Genomic approaches to understanding rare disease
Neurodevelopmental diseases affect one to three percent of children worldwide. They cause a range of physical and intellectual disabilities including impaired cognition, failure to meet developmental milestones, craniofacial and skeletal abnormalities, autism, and seizures. Identifying the genetic variants, or changes in DNA, that lead to these diseases can provide a precise diagnosis, guide treatment approaches, and give families the answer to their years-long medical mystery.
Cooper’s lab uses genome sequencing technology, along with experimental and computational techniques, to identify disease-causing genetic variants within an individual’s genome. The group is part of several research studies that enroll children with rare and undiagnosed diseases and provide them with DNA sequencing. The group identifies genes of interest that could be responsible for the disease. Many of the variants are classified as variants of uncertain significance (VUS), meaning there is not enough evidence to prove they cause disease.
Cooper’s lab frequently submits VUS to an online platform called GeneMatcher, which allows researchers to input genes of interest and match with other scientists all over the world. By identifying more individuals with similar variants and similar symptoms, the team can confirm the gene is likely the cause of symptoms. Further experimental techniques and genomic assays can help investigate the function of the variants.
The group has submitted more than 200 genes to GeneMatcher since 2016. Through these GeneMatcher collaborations, Cooper’s team has linked more than a dozen genes to developmental disorders including EBF3, RALA, and BRSK2.
Advancing genetic disease diagnosis
Despite advances in genome sequencing technology used in the diagnosis of many genetic disorders, specific diagnoses for children with neurodevelopmental diseases remain elusive in many cases. This is likely because many disease-causing genetic variants are difficult or impossible to detect through typical genomic sequencing approaches.
Through several research studies, Cooper’s lab and their collaborators have enrolled and sequenced the genomes of over 1,800 children, and often their parents. The group has found the genetic cause for about 30 percent of affected children. However, the team is constantly looking for ways to improve the technology and increase diagnostic rates for patients with rare diseases. More recently the lab has begun using long-read sequencing technology to help them identify pathogenic variants responsible for previously undiagnosable, rare neurodevelopmental disorders in children.
Increasing access to genomic information
Children who have physical and intellectual disabilities suspected to be of genetic origin may benefit from genetic testing to find out whether there is a genetic cause. In many cases, rare genetic conditions are not responsive to pharmacological intervention. For this reason, efforts to translate genomic sequencing technologies into clinical care have faced ongoing challenges defining and measuring utility. It is currently unknown whether receiving a genomic diagnosis provides an improvement in the quality of life for children and their families.
Most of the care and services that improve functioning and quality of life for children with complex genetic conditions occur outside doctors’ offices: physical therapy; occupational therapy; speech-language pathology; behavioral intervention and other mental healthcare; and special education services. In addition, families can connect with support groups of others with similar diagnoses. Cooper and University of Louisville pediatrician and associate professor Kyle Brothers, MD, PhD, aim to assess the potential benefits to clinical care and quality of life that a genetic diagnosis provides families and individuals with a genetic disorder.
By interviewing families of children who have received a genetic diagnosis for their previously undiagnosed condition, Cooper and Brothers hope to shed light on the impacts on the children and their families that follow such a diagnosis. The ultimate goal is to define the utility of genetic testing so that it is more widely accessible to every individual who may benefit from the technology.