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

Self Cite

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.

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

See 2 more Smart Citations

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

Sewani

Nugent

Blackburn

et al. 2019

Self Cite

“…Mice lacking NONO have small cerebellums, spatial memory impairment, and changes at inhibitory synapses (Mircsof et al, ). Immunohistochemistry indicates that NONO is broadly expressed in mouse tissues, including in neurons and granule cells of the cortex and hippocampus (Mircsof et al, ) as well as in the heart (Scott et al, ). 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, ).…”

Section: Introductionmentioning

confidence: 99%

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

Carlston

Bleyl

Andrews

et al. 2019

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 ...

Novel hemizygous loss‐of‐function variant in NONO identified in a South African boy

Coetzer

Moosa

2021

Hemizygous loss-of-function variants in the non-POU domain-containing, octamerbinding gene, NONO, cause X-linked mental retardation syndrome 34 (MRXS34).Here, we describe the 12th patient in the literature with this rare syndrome, the first affected male from sub-Saharan Africa. This South African patient presented with dysmorphic features, congenital cardiac abnormalities (Ebstein's anomaly, left ventricular non-compaction, and a VSD), and developmental delay. He was enrolled in our "Undiagnosed Disease Programme." Exome sequencing identified a novel hemizygous 14bp deletion in NONO, which he inherited from his unaffected, healthy mother. His features overlap with the previous patients described, lending more support to the assertion that MRXS34 is a recognizable, albeit rare, syndrome. The cardiac anomalies are particularly distinctive, which combined with a variety of other associated features, should prompt the inclusion of NONO-associated MRXS34 in the differential diagnosis.