Background Variants of ubiquitin-specific protease 7 (USP7) gene in humans are associated with a neurodevelopmental disorder—Hao-Fountain syndrome, its core symptoms including developmental delay, intellectual disability, and speech delay. Other variable symptoms can affect multiple systems. In present study, we report two patients with core features from two unrelated consanguineous families originating from the Tianjin Children's Hospital.

Methods and Results Genomic DNA was extracted from the peripheral blood samples collected from the probands with their family members and whole-exome sequencing (WES) was used to detect the pathogenic genes in the probands. Suspected variants were subsequently validated by Sanger sequencing. In family 1, WES revealed that the proband carried the de novo variant c.2697A > C (p.Leu899Phe) in USP7 (NM_003470.3). In family 2, WES identified the variant c.3305A > C (p.Asn1102Thr) in USP7 (NM_003470.3) from the proband.

Conclusion We reported two cases of Hao-Fountain syndrome caused by novel USP7 variants. In addition, we report the first case of mosaicism with a USP7 variant in Chinese family. Our findings demonstrate the importance of WES in diagnosis of genetic diseases and expands the USP7 variants spectrum in Hao-Fountain syndrome. Moreover, we summarize the cases caused by USP7 variants in the literature. Our study can provide a vital reference for the diagnosis of future cases.

This study was approved by the Ethics Committee of Tianjin Children's Hospital. The study complied with Chinese bioethics laws as well as the Helsinki declaration and its later amendments.

Written informed consent to participate in this study and for publication were obtained from the parents of the patients.

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

M.S. and Y.Z. performed the literature search, collection, gene sequencing, and drafting of the manuscript. Q.L. provided clinical information. Y.C. and Y.D. completed all examination and photograph collection and confirmed the final diagnosis. J.S., D.L., and C.C. performed conceptualization and funding acquisition. All authors read, edited, and approved the final version of the manuscript.

* These authors contributed equally to this work and should be considered co-first authors.

# These authors contributed equally to this work and should be considered co-corresponding authors.

Article published online:
16 January 2024

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