Exploration of long-read sequencing in the resolution of newborn screening

Abstract

Newborn screening (NBS) is a public health program designed to identify and treat certain conditions in infants as early as possible. For some of these conditions, a positive screening result must be confirmed via a diagnostic test, which could include Sanger or short-read sequencing approaches. These techniques, however, are limited in their ability to detect copy number variants or variants in regions of low complexity. Additionally, because many of these conditions, such as galactosemia and Pompe disease, are inherited in an autosomal recessive manner, phasing is needed to determine if one or both copies of the gene are affected. This process can lead to delays, as it will often require collection of samples from both parents for complete interpretation. We sought to explore the use of long-read sequencing (LRS) for rapid follow-up of NBS results. We found that LRS performed on DNA extracted from blood can be used to efficiently analyze regions of interest, including detection of variants of potential clinical relevance and to phase variants into haplotypes without the need for parental samples. In addition, we have used this approach using DNA extracted from dried blood spot cards — a critical advance as it would eliminate the need for an additional sample to be collected from the newborn. This exploratory study underscores the potential for LRS to streamline the process of NBS follow-up, which is necessary to guide treatment in this critical time period.

Biography

Cate Paschal received her PhD from Weill Cornell Medical College, New York. She is board certified in clinical cytogenetics and genomics, as well as clinical molecular genetics and genomics. Cate is the director of the integrated cytogenetics and molecular genetics laboratory at Seattle Children’s Hospital, where she signs out a variety of clinical tests for both pediatric oncology and constitutional disorders. She is also Clinical Assistant Professor in the department of Laboratory Medicine and Pathology at the University of Washington.