RGD Reference Report - A novel NONO variant that causes developmental delay and cardiac phenotypes. - Rat Genome Database

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A novel NONO variant that causes developmental delay and cardiac phenotypes.

Authors: Itai, Toshiyuki  Sugie, Atsushi  Nitta, Yohei  Maki, Ryuto  Suzuki, Takashi  Shinkai, Yoichi  Watanabe, Yoshihiro  Nakano, Yusuke  Ichikawa, Kazushi  Okamoto, Nobuhiko  Utsuno, Yasuhiro  Koshimizu, Eriko  Fujita, Atsushi  Hamanaka, Kohei  Uchiyama, Yuri  Tsuchida, Naomi  Miyake, Noriko  Misawa, Kazuharu  Mizuguchi, Takeshi  Miyatake, Satoko  Matsumoto, Naomichi 
Citation: Itai T, etal., Sci Rep. 2023 Jan 18;13(1):975. doi: 10.1038/s41598-023-27770-6.
RGD ID: 155900764
Pubmed: PMID:36653413   (View Abstract at PubMed)
PMCID: PMC9849200   (View Article at PubMed Central)
DOI: DOI:10.1038/s41598-023-27770-6   (Journal Full-text)

The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g., distinctive facial features, cardiac symptoms, and skeletal symptoms) in an X-linked recessive manner. Most of the reported variants have been LoF variants, and two missense variants have been reported as likely deleterious but with no functional validation. We report three individuals from two families harboring an identical missense variant that is located in the nuclear localization signal, NONO: NM_001145408.2:c.1375C > G p.(Pro459Ala). All of them were male and the variant was inherited from their asymptomatic mothers. Individual 1 was diagnosed with developmental delay and cardiac phenotypes (ventricular tachycardia and dilated cardiomyopathy), which overlapped with the features of reported individuals having NONO LoF variants. Individuals 2 and 3 were monozygotic twins. Unlike in Individual 1, developmental delay with autistic features was the only symptom found in them. A fly experiment and cell localization experiment showed that the NONO variant impaired its proper intranuclear localization, leading to mild LoF. Our findings suggest that deleterious NONO missense variants should be taken into consideration when whole-exome sequencing is performed on male individuals with developmental delay with or without cardiac symptoms.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Developmental Disabilities  IAGP 155900764DNA:missense mutation:CDS:p.P459A (human)RGD 
Developmental Disabilities  ISONONO (Homo sapiens)155900764; 155900764DNA:missense mutation:CDS:p.P459A (human)RGD 
intellectual disability  IAGP 155900764DNA:missense mutation:CDS:p.P459A (human)RGD 
intellectual disability  ISONONO (Homo sapiens)155900764; 155900764DNA:missense mutation:CDS:p.P459A (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Global developmental delay  IAGP 155900764DNA:missense mutation:CDS:p.P459ARGD 
Intellectual disability  IAGP 155900764DNA:missense mutation:CDS:p.P459ARGD 
Objects Annotated

Genes (Rattus norvegicus)
Nono  (non-POU domain containing, octamer-binding)

Genes (Mus musculus)
Nono  (non-POU-domain-containing, octamer binding protein)

Genes (Homo sapiens)
NONO  (non-POU domain containing octamer binding)


Additional Information