Main clinical features
Individuals with HAFOUS have 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. Other additional clinical characteristics include an increased prevalence of neonatal hypotonia, feeding problems, joint contractures and hypogonadism.
Prevalence
HAFOUS is an extremely rare disorder that have been described in only around 70 families worldwide. The incidence and prevalence of this syndrome is unknown owing to the limited number of cases identified so far. It is likely that people with this disorder go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
Molecular characteristics
The USP7 gene, located on the short (p) arm of chromosome 16 (16p13.2), encodes for 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. A disruption in the USP7 gene causes a neurodevelopmental disorder called USP7-related syndrome or HAFOUS.
Inheritance
Mutations in USP7 are either point mutations or gene deletions. Mutations are diagnosed through either whole-exome sequencing or chromosome microarray analysis. The inheritance pattern of the disease caused by USP7 mutations is autosomal dominant and to date, the majority of documented cases are considered de novo mutations. Thus, most affected individuals represent simplex cases, i.e., a single occurrence in a family. The recurrence risk for future pregnancies is low (probably <2%) but greater than that of the general population because of the possibility of germline mosaicism in one of the parents.