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Abstract In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two. Singleton WES facilitated the diagnostic process in the Czech undiagnosed pediatric population. We believe it is an effective approach to enable appropriate counseling, surveillance, and personalized clinical management.

Abstract Background Cardiac‐urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin‐related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. Case Presentation We present case reports of two siblings of unrelated parents in whom whole‐exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. Conclusions To our knowledge, this is the first published case of familial cardiac‐urogenital syndrome indicating gonadal mosaicism.

Background. Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms. Case report. We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation. Conclusion. Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.

In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two. Singleton WES facilitated the diagnostic process in the Czech undiagnosed pediatric population. We believe it is an effective approach to enable appropriate counseling, surveillance, and personalized clinical management. [ABSTRACT FROM AUTHOR]

Background: Cardiac‐urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin‐related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. Case Presentation: We present case reports of two siblings of unrelated parents in whom whole‐exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. Conclusions: To our knowledge, this is the first published case of familial cardiac‐urogenital syndrome indicating gonadal mosaicism. [ABSTRACT FROM AUTHOR]

We develop a multigrid solver steered by an a posteriori estimator of the algebraic error. We adopt the context of a second-order elliptic diffusion problem discretized by conforming finite elements of arbitrary polynomial degree p ≤ 1. Our solver employs zero pre- and one postsmoothing by the overlapping Schwarz (block-Jacobi) method and features an optimal choice of the step-sizes in the smoothing correction on each level by line search. This leads to a simple Pythagorean formula of the algebraic error in the next step in terms of the current error and levelwise and patchwise error reductions. We show the following two results and their equivalence: the solver contracts the algebraic error independently of the polynomial degree p; and the estimator represents a two-sided p-robust bound on the algebraic error. The p-robustness results are obtained by carefully applying the results of [J. Schöberl et al., IMA J. Numer. Anal., 28 (2008), pp. 1-24] for one mesh, combined with a multilevel stable decomposition for piecewise affine polynomials of [J. Xu, L. Chen, and R. H. Nochetto, Optimal multilevel methods for H(grad), H(curl), and H(div) systems on graded and unstructured grids, in Multiscale, Nonlinear and Adaptive Approximation, Springer, Berlin, 2009, pp. 599-659]. We consider quasi-uniform or graded bisection simplicial meshes and prove at most linear dependence on the number of mesh levels for minimal H¹-regularity and complete independence for H²-regularity. We also present a simple and effective way for the solver to adaptively choose the number of postsmoothing steps necessary at each individual level, yielding a yet improved error reduction. Numerical tests confirm p-robustness and show the benefits of the adaptive number of smoothing steps. [ABSTRACT FROM AUTHOR]

In this work, we consider conforming finite element discretizations of arbitrary polynomial degree p \geq 1 of the Poisson problem. We propose a multilevel a posteriori estimator of the algebraic error. We prove that this estimator is reliable and efficient (represents a two-sided bound of the error), with a constant independent of the degree p. We next design a multilevel iterative algebraic solver from our estimator and show that this solver contracts the algebraic error on each iteration by a factor bounded independently of p. Actually, we show that these two results are equivalent. The p-robustness results rely on the work of Sch\"oberl et al. [IMA J. Numer. Anal., 28 (2008), pp. 1-24] for one given mesh. We combine this with the design of an algebraic residual lifting constructed over a hierarchy of nested unstructured, possibly highly graded, simplicial meshes. The lifting includes a global coarse-level solve with the lowest polynomial degree one together with local contributions from the subsequent mesh levels. These contributions, of the highest polynomial degree p on the finest mesh, are given as solutions of mutually independent local Dirichlet problems posed over overlapping patches of elements around vertices. The construction of this lifting can be seen as one geometric V-cycle multigrid step with zero pre- and one postsmoothing by (damped) additive Schwarz (block Jacobi). One particular feature of our approach is the optimal choice of the step-size generated from the algebraic residual lifting. Numerical tests are presented to illustrate the theoretical findings. [ABSTRACT FROM AUTHOR]

Spindle cell hemangioma is a benign vascular tumor typically occurring in the dermis or subcutis of distal extremities as red–brown lesions that can grow in both size and number over time. They can be very painful and potentially disabling. A family history of cancer or previous history may be relevant and must be taken into consideration. Juxtaglomerular cell tumor (reninoma) is an extremely rare cause of secondary hypertension diagnosed mostly among adolescents and young adults. Excessive renin secretion results in secondary hyperaldosteronism. Subsequent hypokalemia and metabolic alkalosis, together with high blood pressure, are clues for clinical diagnosis. Histological examination of the excised tumor leads to a definitive diagnosis. Reninoma is found in subcapsular localization, in most cases as a solitary mass, in imaging studies of kidneys. Exceptionally, it can be located in another part of a kidney. Both spindle cell hemangioma and reninoma are extremely rare tumors in children and adolescents. Herein, the authors present a case report of a patient with hereditary BRCA1 interacting protein C-terminal helicase 1 (BRIP1) mutation, spindle cell hemangioma, and secondary hypertension caused by atypically localized reninoma. [ABSTRACT FROM AUTHOR]