐bulbar palsy (Carlston et al, ; Reinstein et al, ). Another individual was been reported to have absence seizures (Mircsof et al, ).…”

“…Atrial septal defects (ASDs), ventricular septal defects (VSDs), and patent ductus arteriosus (PDA) were each found in three individuals (38%), and patent foramen ovale (PFO) was found in two (25%). One individual had Ebstein anomaly (13%) (Carlston et al, ). We note that the maternal half‐brother of another subject died with an Ebstein anomaly (Scott et al, ).…”

“…One individual was diagnosed with autism spectrum disorder, and another individual had mild pseudo-bulbar palsy (Carlston et al, 2019;Reinstein et al, 2016). Another individual was been reported to have absence seizures (Mircsof et al, 2015).…”

“…Two individuals (20%) also had abnormalities in the cerebellum; one with cerebellar hypoplasia, and one with cerebellar dysplasia (Mircsof et al, 2015;Scott et al, 2017). Two individuals were also diagnosed with Chiari I malformation (20%) (Carlston et al, 2019;Mircsof et al, 2015). Hypotonia was specifically reported in seven individuals (70%).…”

“…Subsequent studies demonstrated that males with loss-of-function variants in NONO can also have left ventricular noncompaction (LVNC) and congenital heart defects in addition to the phenotypes previously described (Carlston et al, 2019;Reinstein, Tzur, Cohen, Bormans, & Behar, 2016;Scott et al, 2017). Among the eight males with hemizygous variants in NONO that have been described to date, macrocephaly, frontal bossing, an elongated face, slanted palpebral fissures, and malar hypoplasia have been recurrently described.…”