CNVs as Risk Factors
“In psychiatry, people have been interested in CNVs because they represent important risk factors,” says Judith L. Rapoport, M.D., senior investigator and chief of the Child Psychiatry Branch at the National Institute of Mental Health. While looking at a very rare, childhood-onset form of schizophrenia, Dr. Rapoport and colleagues found that a pediatric group of schizophrenia patients exhibits a higher prevalence of the 22q11 microdeletion, of approximately 5%, than any adult-onset population with schizophrenia that was previously studied.
The finding that the same 22q11 microdeletion is also present in children with other neurodevelopmental conditions promises to make the interpretation of sequencing data more challenging. “Approximately 80% of the children born with this deletion have some kind of severe disorder, whether it is a mood disorder, autism, obsessive-compulsive disorder, or delayed language development, and the possibility of conducting prenatal screening has enormous implications,” says Dr. Rapoport.
The 22q11 microdeletion, which involves an approximately 3 Mb chromosomal region, contains many genes. The large number of genes, together with the microdeletion’s involvement in several neuropsychiatric conditions, makes the identification of the microdeletion’s specific role in disease, and the elucidation of the molecular basis of pathogenesis, more challenging. “There are investigators currently exploring the effects that CNVs from our patients have on neurons grown by cellular reprogramming,” says Dr. Rapoport.
The identification and characterization of pathological CNVs has ramifications in terms of prenatal screening, particularly since many common structural variants are found in patients who appear to be clinically unaffected. While approximately 26% of the individuals harboring the 22q11 microdeletion will develop schizophrenia, a disorder for which few risk factors are known, approximately 75% of these individuals will not develop this condition. “But having an identical twin with schizophrenia confers a 50% risk, and this deletion represents, therefore, the second largest risk factor that currently exists,” explains Dr. Rapoport.