NORD gratefully acknowledges Megan Rech, Research Coordinator, Baylor College of Medicine, Department of Molecular and Human Genetics; Bo Bigelow, Chairman and Cofounder, Foundation for USP7-Related Diseases; Kate McCrann, Treasurer and Co-Founder, Foundation for USP7-Related Diseases; and Christian Schaaf, MD, PhD, Assistant Professor, Molecular and Human Genetics, Baylor College of Medicine, for the preparation of this report.
USP7-related diseases are caused by changes (mutations) in a protein-coding gene called USP7. The clinical features in affected children include developmental delay/intellectual disability, autism spectrum disorder, increased prevalence of epilepsy, abnormal brain MRIs, and speech/motor impairments, with some patients being completely non-verbal.
Individuals with USP7 mutations also show an increased prevalence of neonatal hypotonia, feeding problems, joint contractures, and hypogonadism. Additional clinical features include eye problems such as strabismus, myopia, or nystagmus, short stature, and difficulty gaining weight. Many patients experience gastrointestinal issues, such as reflux/GERD, chronic constipation, or chronic diarrhea. It is important to note that the clinical features (phenotypic spectrum) of USP7 mutations is still being uncovered, and that each individual case is unique. Currently, there are 25 individuals across the globe identified with USP7 mutations.
The symptoms and severity of USP7-related diseases can vary from one person to another. Many features of the disorder are nonspecific and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Often this requires input from a clinical geneticist or genetic counselor to supply the most recent and accurate information about the disorder and discuss genetic testing options or treatment plans.
Initially, some affected infants (43%) may exhibit diminished muscle tone, known as hypotonia, which can cause a baby to feel “floppy” when held. Hypotonia can be associated with poor sucking ability, which may result in feeding difficulties (58%) and difficulty gaining weight (36%). Infants may also exhibit contractures of the joints (27%) and eye abnormalities (61%) such as strabismus (misalignment of the eyes), myopia (nearsightedness), or nystagmus (repetitive involuntary eye movements).
In addition, individuals may exhibit hypogonadism (58%) in infancy. Hypogonadism refers to inadequate function of the sex organs, the testes in males and the ovaries in females. The sex organs in affected individuals fail to produce sufficient sex hormones, which can result in underdeveloped sex organs. Affected males may exhibit a small penis, underdeveloped scrotum, and small testes. Testes may not be descended into the scrotal sac at the time of birth (cryptorchidism). Affected females may exhibit an abnormally small clitoris or labia minor. Hypogonadism is also associated with delayed onset of puberty, incomplete development at puberty, and infertility.
Dysmorphic facial features in affected individuals are generally variable and nonspecific, but can include deep-set eyes, straight eyebrows, and a deeper top fold on the ears with a straight edge on the bottom of the fold. These features can be noticeable shortly after birth or may develop slowly over time. Other common physical features include walking with the knees slightly bent and flat feet.
As affected individuals grow older, the most commonly experienced clinical features include developmental delay/intellectual disability (94%), absence of language (25%) or speech impairment (100%), and autism spectrum disorder (58%), as well as short stature (33%).
The most common gastrointestinal feature is gastroesophageal reflux disease (GERD), which occurs when the muscle at the end of the esophagus does not close properly, allowing stomach acid to flow back up into the esophagus and causing a burning sensation. Other common gastrointestinal features include chronic constipation (36%) and chronic diarrhea (20%).
USP7-related diseases can also be accompanied by neurological features, including an abnormal brain MRI (90%), seizures (44%), and an abnormal gait (40%).
Our bodies are made up of trillions of cells. Within each cell is a nucleus, which contains X-shaped structures called chromosomes. These chromosomes are made up of tightly wound strands of DNA, our genetic material. Segments of DNA that provide instructions for the body to make proteins are called genes. Proteins play a critical role in many functions of the body. When a change (mutation) in a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The gene that is altered in patients with USP7-related diseases is the USP7 gene, located on the short (p) arm of chromosome 16.
Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The specific location of the USP7 gene is chromosome 16p13.2.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. The inheritance pattern of the disease caused by USP7 mutations is autosomal dominant, which means that only a single abnormal copy of the gene is necessary to cause the disease. Mutations in USP7 are either gene deletions, meaning the entire gene is missing, or point mutations, meaning just one letter in the DNA code is changed.
Abnormal genes can either be inherited from a parent, or can result from de novo mutations, meaning that the parents are unaffected and the mutation arose spontaneously during the development of the parents’ sperm and egg cells. The majority of documented cases of USP7 diseases are considered de novo mutations.
If the parents of an affected child are considering having another baby, the risk of recurrence in a sibling depends on the type of mutation. If the child has a de novo mutation, the risk of a sibling also being affected is <3%. If the child’s mutation was inherited from a parent, the risk of a sibling also having the mutation is 50%.
The USP7 gene contains instructions for producing (encoding) the USP7 protein, which plays a role in tumor suppression, control over the process of converting DNA into a protein (transcriptional regulation), immune response, and endosomal protein recycling. Endosomes are compartments within cells that transport molecules such as proteins. Endosomes direct proteins in three different directions: 1) towards the thin structure surrounding the surface of the cell (cell membrane) for recycling, 2) to a structure in cells called the Golgi apparatus, which helps modify and package proteins to leave the cell, or 3) to a structure called the lysosome to be broken down (degraded).
Sometimes, endosomes mistakenly bring proteins inside the cell that are supposed to stay on the cell’s surface. When this happens, endosomes need to direct these proteins back to the cell membrane for recycling, and not to the lysosome where they would be broken down. In order for proteins to get back to the cell membrane, a protein called actin needs to be added to the endosome. It turns out that actin gets put on the endosome by a structure called WASH. For WASH to be working, it needs to be activated by a small protein mark, called ubiquitin. Ubiquitin gets added to WASH by a structure called the MUST complex, which is made up of 3 proteins including the USP7 protein. (In fact, USP7 actually stands for ubiquitin-specific protease 7). To put it all together, USP7 is a component of MUST, which uses ubiquitin to activate WASH, which adds actin to the endosome, which instructs the endosome to send important proteins back to the surface of the cell where they belong. When the USP7 gene has a mutation, this process doesn’t work, and the recycling and degradation of proteins in the cell will be changed, causing the symptoms seen in USP7-related diseases.
Interestingly, USP7 actually has two functions on WASH: not only does it promote ubiquitination of WASH to activate it (which ultimately helps recycle proteins back to the membrane), but it also takes ubiquitin off of WASH to deactivate it (which would lead to proteins being degraded in the lysosome). Though these two functions seemingly oppose each other, this finding suggests that USP7 helps with precision control and fine-tuning of the protein recycling process.
USP7-related diseases are extremely rare disorders that have been described in only 25 families worldwide. The incidence and prevalence of the disorder is unknown. It is likely that people with these disorders go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
USP7 mutations are diagnosed through either whole exome sequencing, USP7 sequencing, or chromosome microarray analysis.
Chromosome microarray analysis (CMA) studies can be compared to doing an inventory of books in a library – this type of testing checks 200,000 regions of chromosome material to see if there are extra or missing genes in an individual’s genome (a person’s complete set of DNA). Chromosome microarray testing can detect if the entire USP7 gene or pieces of the gene are missing (deleted), but misspellings within the USP7 gene will not be detected.
Whole exome sequencing (WES) can be compared to checking for misspellings in books – this test examines 30,000,000 letters of DNA making up our genetic code. Specifically, whole exome sequencing looks for genetic changes (mutations) in a small portion of the human genome called the exome. While the human genome is a person’s complete set of DNA, including all of his or her genes, the exome is the part of the genome that contains the coding portions of the genes (exons) that code for the various amino acids that make up individual proteins. These proteins have wide and varied responsibilities in the body. Up to 84% of genetic disorders occur because of a change or alteration in these coding exons of the gene. Whole exome sequencing can identify a diagnosis of a USP7-related disorder by detecting even very small DNA mutations of a single letter (point mutations) in the USP7 gene.
Sequencing of USP7 alone can make the diagnosis, but currently there appear to be no clinical laboratories offering this specific test.
Clinical Testing and Work-Up
Once diagnosed, recommended tests include:
1. Measurement of IGF-1 and IGF-BP3 to screen for growth hormone deficiency
2. A brain MRI after 40 months of age to assess for abnormalities of white matter
3. Full assessment by a speech pathologist
4. Full assessment for physical and occupational therapy
5. Formal cognitive and behavioral testing by a licensed pediatric psychiatrist
6. A sleep apnea test/sleep study
7. An EEG test to test for abnormal electric activity that could cause/predispose seizures
8. A consultation with a gastroenterologist for any reflux, vomiting, or chronic constipation/diarrhea issues
9. An assessment by a pediatric ophthalmologist
Treatment is directed toward the specific symptoms that are apparent in each individual. While at present a cure is not available for these diseases, early intervention and maintenance to treatment can greatly improve the overall health and quality of life for affected individuals and their families. Treatment may require the coordinated efforts of a team of specialists. Clinical geneticists, pediatricians, endocrinologists, speech therapists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an effective program for the child’s treatment. Genetic counseling may be of benefit for affected individuals and their families to further discuss the condition, provide information and to examine recurrence risks.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the family based upon the specifics of the patient’s case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
In infants, special nipples or gavage feeding may be used to ensure adequate nutrition. Gavage feeding is a procedure in which a small, thin tube is passed through the nose and mouth to the stomach to directly feed a newborn who has feeding difficulties.
In males, the treatment of hypogonadism with either testosterone or human chorionic gonadotropin may be beneficial during infancy, potentially increasing the size of the genitalia or prompting testicular descent into the scrotum when cryptorchidism is present. Although cryptorchidism may occasionally resolve spontaneously or with hormone therapy, most males may require surgical treatment.
Individuals may also benefit from growth hormone (GH) therapy, which can help to increase height, improve lean body mass, and ultimately improve the quality of life.
Children benefit from early intervention to assess and treat issues with motor skills, intellectual disability, and speech and language development. Early intervention may include physical and occupational therapy, special education, and speech therapy. An individualized education plan should be created at the start of school. Behavioral therapy may be beneficial to manage difficult behavior.
Children should receive an ophthalmological exam to evaluate for eye abnormalities potentially associated with USP7-related diseases such as strabismus and to assess visual acuity.
Sex hormones can be replaced at puberty as they can stimulate the development of secondary sexual characteristics and improve self-image. In males, the use of such therapy has been controversial because testosterone replacement by monthly injection may contribute to behavioral issues in males; use of a testosterone patch or gel will avert this problem. Sex hormone replacement therapy may increase the risk of stroke in females, as in the general population, and hygiene issues should also be considered. Sex education and consideration of contraception are important, particularly in females.
Proposed therapeutic strategies include targeting USP7 itself, activating the WASH complex with something other than ubiquitin, or modulating the activity of proteins regulated by USP7.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about USP7:
Christian Schaaf, MD, PhD
The Joan and Stanford Alexander Endowed Chair for Neuropsychiatric Genetics
Baylor College of Medicine
Department of Molecular and Human Genetics
Jan and Dan Duncan Neurological Research Institute
1250 Moursund Street, 1325.18
Houston, TX 77030
office phone 832-824-8787
Hao YH, Fountain MD, Tacer KF, Xia F, Bi W, Kang SH, Patel A, Rosenfeld JA, Le Caignec C, Isidor B, Krantz ID, Noon SE, Pfotenhauer JP, Morgan TM, Moran R, Pedersen RC, Saenz MS, Schaaf CP, Potts PR. USP7 acts as a molecular rheostat to promote WASH-dependent endosomal protein recycling and is mutated in a human neurodevelopmental disorder. Molecular cell. 2015;59(6):956-969. doi: 10.1016/j.molcel.2015.07.033.
McCann-Crosby B. Endocrine Considerations in USP7. Oral presentation at: USP7 Family Conference; April 2017; Houston, TX.
Potts R. Molecular Aspects of USP7. Oral presentation at: USP7 Family Conference; April 2017; Houston, TX.
Schaaf CP. Clinical Aspects. Oral presentation at: USP7 Family Conference; April 2017; Houston, TX.
Ubiquitin-Specific Protease 7; USP7. OMIM website. https://www.omim.org/entry/602519. Updated June 22, 2017. Accessed January 16, 2018.
USP7 Portal. Christian Schaaf Lab website. https://www.bcm.edu/research/labs/christian-schaaf/usp7portal .Accessed January 16, 2018.
USP7-Related Diseases Physician Brochure. https://storage.googleapis.com/wzukusers/user-28226240/documents/59879b7dbcf45MZ20ydM/PhysicianBrochureEnglish.pdf. Accessed January 16, 2018.
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