A novel NONO variant that causes developmental delay and cardiac phenotypes

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• The NONO gene, part of the Drosophila behavior/human splicing protein family, is crucial for gene regulation.
• Loss-of-function (LoF) variants in NONO cause X-linked developmental delay with various complications.
• Previously reported missense variants lacked functional validation.

Purpose of the Study:

• To investigate the functional impact of a novel NONO missense variant (c.1375C>G, p.Pro459Ala) identified in individuals with developmental delay.
• To determine if this variant affects NONO protein localization and function.

Main Methods:

• Clinical evaluation of three affected males from two families.
• Genetic analysis to identify the NONO variant.
• In vivo Drosophila melanogaster model experiments.
• In vitro cell-based localization studies.

Main Results:

• Identical NONO missense variant (c.1375C>G, p.Pro459Ala) found in three males, inherited from asymptomatic mothers.
• Affected individuals presented with developmental delay; one also had significant cardiac phenotypes (ventricular tachycardia, dilated cardiomyopathy).
• The NONO variant impaired intranuclear localization in both fly and cell models, indicating a mild loss-of-function effect.

Conclusions:

• Missense variants in NONO, particularly those affecting nuclear localization, should be considered in male individuals with developmental delay and/or cardiac symptoms.
• This study provides functional evidence for a mild LoF mechanism caused by a NONO missense variant.
• Highlights the importance of evaluating missense variants in genetic diagnostics for neurodevelopmental disorders.