Identification of Two Variants c.2697A > C and c.3305A > C in USP7 by Analysis of Whole-Exome Sequencing in Chinese Patients with Hao-Fountain Syndrome

Abstract

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.

Keywords

USP7 - development delay - intellectual disability - whole-exome sequencing - Hao-Fountain syndrome

Ethics Approval Statement

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.

Patient Consent Statement

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

Data Availability Statement

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

Authors' Contributions

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.

Publication History

Article published online:
16 January 2024

• References

• 1 Hao YH, Fountain Jr MD, 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 (06) 956-969
• 2 Hao YH, Doyle JM, Ramanathan S. et al. Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination. Cell 2013; 152 (05) 1051-1064
• 3 Li M, Chen D, Shiloh A. et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 2002; 416 (6881) 648-653
• 4 Nicholson B, Suresh Kumar KG. The multifaceted roles of USP7: new therapeutic opportunities. Cell Biochem Biophys 2011; 60 (1-2): 61-68
• 5 Colland F, Formstecher E, Jacq X. et al. Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther 2009; 8 (08) 2286-2295
• 6 Harakandi C, Nininahazwe L, Xu H. et al. Recent advances on the intervention sites targeting USP7-MDM2-p53 in cancer therapy. Bioorg Chem 2021; 116: 105273
• 7 Hernández-Pérez S, Cabrera E, Salido E. et al. Correction: DUB3 and USP7 de-ubiquitinating enzymes control replication inhibitor Geminin: molecular characterization and associations with breast cancer. Oncogene 2019; 38 (24) 4886
• 8 Nicklas S, Hillje AL, Okawa S. et al. A complex of the ubiquitin ligase TRIM32 and the deubiquitinase USP7 balances the level of c-Myc ubiquitination and thereby determines neural stem cell fate specification. Cell Death Differ 2019; 26 (04) 728-740
• 9 Song MS, Salmena L, Carracedo A. et al. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 2008; 455 (7214) 813-817
• 10 Xia X, Liao Y, Huang C. et al. Deubiquitination and stabilization of estrogen receptor α by ubiquitin-specific protease 7 promotes breast tumorigenesis. Cancer Lett 2019; 465: 118-128
• 11 Fountain MD, Oleson DS, Rech ME. et al. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. Genet Med 2019; 21 (08) 1797-1807
• 12 Capra AP, Agolini E, La Rosa MA, Novelli A, Briuglia S. Correspondence on “Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies” by Fountain et al. Genet Med 2021; 23 (02) 421-422
• 13 Priolo M, Mancini C, Pizzi S. et al. Complex presentation of Hao-Fountain syndrome solved by exome sequencing highlighting co-occurring genomic variants. Genes (Basel) 2022; 13 (05) 889
• 14 Zampieri N, Pulvirenti R, Pedrazzoli E, Camoglio FS. Hao-Fountain syndrome and genital disorders: report of a new possible association. Ital J Pediatr 2022; 48 (01) 182
• 15 Zheng H, Mei S, Li F. et al. Expansion of the mutation spectrum and phenotype of USP7-related neurodevelopmental disorder. Front Mol Neurosci 2022; 15: 970649
• 16 Rio M, Royer G, Gobin S. et al. Monozygotic twins discordant for submicroscopic chromosomal anomalies in 2p25.3 region detected by array CGH. Clin Genet 2013; 84 (01) 31-36
• 17 Liu A, Yang X, Yang X. et al. Mosaicism and incomplete penetrance of PCDH19 mutations. J Med Genet 2019; 56 (02) 81-88
• 18 Arredondo-Vega FX, Kurtzberg J, Chaffee S. et al. Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency. J Clin Invest 1990; 86 (02) 444-452
• 19 Uberti J, Peterson Jr WD, Lightbody JJ, Johnson RM. A phenotypically normal revertant of an adenosine deaminase-deficient lymphoblast cell line. J Immunol 1983; 130 (06) 2866-2870
• 20 Gruber C, Bogunovic D. Incomplete penetrance in primary immunodeficiency: a skeleton in the closet. Hum Genet 2020; 139 (6-7): 745-757
• 21 Karki M, Mahara G. Heart diseases, anxiety disorders, and negative thoughts. Heart Mind (Mumbai) 2022; 6 (01) 22-25