A team of researchers led by HudsonAlpha Institute for Biotechnology and the Clinical Sequencing Exploratory Research (CSER) consortium found that genome sequencing enabled the diagnosis of almost 30 percent percent of children with unexplained developmental delay or seizures. Some of the participants carried genetic variants related to sickle cell disease.
Researchers, who presented their results at the 2018 Genomic Medicine Conference in Huntsville, Alabama, performed genome sequencing on 600 children and their parents to try to pinpoint the cause of their conditions.
Kelly East, genetic counselor at HudsonAlpha and one of the researchers involved in the study, said that 8.6 percent of the participants carried gene mutations related to cystic fibrosis, sickle-cell anemia, or Tay-Sachs disease, according to a press release written by Ciara Curtin.
These variants were found as secondary findings of the study, a term used in medical genetics for findings unrelated to the indication for ordering the sequencing, but of medical value for patient care.
Another team member, Greg Barsh, MD, PhD, faculty investigator at HudsonAlpha, said that more than three quarters of the children contained new mutations not present in other family members.
This type of genetic alteration, called de novo mutations, occur as a result of gene variants that appear in the egg or sperm of one of the parents, or that arise in the fertilized egg during the embryo’s early development.
The team studied 536 of these children who were not able to receive a diagnosis by conventional tests. Both the genome of the child and their parents was sequenced in search for the genetic variants that could explain the child’s disorder.
In total, they identified 3 to 4 million variants, which were filtered down based on genetic annotations, population frequency, and inheritance patterns to a shorter list of 10 to 100 variants per patient.
Then, a variant review committee evaluated which variants caused, or were likely to cause, disease. One variant was identified in 155 of the children, most of which were de novo mutations, including 12 percent autosomal recessive mutations and 7 percent X-linked.
In total, 12 percent of the studies cases had a variant whose association with disease is unknown, a majority of which also were de novo mutations.
Barsh noted, however, that sequencing wasn’t catching everything because there were some patients who had severe symptoms, plus affected family members that, according to him “smell genetic,” but researchers could not diagnose.
This means that diagnosis based on genome sequencing still has room for improvement.
There are new informatics methods that can automate the identification of the genetic variants likely to cause disease, and that can extend the analysis to regions of the genome that usally are not included. An example is the Combined Annotation Dependent Depletion (CADD) algorithm.
Besides, the team also highlights the importance of data sharing between clinicians, which can help to reinforce the link between some genetic variants of uncertain significance and disease. Barsh gave as example of that the Baylor-Hopkins Center for Mendelian Genomics’ GeneMatcher, which enables people to ask others if they’ve seen something like their variants in other patients.
Re-analyzing data also can reassess the disease potential of certain variants. For instance, 15 percent of the disease-causing or likely disease-causing variants researchers found in the study were identified after the initial assessment.
The team of researchers now will move on to perform whole-genome sequencing in newborns in nurseries in Alabama, Mississippi, and Louisiana, a project called SouthSeq, an part of the CSER program. The initiative is particularly targeted at hospitals of underserved communities.