In 2019, Fountain et al. published the article entitled “Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies”,1 which described 23 patients with haploinsufficiency of USP7 (ubiquitin-specific protease 7) gene, causing a new autosomal dominant condition linked to ubiquitination defect, similarly to Schaaf–Yang syndrome (SHFYNG).2 These patients showed developmental delay/intellectual disability, hypotonia, eye anomalies, feeding difficulties, behavioral anomalies, autism spectrum disorder (ASD), and abnormal brain magnetic resonance image (MRI) findings.
Here, we report a novel case with a de novo heterozygous variant in USP7 in a patient with a phenotype resembling this new syndrome. Furthermore, this is the first description of fetal complications during pregnancy and cardiac involvement related to USP7 disorder.
The patient is a 7-year-old girl, the second child of nonconsanguineous and healthy parents. She was born at preterm (35th week), with weight of 2690 g (50th centile), height 50 cm (50th centile), and head circumference 32.5 cm (50th centile). APGAR score was 6–8 at 1 and 10 minutes. The pregnancy was complicated by fetal cystic hygroma, threatened abortion, and hesitated in Cesarean section. The fetal karyotype was 46,XX.
At birth, ultrasound examination displayed congenital heart defect, with atrial septal defect and patent ductus arteriosus, ventriculomegaly, and cerebellar worm hypoplasia. At first clinical examination she showed hypotonia, psychomotor and language delay, congenital hydrocephalus, macrocrania, joint lassity, constipation, gastroesophageal reflux with recurrent vomiting in the first year of life, and recurrent respiratory infections.
The ophthalmic and fundus exam, the electroencephalogram, and standard laboratory tests were normal.
The neurologic assessment confirmed generalized hypotonia, muscle hypotrophy, motor delay and medium–severe cognitive disability, impairment of communicative and relational areas, and oral dyspraxia. She had sporadic seizures, not treated pharmacologically to date.
The brain MRI, at the age of six years, disclosed bilateral slight enlargement of the subarachnoid spaces in the frontal region and of the supratentorial ventricles, hippocampal anomaly, and suspicion of mesial temporal sclerosis.
The electrocardiogram showed disturbed ventricular repolarization and the echocardiogram displayed mitral valve prolapse with mild–moderate failure. Comparative genomic hybridization (CGH) array and sequencing analysis of genes associated with RASopathies were negative.
On physical examination at the age of three, she showed weight 16.000 g (75th centile), height 105.5 cm (95th centile), head circumference over + 2 SD, frontal bossing, arched and medially sparse eyebrows, hypotelorism, bilateral palpebral ptosis and long palpebral fissures, flat and large nose root, anteverse nostrils, long and smooth philtrum, thin upper lip, deep labial nose grooves, small and low-set ears, thick and folded helix, micrognathia, normal hands and fingers, bilateral flat foot, and ligamentous lassity.
Exome sequencing revealed a novel de novo variant, c.2232_2235delGAGA (p.Arg745PhefsTer15) in USP7 gene, that resulted in a premature stop codon in the C-terminal tandem ubiquitin-like (Ubl) domain (amino acids 560–1102) of USP7 protein.3 As reported, the C-terminal Ubl domain is essential to achieve full enzymatic efficiency;4 in fact, the binding of ubiquitin initiates a series of conformational changes not only in the catalytic domain (amino acids 208–560) but also in the C terminus, stabilizing the active conformation and the catalytic triad.3,5 A recent study demonstrated that Ubl-45 is sufficient to reconstitute the USP7 activation in vitro and in vivo.3
We describe a patient with a pathogenic variant in USP7 with hypotonia, psychomotor and language delay, congenital hydrocephalus, seizures, and brain MRI anomaly. She had also fetal cystic hygroma, preterm birth, and congenital heart defects, never described previously.
This case expands the clinical and molecular spectrum of the extremely rare phenotype related to USP7 variants, suggesting the possibility of congenital heart defects and pregnancy complications as new clinical features of this condition. Literature data show the possibility of endocrine complications (pubertal delay, autoimmune diseases), immunological deficit, and predisposition to autoimmune diseases and a wide variety of cancers.3 Moreover, in this case, the correct diagnosis allowed us to plan neuropsychiatric, endocrinological, immunological, cardiological, and potential oncological risk follow-up.
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;21:1797–1807.
Schaaf CP, Gonzalez-Garay ML, Xia F, et al. Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism. Nat Genet. 2013;45:1405–1408.
Wang Z, Kang W, You Y, et al. USP7: novel drug target in cancer therapy. Front Pharmacol. 2019;10:427.
Faesen AC, Dirac AM, Shanmugham A, et al. Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase. Mol Cell. 2011;44:147–159.
Rougé L, Bainbridge TW, Kwok M, et al. Molecular understanding of USP7 substrate recognition and C-terminal activation. Structure. 2016;24:1335–1345.
The authors declare no conflicts of interest.
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Capra, A.P., Agolini, E., La Rosa, M.A. et al. Correspondence on “Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies” by Fountain et al.. Genet Med (2020). https://doi.org/10.1038/s41436-020-00978-x