Inherited retinal diseases (IRDs) are a common cause of visual impairment. IRD covers a set of genetically highly heterogeneous disorders with more than 150 genes associated with one or more clinical forms of IRD. Molecular genetic diagnosis has become increasingly important especially due to expanding number of gene therapy strategies under development. Next generation sequencing (NGS) of gene panels has proven a valuable diagnostic tool in IRD. We present the molecular findings of 677 individuals, residing in Denmark, with IRD and report 806 variants of which 187 are novel. We found that deletions and duplications spanning one or more exons can explain 3% of the cases, and thus copy number variation (CNV) analysis is important in molecular genetic diagnostics of IRD. Seven percent of the individuals have variants classified as pathogenic or likely-pathogenic in more than one gene. Possible Danish founder variants in EYS and RP1 are reported. A significant number of variants were classified as variants with unknown significance; reporting of these will hopefully contribute to the elucidation of the actual clinical consequence making the classification less troublesome in the future. In conclusion, this study underlines the relevance of performing targeted sequencing of IRD including CNV analysis as well as the importance of interaction with clinical diagnoses.

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Itisw ell established thatdynamic conditions expressed ast ilted fluid contacts characterizemost hydrocarbon accumulations inNorthSea Chalkreservoirs.Chalkisalow-permeability,high-porosity rock and propertiesgrade smoothly from reservoiro verbaffle to seal. The naturaldynamic conditionsp revailbecause pressuredissipation takesplace through the rock matrix,asfracture-supported flow oftenisminimal. The dynamic conditions arei mposed byp rocesseso ccurringon ag eologicalt ime-scalea ndresult mainly inl ateralp ressure differencesint he waterz onea nde veninl ateralp ressured ifferencesint he oilz one.Re-equilibration offl uid contacts also occurs on ageologicaltime-scale.Theseprocessesareofparamount importance for trapdefinition andimposesevererestrictions on migration distances.Reservoirs imulation techniquesarea pplied, incombination withb ack-stripping, to the simulation of geologicalt ime-scalesecondary migration andtrapping.Flow simulation ofthe fillingd ynamicso fachalk reservoirs hows ac omplexfillingg eometry dueto the high capillary entry pressuresint he low-permeability chalks. Such internalbarriers will re-directhydrocarbons andresidualoilcanbe leftonthe migration route.The process ofh ydrocarbon chargingi ss low ande quilibration ofh ydrocarbons withrespectt op ressureg radients, therefore, also occurs very slowly. The Kraka Fielda ndthe DanandH alfdanfieldsaresubjected to studieso f primary oilchargingandre-migration inthispaperandthe dynamic oilonDanFieldwest flankissuccessfully mimicked.Results show thatatimespaninthe orderof2Ma isrequired for the hydrocarbons to reach the summit inanapproximately equilibrium statefrom aflankingposition. However,evendynamic equilibrium maynot be fully obtained dueto re-perturbation bytectonic movementsandchangingwaterzonepressuregradients. Results show thatsaturation profilesindrilled wells mayappearindrainage equilibrium whileunderpartialre-imbibition, which impairs saturation modelling.

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Summary A matrix/fracture exchange model for a fractured reservoir simulator isdescribed. Oil/water imbibition is obtained from a diffusion equation withwater saturation as the dependent variable. Gas/oil gravity drainage andimbibition are calculated by taking into account the vertical saturationdistribution in the matrix blocks. Introduction In most simulators intended for naturally fractured reservoirs, the fractureand matrix systems are considered to be two overlapping media. Flow between thetwo is described in various ways by means of source and sink terms. Thedescription of the matrix/fracture interaction is a key point in the modeling of dual-porosity systems. In this paper, the modeling of oil/water imbibition is based on thediffusion equation approach of Beckner et al. The effect of gravity isincorporated through a modification of the boundary conditions imposed. Analytical and numerical solutions are presented, and computed results arecompared with experimental data. presented, and computed results are comparedwith experimental data. Gas/oil gravity drainage and imbibition are calculatedby taking into consideration the vertical saturation distribution in thematrix. The principles for the implementation of the proposed methods in areservoir simulator are described. The following limitations and assumptions apply.The models presented are valid only for two-phase oil/water and gas/oilsystems.Matrix blocks within a grid cell are identical and box-shaped withdimensions L, L, and L.For oil/water systems, capillary continuity exists inside a grid cellbetween vertically stacked matrix blocks.The two phases in the fracture system are gravity segregated.Analytical solutions can be obtained only in the oil/water case and onlyif the water level in the fracture system rises with a constant velocity andthe diffusion coefficient is constant.The matrix-block gas and oil are at capillary/gravitationalequilibrium. Flow Equations Dual-porosity reservoirs are modeled by the continuum approach, where thefracture and matrix systems are considered to be two overlapping continuousmedia. The basic equations for isothermal fluid flow in porous media aretransformed to a system of ordinary differential equations by means of theintegral finite-difference method (see Pruess and Bodvarsson). In case of adual-porosity, single-permeability reservoir composed of a continuous fracturesystem containing discontinuous matrix blocks, the following equations areobtained for each component (1 =o, g, or w) and the kth grid cell in thereservoir. Fracture equation: (1) Matrix equation: (2) where mi = (3) (4) The summation is over all phases--i.e., =o, g, and w. The sum over Index isover all grid cells adjacent to grid-cell number k. Hence Index k refers to theboundary between the grid cells k and . The individual terms of Eqs. 1 and 2 describe the transport of Component ithrough Phase by various mechanisms. For further details regarding theequations and their derivation, see Bech. Water/Oil Imbibition The formulations of the matrix/fracture exchange term in manydouble-porosity simulators suffer from two limitations:imbibition from newly contacted matrix-block face as the fracture water level advances is not described andsaturation gradients within the matrix blocks are notmodeled. These factors can be taken into consideration by modeling theimbibition as a diffusion process. The matrix-block water saturationdistribution is determined from (5) (6) In the derivation of Eqs. 5 and 6, it is assumed that the flow is 2D andthat the fluid and the rock are incompressible. It is also assumed thatoil-phase pressure gradients and gravity terms are negligible. The diffusion equation (Eq. 5) has been solved with the boundary condition S= S at the part of the matrix-block surface that is submerged in water and Sw =S, elsewhere on the surface (see Fig. 1). Initially, the matrix-block watersaturation is S everywhere. The boundary condition (7) where S corresponds to zero capillary pressure at the surface, implies thatinstantaneous imbibition occurs at the matrix/fracture in-terface. A delayedimbibition can be introduced by the boundar conditions: (8) (9) and S = S (z) is the ultimate matrix-block water saturation at the height z, which may be equal to or less than 1 - Sor. Here t = t (z) denotes the time when zwf = z; i.e., t (z) is the time whenimbibition starts at the height z. is an inverse time constant. The problem as presented in Eqs. 5 through 9 must be solved numerically. This is done by using central differences and applymg a Newton-Raphsonalgorithm in solving the nonlinear algebraic equations.

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