USP7 is a protein-coding gene that plays a role in tumor suppression, transcriptional regulation, immune response, and endosomal protein recycling. Individuals who are born with a mutation in USP7 have been found to have a neurodevelopmental disorder. The clinical features of USP7 mutations 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 phenotypic spectrum of USP7 mutations is still being uncovered, and that each individual case is unique. Currently, there are 20 individuals across the globe identified with USP7 mutations.
Diagnosis and Management of USP7 Mutations
Mutations in USP7 are either point mutations or gene deletions. USP7 mutations are diagnosed through either whole exome sequencing or chromosome microarray analysis (CMA). The inheritance pattern of the disease caused by USP7 mutations is autosomal dominant, which means that someone who receives a single copy of an abnormal USP7 gene from either parent may have this disorder. For someone who has a USP7 mutation, their chance of passing it to their children is 50%, The majority of documented cases are considered de novo mutations, meaning that the mutation arose spontaneously during the development of the parents' sperm and egg cells. With de novo mutations, the mother and father would be unaffected by the mutation; if these parents were considering having another child, they would be expected to have a <3% chance of having another child with a USP7 mutation.
Once diagnosed, there are certain tests that are recommended for each patient. These tests include:
1. Measurement of IGF-1 and IGF-BP3 to screen for growth hormone deficiency
2. A brain MRI taken after 40 months of age to assess for abnormalities of white matter
3. A full assessment by a speech pathologist
4. A 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