Hao-Fountain Syndrome · USP7

What this is

Hao-Fountain syndrome is a neurodevelopmental disorder caused by heterozygous loss-of-function mutations in USP7, the gene encoding ubiquitin-specific protease 7. USP7 is a deubiquitinating enzyme that regulates the stability of many proteins involved in cell-cycle control, DNA damage response, and chromatin remodeling. The protein is essential, and most disease-causing variants reduce protein function or expression.

The clinical phenotype includes developmental delay apparent in the first year of life, intellectual disability ranging from moderate to profound, severe speech delay (most affected children remain nonverbal or develop only limited speech), autism spectrum features, abnormal brain MRI findings (white-matter abnormalities, reduced myelination), motor impairments, hypotonia in infancy with subsequent spasticity, and an increased prevalence of epilepsy. Many affected children also have feeding difficulties, gastrointestinal issues, and behavioral challenges.

The condition was first molecularly characterized in 2015 by Hao and Fountain, after whom the syndrome is named, working with collaborators at Baylor College of Medicine. The gene was previously known to be involved in cancer biology; the discovery that USP7 haploinsufficiency causes a developmental syndrome was a separate finding from a series of clinical exome sequencing cases.

Approximately 70 to 100 individuals have been identified with Hao-Fountain syndrome as of 2025, though the actual prevalence is likely higher and unrecognized cases are common in the broader population of unsolved neurodevelopmental disorders. Most cases are de novo (the mutation occurs in the affected child but not in either parent). Diagnosis is by clinical exome or genome sequencing on a developmental-disorder gene panel. There is no approved disease-modifying therapy. Standard of care is symptomatic: speech and occupational therapy, anticonvulsants for the seizures, and educational accommodations.

The case

Tess Bigelow was born in 2009 in Falmouth, Maine, to Bo and Kristen Bigelow. Her early development was visibly atypical, and the diagnostic workup that began in her infancy continued through her early childhood without a definitive answer. By her fifth birthday in 2014, Tess had been seen at multiple academic medical centers, had undergone extensive metabolic and chromosomal testing, and remained without a diagnosis. She was nonverbal, had developed epilepsy, and met clinical criteria for autism. Her parents had been told that they had a "syndrome of one" and that no test, evaluation, or specialist had been able to identify the underlying cause.

In late 2014, Bo Bigelow posted on the social-media platform Reddit, in a community for rare disease and undiagnosed conditions, describing Tess's clinical features and asking whether anyone had encountered a similar case. The post was specific about the phenotype, included photographs, and explicitly asked for the help of researchers who might recognize the constellation of symptoms.

Within twelve hours, Mike Fountain, a clinical geneticist and researcher at Baylor College of Medicine in Texas, had read the post and emailed Bo Bigelow. Fountain's group had recently identified a series of cases of USP7 haploinsufficiency syndrome (the condition that would later carry his and Hao's name). Tess's clinical presentation matched the cohort. Whole-exome sequencing on Tess confirmed a USP7 variant. Tess was the eighth identified individual in the world with what would become Hao-Fountain syndrome.

The diagnosis closed Tess's diagnostic odyssey but produced no therapy. There was no approved drug, no clinical trial, and at the time no clinically meaningful therapeutic program in development. The Bigelow family's response was the same response several other ultra-rare-disease families have given when handed a diagnosis without a treatment: build the infrastructure that future therapy programs will require.

Bo and Kristen Bigelow co-founded the Foundation for USP7 Related Diseases. The foundation's stated purposes are to identify additional affected individuals through outreach to clinicians and families, to fund research on USP7 biology and therapeutic development, to maintain a patient registry that any eventual therapeutic program can use as the natural-history reference, and to provide community and information resources for affected families. Through the foundation and through continued social-media outreach, the Bigelow family has connected with the global cohort of Hao-Fountain syndrome families, which has grown from eight identified individuals in 2015 to roughly 70 to 100 by 2025.

Tess herself, as of 2025, is in her teens. She remains nonverbal, has continued seizures despite anticonvulsant management, and requires substantial daily care. The Bigelow family has been public about the difficulty of her condition and the absence of meaningful therapeutic options, and they have used the foundation as a platform to fund the research that might eventually produce one.

The research

USP7 biology is well-studied because the protein has been a target in cancer drug discovery for two decades; small-molecule USP7 inhibitors are in development as anti-cancer agents, where the goal is to reduce USP7 activity. Hao-Fountain syndrome involves the opposite problem: insufficient USP7 activity in developing neurons. The therapeutic target for the disorder is therefore upregulating residual USP7 expression or compensating for the deficiency through a different mechanism.

Several research approaches are in early stages. Antisense oligonucleotide programs aimed at increasing expression from the wild-type USP7 allele in the heterozygous condition are being explored. Gene replacement therapy with AAV-delivered USP7 is theoretically possible, though USP7 protein dosage is tightly regulated and overexpression is itself problematic. Small-molecule USP7 stabilizers, drugs that would prolong the half-life of the wild-type USP7 protein the cell still produces, are an additional research direction.

The patient registry the Foundation for USP7 Related Diseases has built is the central scientific resource the field has. The registry includes longitudinal clinical data, genotype information, and biospecimens from a substantial fraction of identified affected individuals globally. As of 2025, no published clinical trial of a disease-modifying therapy has begun for Hao-Fountain syndrome, though several preclinical programs are referenced in foundation publications and in the GeneReviews chapter on the condition.

The McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, the Baylor College of Medicine clinical genetics service where Mike Fountain is based, and a small number of other academic centers maintain clinical and research programs for Hao-Fountain families. Funding for the research has come from the Foundation, from individual donors, and from limited federal grants.

What is blocking the next case

The Hao-Fountain syndrome case is structurally different from the ASO-class and AAV-class cases that have moved further into therapeutic development. The blocker is upstream: the molecular target for therapy in haploinsufficiency disorders is not as straightforward as it is for splice-disrupting variants or for recessive loss-of-function conditions where simple gene replacement works.

The first blocker is mechanism. Increasing expression from the wild-type allele, the most plausible ASO-style approach, requires identifying a regulatory element in the USP7 gene or its regulators that can be modulated. The biology has not yet identified a confidently druggable target.

The second blocker is dose sensitivity. USP7 protein levels are tightly regulated. Both increased and decreased activity produce phenotypes. Any therapy that raises USP7 expression risks tipping the cell from haploinsufficiency-related phenotypes into overexpression-related ones, a problem that the AAV gene-therapy field knows well from other dose-sensitive conditions and that drives the engineering of auto-regulation elements like Gray's miRARE.

The third blocker is the small affected population. Even with the foundation's identification work, fewer than one hundred individuals are known to have Hao-Fountain syndrome globally. Therapeutic-program funding at the scale needed to take a candidate through preclinical development, IND-enabling toxicology, and clinical evaluation is difficult to assemble for a population this size, particularly without the proof-of-concept that an early single-patient program would provide.

The fourth blocker is the absence of validated outcome measures. Pediatric neurodevelopmental disorders generally lack the objective biomarkers and clinical endpoints that smaller and more biochemically tractable conditions (like the metabolic disorders or the specific seizure syndromes) have. Trial design in Hao-Fountain syndrome will face the same outcome-measurement problem that the KIF1A and KAND community have spent a decade addressing through natural-history work.

The Foundation's longer-term strategy, as publicly described, is to spend the late-2020s building the registry, the natural-history dataset, and the basic-science knowledge of USP7 biology that will make a clinical program viable when one of the technical approaches above matures. The case is a slower trajectory than the milasen-class or Pirovolakis-class programs, and the Bigelow family has been explicit about what that timeline looks like.

Where this connects

The diagnostic-odyssey shape of Tess Bigelow's case sits inside the broader pattern described in the existing magazine piece The end of the diagnostic odyssey, which discusses how genome-scale sequencing and global patient-finding networks are collapsing the time from undiagnosed presentation to molecular diagnosis. The natural-history-and-registry approach the Foundation for USP7 Related Diseases has built parallels the model described in Wendy Chung and the natural-history-first model. The longer-term therapeutic infrastructure that a future Hao-Fountain trial will require is described in the foundations of the n-of-1+ desk.

Sources

• Hao YH, Fountain MD Jr, Fon Tacer K, et al. USP7 acts as a molecular rheostat to promote WASH-dependent endosomal protein recycling and is mutated in a human neurodevelopmental disorder. Mol Cell. 2015;59(6):956-969. PMID: 26365383.
• Fountain MD, Oleson DR, Aten E, et al. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. Genet Med. 2019;21(8):1797-1807.
• USP7-Related Hao-Fountain Syndrome. GeneReviews. NBK619577. NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK619577/
• Foundation for USP7 Related Diseases. https://www.usp7.org
• DNA Science (PLoS). Tess's tale: social media catalyzes rare disease diagnosis. September 17, 2015.
• ABC News. Girl diagnosed with rare genetic disorder thanks to Reddit after years of inconclusive testing. 2015.
• News Center Maine. Falmouth couple searches for answers to daughter's rare disease, connects with other patients worldwide. 2024.
• Child Neurology Foundation. Hao-Fountain Syndrome disorder page. https://www.childneurologyfoundation.org/disorder/hao-fountain-syndrome/
• Orphanet. Hao-Fountain syndrome (ORPHA 643549).