Two-hit wonder: a novel genetic model to explain variable expressivity in severe pediatric phenotypes.

Genomic disorders involving microdeletions and microduplications have been reported in many individuals with neuropsychiatric disorders such as autism and mental retardation. The recurrent nature of these disorders is often explained by nonallelic homologous recombination (NAHR) mediated by large blocks of highly identical segmental duplications or low copy repeats (LCR). The rapidly growing list of genomic disorders is partly attributable to methodological advances in DNA microarray technologies that have enabled the identification of microscopic DNA losses and gains previously undetectable by standard cytogenetic approaches. Knowledge of the prevalence and characteristics of recurrent microdeletions and microduplications is clinically invaluable; however, molecular diagnostics using copy number variant (CNV) data is frequently hampered by the phenomenon of ‘variable expressivity’ – when a phenotype is expressed to a different degree among individuals with the same genotype (or underlying mutation/CNV). For example, 16p11.2 microdeletions and duplications have been reported in autism, schizophrenia, mental retardation, and even in apparently healthy individuals (1–5). Explaining the genetic basis of variable expressivity is of great medical and scientific importance. In the current study, Girirajan and colleagues used CNV data from one of the largest collections of individuals with intellectual disability and developmental delay and identified a recurrent pathogenic 16p12.1 microdeletion with an incidence of ∼1/15,000 live births. The authors propose a novel genetic basis of variable expressivity in pediatric phenotypes that involves a ‘twohit’ hypothesis. The authors previously performed a genomewide meta-analysis study of microdeletions and microduplications in individuals with intellectual disability, autism, and schizophrenia, and identified a potentially pathogenic microdeletion on chromosome 16p12.1 in five of 6860 individuals compared with zero of 5674 control individuals. To further characterize this recurrent microdeletion, the authors investigated a discovery cohort comprising 11,873 children with intellectual disability/developmental delay and congenital malformations (cases) and 8540 controls. The 16p12.1 microdeletion was significantly enriched in cases (n = 20) vs controls (n = 2) (Fisher’s exact test, p = 0.0009, odds ratio (OR) = 7.2). Next, the authors investigated a replication cohort comprising 9254 cases and 6299 controls and again found a significant enrichment of the microdeletion in cases (n = 22) vs controls (n = 6) (Fisher’s exact test, p = 0.028, OR = 2.5). Combining the two cohorts showed a highly significant association of the 16p12.1 microdeletion in cases vs controls (Fisher’s exact test, p = 1.18 × 10−4, OR = 3.7). The authors also examined a schizophrenia cohort comprising 3061 individuals and identified three sporadic cases with 16p12.1 microdeletions; however, this association was not significant when compared to the frequency of the microdeletion in controls (n = 14,839) (Fisher’s exact test, p = 0.29, OR = 1.8). The authors considered the possibility that the lack of association may be due to a lack of statistical power in the schizophrenia cohort (n = 3061) compared to the intellectual disability/developmental delay cohort (n = 21,127). Interestingly, in one family (LD1205) segregating for both schizophrenia and mental retardation, the 16p11.2 microdeletion was only found in individuals diagnosed with both psychosis and intellectual disability. To characterize the phenotypic features associated with the 16p12.1 microdeletion, the authors evaluated available medical records and identified multiple features associated with the deletion (note: not all patients could be ascertained for all clinical features, hence the total number of individuals characterized for each phenotypic feature varies). The phenotypic features included developmental delay and learning disability (18 of