Submission Details

UPF3B was first reported in relation to X-linked complex neurodevelopmental disorder in 2007 (Tarpey et al, PMID: 22957832). UPF3B is involved, along with UPF3A and UPF2, in the exon junction complex, mRNA nuclear export, and mRNA surveillance, initiating nonsense-mediated decay of mRNAs with truncated open reading frames. Observed phenotypes in affected males include, but are not limited to, facial dysmorphism, varying severity of intellectual disability, seizures, ADHD, childhood-onset schizophrenia, and other behavioral problems.

Ten variants (nonsense, frameshift) that have been reported in 10 probands in 5 publications (PMIDs: 17704778, 19238151, 20479756, 22609145, 22957832) are included in this curation. Variants in this gene segregated with disease in 24 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be hemizygous loss of function.

This gene-disease relationship is also supported by in vitro functional assays and a Upf3b-null mouse model (PMIDs: 23821644, 26012578, 28948974). Variants in UPF3B are reported to affect neuronal development by impairing the nonsense-mediated decay mechanism.

In summary, there is definitive evidence supporting the relationship between UPF3B and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 3, 2019 (SOP Version 6).

UPF3B was first reported in relation to X-linked Complex Neurodevelopmental Disorder in 2007 (Tarpey et al, PMID: 22957832), as a result of a study to identify candidate genes in X-linked intellectual disability. Observed phenotypes in affected individuals include, but are not limited to, facial dysmorphism, ADHD, varying severity of intellectual disability, seizures, childhood-onset schizophrenia, and behavioral problems. UPF3B is involved, along with UPF3A and UPF2 in the exon junction complex, in mRNA nuclear export as well as mRNA surveillance (initiating nonsense-mediated decay of mRNAs with truncated ORFs). At least 10 nonsense, frameshift and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Variants in this gene have been reported in at least 10 probands in 5 publications (PMIDs: 22957832, 17704778, 22609145, 19238151, 20479756. Variants in this gene segregated with disease in 24 additional family members. More case-level data is available in the literature, but the maximum score for genetic evidence has been reached.

The mechanism for disease is expected to be hemizygous loss of function.

This gene-disease association is supported by in vitro functional assays and animal models (PMIDs 28948974, 26012578, 23821644). UPF3B-null mice show phenotype suggestive of the human phenotype, which is highly variable. Mutations in UPF3B are reported to affect neuronal development due to impaired NMD mechanism.

In summary, UPF3B is definitively associated with X-linked Complex Neurodevelopmental Disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Autism and Intellectual Disability GCEP on 07/3/2019 (SOP Version 6).