A paper published online this week at Nature Genetics uses an innovative method to find new genes that contribute to neurocognitive disorders, such as autism.

The paper reports 10 new candidate genes for developmental delay or autism. The results also led to the discovery of two new subtypes of developmental delay, caused by loss of the genes SETBP1 and ZMYND11, respectively. You can find the paper reporting this study here.

One example of a CNV. In this case, the region is duplicated. {credit}Wikipedia{/credit}

The authors of the study narrowed in on the 10 candidate genes by first building a map of all the regions in the genome with different copy numbers between the developmentally delayed and normal children. These differences, known as copy number variants (CNVs), can each include many different genes. By then integrating this map with single base-pair changes (SNVs) between the two groups, the researchers were able narrow in on the genes most likely to contribute to cognitive disorders.

I asked one of the senior authors of the paper, Evan Eichler, to tell us a little more about the background of the study and why it is important:

Q: The study includes authors from many institutions–how did you all come together to work on this project?

A: The multi-center collaboration is one that developed over the last ten years when we began our work on CNVs and genomic hotspots flanked by segmental duplications. Some connections go further back, for example, I have known Lisa Shaffer from the days when I was a graduate student and she was in charge of the molecular cytogenetics laboratory at Baylor College of Medicine.

Q: Why did you decide to focus on CNVs rather than other types of variants? Was this the plan from the start?

A: The paper actually goes after both CNVs and SNVs. We used the very large number of cases and controls to identify regions that reached nominal significance for burden (i.e excess of deletions and duplications in patients when compared to controls). We then selected genes for resequencing (using MIPs [molecular inversion probes]) and show excess of loss-of-function mutations and similarity in clinical phenotypes between the SNV and CNV patients. It was the plan from the start.

Q: What would you say is the major new breakthrough in this study?

A: A systematic approach to go from large CNVs to pinpointing the underlying gene responsible for specific forms of developmental delay and ID. The paper bridges between those two types of variants and shows the power of combining these different datasets to make discoveries.

Q: How do you envision clinicians using the results? Are there any caveats that they need to consider?

A: Hopefully, the CNV morbidity map will provide clinicians and families some guidance in terms of interpreting previous variants of unknown significance. The discovery of specific genes and intersection of exomes and CNVs should also help with interpretation of clinical exomes that are now being generated. I anticipate that more than 1/2 of the genes listed in Table 2, for example, are relevant to pediatric DD as well as other diseases. The caveat is that more data and clinical assessment are required. Despite 30,000 cases and 20,000 controls many regions are still underpowered to move them to a category of benign or pathogenic. Large clinical labs should exchange their CNV data more freely.

Q: Do you think the approach used in this study (coupling exomes and CNVs) will be useful for other neuropsychiatric (or other) disorders?

A: Yes. Many complex neuropsychiatric disorders may in fact manifest as mild DD or other learning disorders early in childhood. Case-in-point is ZMYND11. We show that it is most likely the gene responsible for the 10p15.3 microdeletion syndrome but also find that 3/4 males with truncating mutations also have neuropsychiatric diagnoses as adults. A sporadic truncating mutation of ZMYND11 was also identified in a recent trio exome sequencing study of schizophrenia family. It still surprises me that the neuropsychiatric and pediatric developmental delay fields don’t compare notes more often.