Search

Background and Objectives Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes. Methods A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient. Results We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD. Discussion Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel disease-causing genes and phenotypes, and predicts novel putative candidate genes, shedding light on etiopathogenic mechanisms that are pivotal for myelin generation and maintenance.

BACKGROUND: Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K(+) channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. METHODS: A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. RESULTS: WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K(+) ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K(+) currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. CONCLUSION: This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

International audience; Sub-continental lithospheric mantle rocks are exhumed at the foot of magma-poor distal passive margins as aresponse to extreme stretching of the continental crust during plate separation. Remnants of the Northern Iberianpaleo-passive margin are now exposed in the North-Pyrenean Zone (NPZ) and represent field analogues to studythe processes of continental crust thinning and subcontinental mantle exhumation. The NPZ results from theinversion of basins opened between the Iberia and Europa plates during Albo-Cenomanian times. In the westernNPZ, the ‘Chaînons Béarnais’ ranges display a fold-and-thrust structure involving the Mesozoic sedimentarycover, decoupled from its continental basement and associated with peridotite bodies in tectonic contact withPalaeozoic basement lenses of small size. Continental extension developed under hot thermal conditions, asdemonstrated by the syn-metamorphic Cretaceous ductile deformation affecting both the crustal basement and theallochthonous Mesozoic cover.In this study, we present structural and geochemical data providing constraints to reconstruct the evolution ofthe northern Iberia paleo-margin. Field work confirms that the pre-rift Mesozoic cover is intimately associatedto mantle rocks and to thin tectonic lenses of crustal basement. It also shows that the pre-rift cover was detachedfrom its bedrock at the Keuper evaporites level and was welded to mantle rocks during their exhumation atthe foot of the hyper-extended margin. The crust/mantle detachment fault is a major shear zone characterizedby anastomosed shear bands defining a plurimetric phacoidal fabric at the top of the serpentinized mantle. Thedetachment is marked by a layer of metasomatic rocks, locally 20 meters thick, made of talc-chlorite-pyrite-richrocks that developped under greenschist facies conditions. Raman Spectroscopy on Carbonaceous Materials(RSCM), performed on the Mesozoic cover reveal that the entire sedimentary pile underwent temperatures rangingbetween 200C and 480C.We show that: (i) at the site of mantle rocks exhumation, the boudinaged pre-rift sediments have undergone drasticsyn-metamorphic thinning with the genesis of a S0/S1 foliation and, (ii) the Paleozoic basement has been ductilelydeformed, into thin tectonic lenses that remained welded to the exhumed mantle rocks. Therefore the overallcrustal rheology appears dominated by shallow levels having a ductile behavior. This rheology is related to thepresence of a thick pre- and syn-rift decoupled cover acting as an efficient thermal blanket. This new geologicaldata set highlights important characteristics of ductile-type hyper-extended passive margin that cannot be obtainedfrom the study of seismic lines. Finally, we stress that studying field analogues represents a major tool to betterunderstand the mechanisms of extreme crustal thinning associated with mantle exhumation and their structuralinheritance during tectonic inversion.

Sirtuin 2 (SIRT2) is a member of a family of NAD + -dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT2 in the nervous system specifically during aging. Here, we show that middle-aged, 13-month-old mice lacking SIRT2 exhibit locomotor dysfunction due to axonal degeneration, which was not present in young SIRT2 mice. In addition, these Sirt2 -/- mice exhibit mitochondrial depletion resulting in energy failure, and redox dyshomeostasis. Our results provide a novel link between SIRT2 and physiological aging impacting the axonal compartment of the central nervous system, while supporting a major role for SIRT2 in orchestrating its metabolic regulation. This underscores the value of SIRT2 as a therapeutic target in the most prevalent neurodegenerative diseases that undergo with axonal degeneration associated with redox and energetic dyshomeostasis.

International audience