NONO – X-linked Syndromic Intellectual Disability 34

Hemizygous loss-of-function variants in NONO (HGNC:7871) on Xq13.1 cause X-linked syndromic intellectual disability 34 (MONDO:0010501), a disorder characterized by developmental delay, intellectual disability, hypotonia, macrocephaly, corpus callosum anomalies, and congenital heart defects including left ventricular non-compaction (LVNC).

Clinical Validity

A total of 13 unrelated male probands harboring hemizygous NONO variants have been reported, including 8 cases in an American Journal of Medical Genetics series and 3 new individuals (11 probands total) ([PMID:31883306]), plus a fetus with an intronic splice variant ([PMID:33304389]), a male with a 3′UTR deletion ([PMID:36292043]), and a de novo nonsense variant in a fetus ([PMID:38110236]). Segregation is consistent with X-linked recessive inheritance, with asymptomatic heterozygous mothers. Based on multiple independent LoF alleles, consistent phenotype across studies, and corroborating functional data, the gene–disease association is classified as Strong.

Genetic Evidence

Inheritance is X-linked recessive. No additional affected relatives beyond probands were reported. Variants include nonsense (e.g., c.457C>T (p.Arg153Ter)), frameshift, essential splice-site, intronic cryptic splice variants causing 4 bp insertions, and 3′UTR deletions, all predicted or demonstrated to abolish NONO function. One recurrent nonsense allele (c.457C>T (p.Arg153Ter)) was identified in an unrelated patient ([PMID:31883306]). Overall, 13 hemizygous LoF variants across independent families meet ClinGen Genetic Evidence Tier Strong.

Functional Evidence

An in vitro minigene splicing assay demonstrated that the intronic c.154+9A>G variant activates a cryptic splice site leading to a 4 bp insertion in mRNA ([PMID:33304389]). Knockout murine embryonic fibroblasts lacking NONO exhibit impaired double-strand break repair and compensation by PSPC1 upregulation, supporting a loss-of-function mechanism in DNA repair pathways ([PMID:25100870]).

Conflicting Evidence

No studies have refuted the association or described unaffected hemizygous males, and clinical phenotypes are consistently replicated.

Integrated Conclusion

NONO haploinsufficiency leads to an X-linked neurodevelopmental syndrome with a distinctive combination of intellectual disability, hypotonia, macrocephaly, brain malformations, and cardiomyopathy. Genetic testing for NONO variants, including noncoding and copy-number changes, is indicated in males with syndromic ID and congenital heart defects. Functional assays confirm deleterious splicing and loss of DNA repair activity.

Key Take-home: Hemizygous LoF variants in NONO cause a recognizable X-linked syndrome with neurodevelopmental and cardiac features, supporting its utility for diagnostic testing and genetic counseling.

References

• American Journal of Medical Genetics. Part A • 2020 • Further delineation of the phenotypic spectrum associated with hemizygous loss-of-function variants in NONO. PMID:31883306
• Frontiers in Genetics • 2020 • Case Report: Characterization of a Novel NONO Intronic Mutation in a Fetus With X-Linked Syndromic Mental Retardation-34. PMID:33304389
• Diagnostics • 2022 • 3'UTR Deletion of NONO Leads to Corpus Callosum Anomaly, Left Ventricular Non-Compaction and Ebstein's Anomaly in a Male Fetus. PMID:36292043
• Prenatal Diagnosis • 2024 • A novel NONO nonsense variant in a fetus with renal abnormalities. PMID:38110236
• Nucleic Acids Research • 2014 • Double-strand break repair deficiency in NONO knockout murine embryonic fibroblasts and compensation by spontaneous upregulation of the PSPC1 paralog. PMID:25100870

Evidence Based Scoring (AI generated)