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Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.

At the dawn of the second millennium, the expansion of the Indian Ocean trading network aligned with the emergence of an outward-oriented community along the East African coast to create a cosmopolitan cultural and trading zone known as the Swahili Corridor. On the basis of analyses of new genome-wide genotyping data and uniparental data in 276 individuals from coastal Kenya and the Comoros islands, along with large-scale genetic datasets from the Indian Ocean rim, we reconstruct historical population dynamics to show that the Swahili Corridor is largely an eastern Bantu genetic continuum. Limited gene flows from the Middle East can be seen in Swahili and Comorian populations at dates corresponding to historically documented contacts. However, the main admixture event in southern insular populations, particularly Comorian and Malagasy groups, occurred with individuals from Island Southeast Asia as early as the 8th century, reflecting an earlier dispersal from this region. Remarkably, our results support recent archaeological and linguistic evidence-based suggestions that the Comoros archipelago was the earliest location of contact between Austronesian and African populations in the Swahili Corridor. We acknowledge support from the GenoToul bioinformatics facility of Genopole Toulouse Midi-Pyre´ne´es, France. This research was supported by French Ministry of Research grant ANR-14-CE31-0013-01 (OCEOADAPTO) to F.-X.R, a Rutherford Fellowship from the Royal Society of New Zealand (RDF-10- MAU-001), a fellowship from the Alexander von Humboldt Foundation to M.P.C., and grants from COMPETE 2020 and a Fundac¸a˜o para a Cieˆncia e a Tecnologia-funded project (POCI-01-0145-FEDER-016609) to V.F. We thank Kamil Merito for his help collecting East African samples. We thank all the local Swahili and Comorian communities who participated in this study.

Next-generation sequencing (NGS) studies are becoming routinely used for the detection of novel and clinically actionable DNA variants at a pangenomic scale. Such analyses are now used in the clinical practice to enable precision medicine. Formalin-fixed paraffin-embedded (FFPE) tissues are still one of the most abundant source of cancer clinical specimen, unfortunately this method of preparation is known to degrade DNA and therefore compromise subsequent analysis. Some studies have reported that variant detection can be performed on FFPE samples sequenced with NGS techniques, but few or none have done an in-depth coverage analysis and compared the influence of different state-of-the-art FFPE DNA extraction kits on the quality of the variant calling. Here, we generated 42 human whole-exome sequencing data sets from fresh-frozen (FF) and FFPE samples. These samples include normal and tumor tissues from two different organs (liver and colon), that we extracted with three different FFPE extraction kits (QIAamp DNA FFPE Tissue kit and GeneRead DNA FFPE kit from Qiagen, Maxwell™ RSC DNA FFPE Kit from Promega). We determined the rate of concordance of called variants between matched FF and FFPE samples on all common variants (representing at least 86% of the total number of variants for SNVs). The concordance rate is very high between all matched FF / FFPE pairs, with equivalent values for the three kits we analyzed. On the other hand, when looking at the difference between the total number of variants in FF and FFPE, we find a significant variation for the three different FFPE DNA extraction kits. Coverage analysis shows that FFPE samples have less good indicators than FF samples, yet the coverage quality remains above accepted thresholds. We detect limited but statistically significant variations in coverage indicator values between the three FFPE extraction kits. Globally, the GeneRead and QIAamp kits have better variant calling and coverage indicators than the Maxwell kit on the samples used in this study, although this kit performs better on some indicators and has advantages in terms of practical usage. Taken together, our results confirm the potential of FFPE samples analysis for clinical genomic studies, but also indicate that the choice of a FFPE DNA extraction kit should be done with careful testing and analysis beforehand in order to maximize the accuracy of the results.