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Neurodevelopmental Disorder Variants Identified by Short-Read, Long-Read Genome Sequencing

NEW YORK – New research suggests whole-genome sequencing using long-read and short-read technologies can unearth rare variants behind neurodevelopmental disorders (NDD) in a significant subset of patients who could not be diagnosed by microarray- or exome sequencing-based tests. In addition, the work validated several new NDD-related genes.

"We have contributed to the identification or confirmation of four NDD-associated genes: KMT2B, CACNA1E, WASF1, and GABRA1, which have been published elsewhere," first author Alba Sanchis-Juan, a researcher affiliated with the University of Cambridge and other institutions, and her colleagues wrote in the American Journal of Human Genetics on Thursday.

Using a short-read whole-genome sequencing strategy, the researchers analyzed rare variants in 692 individuals from 465 families, including 489 NDD-affected patients from the National Institute for Health and Care Research (NIHR) BioResource project and 203 unaffected family members.

The NDD individuals had symptoms ranging from intellectual disability or seizures to movement, muscle contraction, or coordination disorders. The family-based analyses included 67 parent-child trios, five parent-child-sibling groups, and dozens more families with other compositions.

In five cases marked by complex rearrangements, the team turned to supplementary long-read sequencing with the Oxford Nanopore Technologies' GridIon platform to get a better look at NDD-associated structural variants (SVs).

"We employed a comprehensive approach that combined [short-read genome sequencing] and [long-read genome sequencing] to identify a broad range of clinically relevant variants associated with NDDs," the authors explained.

This strategy led to diagnoses in a significant subset of the affected individuals. All told, the sequencing approach led to 380 pathogenic variants, likely pathogenic variants, or variants of uncertain significance (VUS) in 289 affected individuals from 276 of the families profiled. That group included 177 individuals with NDD who had causal variants found by genome sequencing, along with 112 affected individuals carrying VUSs.

Nearly 90 percent of the variants detected were single nucleotide changes or small insertions and deletions falling in protein-coding portions of the nuclear genome, the researchers reported. But their analyses also highlighted NDD-related structural variants, variants in noncoding portions of the genome, and variants affecting mitochondrial genome sequences.

"It is worth noting that the diagnostic yield for NDDs can vary considerably and is influenced by many factors, such as phenotype and recruitment criteria, sequencing technology, mode of inheritance, family members studied, date of analysis, and genetic ancestry," the authors noted. "Understanding these factors can help inform recruitment strategies and study design to improve diagnostic yield."

The team's ability to make diagnoses from the genome sequence set increased over time as quality control approaches and the ability to annotate NDD-related genes and variants improved. An initial analysis done between the spring of 2016 and early 2018 led to "reportable" pathogenic, likely pathogenic, or VUS variants in 42 percent of the patients profiled, while 59 percent of affected individuals carried reportable variants in a subsequent analysis.

"This study demonstrates the value of short-read [genome sequencing], complemented with long-read [genome sequencing] in investigating the genetic causes of NDDs," the authors wrote, suggesting that whole-genome sequencing "provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD."