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

Abstract

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 and DNA binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Hemizygous loss‐of‐function variants in NONO have been shown to cause mental retardation, X‐linked, syndromic 34 in males. Features of this disorder can include a range of neurodevelopmental phenotypes, left ventricular noncompaction (LVNC), congenital heart defects, and CNS anomalies. To date only eight cases have been described in the literature. Here we report two unrelated patients and a miscarried fetus with loss‐of‐function variants in NONO. Their phenotypes, and a review of previously reported cases, demonstrate that hemizygous loss‐of‐function variants in NONO cause a recognizable genetic syndrome. The cardinal features of this condition include developmental delay, intellectual disability, hypotonia, macrocephaly, structural abnormalities affecting the corpus callosum and/or cerebellum, LVNC, congenital heart defects, and gastrointestinal/feeding issues. This syndrome also carries an increased risk for strabismus and cryptorchidism and is associated with dysmorphic features that include an elongated face, up/down‐slanted palpebral fissures, frontal bossing, and malar hypoplasia.

Case Report: Characterization of a Novel NONO Intronic Mutation in a Fetus With X-Linked Syndromic Mental Retardation-34

“…The incidence of CHD in LVNC patients caused by NONO mutations seems to be significantly higher than its incidence in overall LVNC patients (Oechslin and Jenni, 2018;Richard et al, 2018;van Waning et al, 2018van Waning et al, , 2019aKayvanpour et al, 2019). In addition, LVNC is diagnosed early in all patients with NONO mutations: five in the prenatal period (Sun et al, 2020b), four in the neonatal period (Scott et al, 2016;Sewani et al, 2019), two in infancy (Reinstein et al, 2016;Carlston et al, 2019), and one at the age of 4 (Sewani et al, 2019), indicating that LVNC is an early diagnostic clue for MRXS34. The severity of cardiac symptoms in these patients varies, ranging from requiring no medical intervention to requiring cardiac transplantation.…”

“…Interestingly, while structural cardiac defects and LVNC have been reported in MRXS34 (Reinstein et al, 2016;Scott et al, 2016;Carlston et al, 2019;Sewani et al, 2019;Sun et al, 2020b), HLHS has not been previously associated with NONO-related disorders. Although this cardiac abnormality might be coincidentally present in the fetus herein described, previous frequent reports of other structural cardiac abnormalities suggest a possible involvement of the NONO defect.…”

“…It is expected to result in either an abnormal truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. In addition, the majority of reported patients with NONO mutations presented with CHD (Mircsof et al, 2015;Reinstein et al, 2016;Scott et al, 2016;Carlston et al, 2019;Sewani et al, 2019;Sun et al, 2020b) suggesting the association between NONO deficiency and CHD.…”

“…It is a highly conserved member of the Drosophila behavior/human splicing protein family thought to be involved in RNA synthesis, transcriptional regulation, and DNA repair (Shav-Tal and Zipori, 2002). Hemizygous mutations in NONO have recently been reported to cause mental retardation, X-linked, syndromic 34 (MRXS34; OMIM: 300967) in several male patients (Mircsof et al, 2015;Reinstein et al, 2016;Scott et al, 2016;Carlston et al, 2019;Sewani et al, 2019;Sun et al, 2020b). The predominant presentation for these patients described so far is that of an X-linked recessive disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum.…”

AUTS2 Syndrome: Molecular Mechanisms and Model Systems

“…AUTS2 syndrome exhibits phenotypic overlap with several other genetic causes of ID, including Rubinstein-Taybi syndrome ( CREBBP or EP300 ) ( Fergelot et al, 2016 ), NONO syndrome ( Sewani et al, 2020 ), TBR1 syndrome ( Nambot et al, 2020 ), and FBRSL1 syndrome ( Ufartes et al, 2020 ). The similarities among these disorders reflect their related roles in genetic pathways and binding interactions.…”