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ACMG: UCSF-led Team Assessing Newborn Sequencing as Second Tier Test for Metabolic Conditions

SALT LAKE CITY (GenomeWeb) – At the American College of Medical Genetics and Genomics annual meeting here this week, the University of California at San Francisco's Robert Nussbaum provided new details on a study investigating the potential of using high-throughput exome sequencing as an ancillary screening test for metabolic conditions in newborns.

The recently launched effort, known as "Newbie Seq," or NB Seq, is one of several ongoing efforts at four centers that are aimed at exploring various aspects of newborn sequencing. By adding sequence data to existing mass spectrometric profiles, those involved in NB Seq hope to dial down the number of healthy newborns that are erroneously flagged as potential metabolic disease carriers.

As reported in GenomeWeb in 2013, Nussbaum is leading the retrospective look at sequencing as a means of augmenting metabolic disorder screens — one of several related studies supported through the National Institutes of Health's Genomic Sequencing and Newborn Screening Disorders research program.

Nussbaum argued that at the moment sequencing-based tests often don't meet all of the criteria needed for population screening efforts focused on finding subgroups of individuals at risk of a given disease.

Ideally, such screening tools should provide high-throughput results for a low price tag, he noted, while picking up as many at-risk individuals as possible with low false-positive tests that can be teased out with a relatively straightforward and affordable follow-up workflow.

But Nussbaum and his colleagues believe there is an opportunity to apply sequencing during second-tier screening to reduce the false positives before screening test results are returned to physicians.

They saw an opportunity to explore that possibility in the realm of metabolic disease screening using 1,600 de-identified dried blood spot samples obtained retrospectively from the California Department of Public Health.

In general, screens for inborn errors of metabolism are done with tandem mass spectrometry-based tests that focus on more than a dozen amino acids and 28 acylcarnitines associated with fatty acid disorders, Nussbaum explained.

Although mass spec screening is well established, false-positive results still pose a problem, particularly for newborns in the neonatal intensive care unit who may display metabolic imbalances related to low birth weight and/or prematurity that don't stem from genetic disease.

The team reasoned that it might be possible to combat the diminished screening specificity observed for some metabolic disorders in the NICU population by folding in sequence information on related genes.

In addition to potentially decreasing the number of false-positive cases that are ultimately reported back to physicians, sequencing and mass spec analyses may be done simultaneously, Nussbaum noted, and both types of data could theoretically be plugged into adjusted screening algorithms.

For the NBSeq project, researchers planned to do whole-exome sequencing on blood spots from de-identified children with or without metabolic disorders, including those who obtained false-positive or false-negative results by mass spec screening.

Their genetic analysis will focus on around 250 genes — a set that includes 44 primary metabolic disease gene players and hundreds more genes pinpointed through pathway analyses.

While the initial variant analysis will be done blinded to individuals' phenotype, the team plans to eventually link genotyping profiles to de-identified phenotype data, again provided by the state's public health department.

Along with insights into sequencing as a second-tier screen, the group hopes to get a clearer sense of the variants that contribute to metabolic disorders and their phenotypic effects.

It remains to be seen whether pathogenic variants identified during the project will be added to NCBI's ClinVar database, since that would require a green light from the California Department of Public Health.

The retrospective study is intended to improve screening test implementation, Nussbaum noted, and has clearance to proceed without parental consent. No results, including incidental findings, will be returned to families or their physicians.