Submission Details

The USP7 gene is located on chromosome 16 at 16p13.2 and encodes the ubiquitin-specific protease 7, a deubiquitinating enzyme that controls stability and localization of proteins involved in DNA replication, epigenetic regulation, cell cycle, and cell survival (Rouge et al., 2016, 27452404). It is a component of the MAGEL2-USP7-TRIM27 (MUST) complex regulating WASH activity, endosomal actin assembly and protein recycling (Hao et al., 2015, PMID 26365382). USP7 also regulates MDM2-p53 pathway implicated in apoptosis and cell cycle (Kon et al., 2011, PMID 21350561). The USP7 gene was first reported in 2015 in relation to autosomal dominant neurodevelopmental disorder, which has been also referred to as Hao-Fountain syndrome and neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies (PMID 26365382; Fountain et al., 2019, PMID 30679821; Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), 2021. World Wide Web URL: https://omim.org/). The USP7-related neurodevelopmental disorder is characterized by global developmental delay, significant speech delay, impaired intellectual development, behavioral abnormalities, including autism spectrum, and mild dysmorphic features. Additional features may include feeding problems, hypotonia, seizures, delayed motor development, hypogonadism in males, joint and ocular anomalies. Brain imaging shows abnormalities in some patients and may include white matter changes, shallow gyra pattern, and ventricle anomalies. At least eight unique de novo variants have been reported, including stop-gained, frameshift and missense variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in two publications (PMID 26365382; PMID 30679821). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. Currently, there is strong evidence supporting loss-of-function variants as disease mechanism, whereas the role of missense variants is less well-understood. This gene-disease association is supported by protein interaction of USP7 with MAGE-L2 and TRIM27 to form a ligase complex that regulates WASH-mediated endosomal protein recycling (Hao et al., 2013, PMID 23452853; PMID 26365382) and by interaction with and stabilization of KMT2E (Ding et al., 2015; PMID 26678539). This gene-disease association is also supported by data from a conditional knockout mouse model (PMID 21350561). In summary, USP7 is definitively associated with USP7-related neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.