Research Report 2019_20

Greg Cooper, PhD / Cooper Lab

Genomic approaches to understanding rare disease

association of genetic variation in BRSK2 with neurode- velopmental disorders 1 . While information gleaned from next-generation sequencing technology has led to many diagnoses, researchers like Cooper are constantly looking for ways to improve the technology and increase diagnostic rates for patients with rare disease. In a recent publication in Human genetics and Genomics Advances 2 , the Cooper lab describes how an exciting new technology, called long- read sequencing, helped them identify pathogenic variants responsible for previously undiagnosable, rare neurodevelopmental disorders. Recent advances in long-read sequencing technolo- gy have allowed for the production of reads, or sequenc- es, that are up to 100 times longer than those resulting from the widely-used short-read sequencing technol- ogy, from Illumina ® , the leading sequencing company. This leads to fewer gaps in the whole sequence once the pieces are assembled. Using long- read sequencing, the team, led by senior scientist Susan Hiatt, PhD, ana- lyzed six family trios (mom, dad, and the affected child) that each had children affected by neurodevelopmental disorders. Although the families had each previously had their genomes sequenced with short-read technol- ogy, no causal genetic variant had been identified. Byusinglong-readsequencing, theyfoundthousands of genetic variants in each family that had previously been missed. Among these newly detected variants, the team identified likely pathogenic variation in two of the six children. This study shows the ability of long-read se- quencing to capture complex variation missed by short- read sequencing. It is likely that it will become a powerful front-line tool for research and clinical testingwithin rare disease genetics. Cooper’s team is also focused on scaling up rare disease diagnosis through the use of genetic screening tests. A recent study led by senior scientist Kevin Bowling, PhD, was published in Genetics in Medicine and highlights findings on the effectiveness of

Two out of every 100 children are born with physical disability or developmental delay, which often arise from genetic factors. However, because many of the underly- ing diseases are so rare, specific diagnoses for children with developmental delay are elusive. Identifying genet- ic variants, whether de novo (not inherited from either parent) or inherited, can provide a disease diagnosis, guide treatment approaches, and give families the an- swer to their years-long medical mystery. By using genome sequencing technology to identify rare variants associated with these diseases, the lab of HudsonAlpha Faculty Investigator Greg Cooper, PhD, is able to help end the diagnostic odyssey for many chil- dren with developmental delay. With collaborators like the University of Alabama at Birmingham, the Clinical Sequencing Evidence-Generating Research (CSER) Consortium and the Alabama Genomic Health Initiative (AGHI), members of Cooper’s lab have sequenced more than 1,467 affected children and approximately 1,511 parents. They have found genetic cause for about twen- ty-seven percent of the affected children, leading to a more precise and definitive clinical diagnosis. In addition to helping physicians diagnose rare disease in children, identifying rare variants is also invaluable to the research community. Members of Cooper’s lab use GeneMatcher , a web service that allows researchers to share genes of interest in order to collaborate with other scientists to solve genetic mysteries. They have submitted 166 genes to GeneMatcher , which has led to 18 collaborative publications since 2016. The Cooper lab discovered variations in one such gene, BRSK2 , in several children with devel- opmental delay or intellectual disability but wanted more instances with which to compare. Using Gen- eMatcher , five more individuals with variations in the gene were identified and compared to one an- other. Through statistical and biological analysis of the mutations in BRSK2 , the group confirmed the


HudsonAlpha Institute for Biotechnology

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