Many Studies Show Causal Variant Discovery Potential of SMRT Sequencing

by Jonas Korlach, CSO
It’s been really exciting to see a spate of publications coming out that demonstrate the utility of SMRT Sequencing for determining the underlying genetic cause of diseases that have long gone unsolved. Discovery of the pathogenic variants behind these diseases is not just academic progress; it can give answers to people who have been seeking them for years or even generations.
Here are several recent examples of the great work happening in this area. Congratulations to these teams and all other scientists who are using SMRT Sequencing to advance our understanding of disease.
 
Mapping the landscape of tandem repeat variability by targeted long read single molecule sequencing in familial X-linked intellectual disability
Scientists from University Hospitals Leuven and collaborating institutions used SMRT Sequencing to test the theory that tandem repeat expansions could explain some cases of X-linked intellectual disability. They targeted more than 1,800 tandem repeats on the X chromosome, finding a candidate causal repeat expansion associated with relevant gene expression changes.
Detecting a long insertion variant in SAMD12 by SMRT sequencing: implications of long-read whole-genome sequencing for repeat expansion diseases
At Yokohama City University Graduate School of Medicine and collaborating organizations, scientists deployed SMRT Sequencing to uncover the genetic mechanism responsible for an unexplained form of epilepsy. Using low-coverage whole genome data, they identified six structural variants in a genetic region of interest and determined that one, a 4.6 kb repeat insertion, was causative for the disease.
CRISPR/Cas9-targeted enrichment and long-read sequencing of the Fuchs endothelial corneal dystrophy-associated TCF4 triplet repeat
In this study, scientists from University College London and the University of Oxford aimed to characterize a triplet repeat associated with Fuchs endothelial corneal dystrophy across several samples. Using an amplification-free CRISPR/Cas9 method with SMRT Sequencing, they accurately determined repeat length and instability levels, generated genotype data, and phased alleles.
A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing
Scientists in Japan turned to SMRT Sequencing to explain a familial form of epilepsy that had not been solved with whole-exome sequencing. Low-fold whole genome sequence data allowed the team to detect more than 17,000 structural variants and quickly filter that list to find the 12.4 kb deletion responsible for this family’s condition.
Somatic APP gene recombination in Alzheimer’s disease and normal neurons
At Sanford Burnham Prebys Medical Discovery Institute, scientists produced the first evidence of somatic gene recombination in the human brain. Using SMRT Sequencing, they found recombination of a gene associated with Alzheimer’s disease and characterized thousands of variants.
De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1
Scientists in the UK and US analyzed a somatically unstable repeat expansion that causes myotonic dystrophy type 1. Thanks to SMRT Sequencing, they were able to characterize the repeat expansion region in several individuals and confirm that people whose expansion regions were interrupted by CCG or CGG variant repeats had milder symptoms than those with pure CTG repeats.
Long-read sequencing identifies GGC repeat expansion in human-specific NOTCH2NLC associated with neuronal intranuclear inclusion disease
This preprint from a large team of scientists describes the use of SMRT Sequencing to investigate the cause of a progressive neurodegenerative disease that is difficult to diagnose. Studying one family, they identified a repeat expansion found in all affected individuals but no unaffected individuals. Similar expansions were then found in several unrelated families with this disease.