“It is never boring to be a physician”

…”because patients are so different.  Each has a story to tell.” This is the beginning of an excellent editorial (NEJM 2012; 367: 1350-52).  The editorial helps translate a study about “Phenotypic Heterogeneity” due to copy-number variants (NEJM 2012; 367: 1321-31).  The study itself involved analyzing 32,587 samples from children with developmental delay.  Ultimately, the study focused on 2312 children with 72 copy-number variants.

Both the study and the editorial try to explain why individuals with the same genetic defect have variability in the severity/expression.  Some of the factors include environment, chance, and modifier genes.  Due to the availability of relatively cheap and quick technology, one can sequence all of the 22,000 human genes.  The techonology for this study used microarray-based comparative genomic hybridization to interogate the entire genome.

Copy-number variation refers to changes in the number of genes compared to normal.  Typically, two gene copies are present.  Thus, a deletion or duplications will result in copy-number variants.

In the aforementioned study, investigators found that large copy-number variants contributed to differences in outcomes.  That is, persons with “the same chromosomal abnormality may have very different clinical outcomes” because they a have a second genetic event (copy-number variant elsewhere) that “makes matters worse for them.”

These copy-number variants contribute to learning disabilities.  Large copy-number variants occur in less than 1% of the unaffected population but in 8.6% of children with learning disabilities.  Males are m much more susceptible to have developmental delay due to these copy-number variants and unaffected women are more likely to transmit these copy-number variants.  These gender differences are thought to be due to the fact that males have only a single X chromosome and are more vulnerable to genetic insults as a consequence.

Besides learning disabilities, copy-number variants have been implicated in well-known diseases such as schizophrenia, autism, cardiac disease, and epilepsy.  In addition, well-defined syndromes, like Smith-Magenis syndrome, Williams-Beuren syndrome, Sotos syndrome, and MAPT (17q21.31) deletion syndrome, are also well-recognized as being associated with de novo copy-number variants.

It really is an exciting time to be a physician.  Widely available genetic tests can finally explain a lot of previously unanswered questions.