USP7 – Hao-Fountain syndrome

Hao-Fountain syndrome is a neurodevelopmental disorder caused by heterozygous pathogenic variants in the deubiquitinase USP7. Clinically, patients present with global developmental delay, intellectual disability, speech impairment and behavioral abnormalities; some exhibit seizures, hypogonadism and mild dysmorphic features.

Genetic evidence supports an autosomal dominant inheritance with predominantly de novo variants. To date, fewer than 50 cases have been described in the literature (<50 cases reported) (PMID:36273155), and subsequent studies identified three additional unrelated patients (PMID:36466803), 18 participants in a DNA methylation cohort (PMID:38126281), and 32 further individuals plus data on six previously reported cases (PMID:38221796). Segregation analysis shows consistent occurrence of de novo heterozygous variants with no affected relatives.

The variant spectrum includes truncating, frameshift, missense and splice‐site changes predicted to result in haploinsufficiency. A representative variant is c.247_250del (p.Glu83ArgfsTer18), a frameshift leading to premature truncation (PMID:36466803). No recurrent or founder alleles have been described.

Functional studies demonstrate that patient-derived USP7 variants impair catalytic activity and reduce protein stability in vitro. A specific DNA methylation episignature diagnostic biomarker has been validated in 18 individuals (PMID:38126281). A novel allosteric activator can rescue catalytic defects in several pathogenic variants (PMID:40166258). Moreover, conditional deletion of Usp7 in mouse glutamatergic neurons recapitulates sensorimotor deficits, cognitive impairment and dendritic spine abnormalities independent of p53, implicating Ppil4 as a neuronal substrate (PMID:39862434).

No conflicting or refuting evidence has been reported to date. All published variants show concordant loss-of-function effects consistent with haploinsufficiency.

In summary, robust de novo genetic findings in over 60 probands, concordant functional assays, an episignature biomarker and a mouse model support a Strong clinical validity for USP7 association with Hao-Fountain syndrome. Key Take-home: USP7 haploinsufficiency due to de novo variants is a well-established cause of Hao-Fountain syndrome, enabling precise molecular diagnosis and informing surveillance for neurodevelopmental and endocrine features.

References

• Italian journal of pediatrics • 2022 • Hao-Fountain syndrome and genital disorders: report of a new possible association. PMID:36273155
• Frontiers in molecular neuroscience • 2022 • Expansion of the mutation spectrum and phenotype of USP7-related neurodevelopmental disorder. PMID:36466803
• Cell reports • 2025 • The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway. PMID:39862434
• Theranostics • 2024 • Knocking out USP7 attenuates cardiac fibrosis and endothelial-to-mesenchymal transition by destabilizing SMAD3 in mice with heart failure with preserved ejection fraction. PMID:38126281
• bioRxiv • 2025 • Functional Spectrum of USP7 Pathogenic Variants in Hao-Fountain Syndrome: Insights into the Enzyme's Activity, Stability, and Allosteric Modulation. PMID:40166258
• American Journal of Molecular Genetics • 2024 • Expansion of clinical and epigenetic profiling in Hao-Fountain syndrome. PMID:38221796

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