Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency.

BACKGROUND & AIMS: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood. METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls. RESULTS: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor. CONCLUSIONS: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

National-scale marine bioregions for the Southwest Pacific.

Existing marine bioregions covering the Pacific Ocean are conceptualised at spatial scales that are too broad for national marine spatial planning. Here, we developed the first combined oceanic and coastal marine bioregionalisation at national scales, delineating 262 deep-water and 103 reef-associated bioregions across the southwest Pacific. The deep-water bioregions were informed by thirty biophysical environmental variables. For reef-associated environments, records for 806 taxa at 7369 sites were used to predict the probability of observing taxa based on environmental variables. Both deep-water and reef-associated bioregions were defined with cluster analysis applied to the environmental variables and predicted species observation probabilities, respectively to classify areas with high taxonomic similarity. Local experts further refined the delineation of the bioregions at national scales for four countries. This work provides marine bioregions that enable the design of ecologically representative national systems of marine protected areas within offshore and inshore environments in the Pacific.