CWH43 Variants Are Associated With Disease Risk and Clinical Phenotypic Measures in Patients With Normal Pressure Hydrocephalus.

Autor:	Tipton PW; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Atik M; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Soto-Beasley AI; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Day GS; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Grewal SS; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Chaichana K; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Fermo OP; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Ball CT; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Heckman MG; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., White LJ; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Quicksall ZS; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Reddy JS; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Ramanan VK; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Vemuri P; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Elder BD; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Ertekin-Taner N; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Ross O; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN., Graff-Radford N; From the Department of Neurology (P.W.T., G.S.D., O.P.F., N.E.-T., N.G.-R.), Department of Neuroscience (M.A., A.I.S.-B., Z.S.Q., J.S.R., N.E.-T., O.R.), Department of Neurosurgery (S.S.G., K.C.), Division of Clinical Trials and Biostatistics (C.T.B., M.G.H., L.J.W.), Mayo Clinic, Jacksonville, FL; Department of Neurology (V.K.R.), Department of Radiology (P.V.), and Department of Neurosurgery (B.D.E.), Mayo Clinic, Rochester, MN.
Jazyk:	angličtina
Zdroj:	Neurology. Genetics [Neurol Genet] 2023 Jul 19; Vol. 9 (5), pp. e200086. Date of Electronic Publication: 2023 Jul 19 (Print Publication: 2023).
DOI:	10.1212/NXG.0000000000200086
Abstrakt:	Background and Objectives: Variants in the CWH43 gene have been associated with normal pressure hydrocephalus (NPH). We aimed to replicate these findings, identify additional CWH43 variants, and further define the clinical phenotype associated with CWH43 variants. Methods: We determined the prevalence of CWH43 variants by whole-genome sequencing (WGS) in 94 patients with NPH. The odds of having CWH43 variant carriers develop NPH were determined through comparison with 532 Mayo Clinic Biobank volunteers without a history of NPH. For patients with NPH, we documented the head circumference, prevalence of disproportionate enlargement of subarachnoid hydrocephalus (DESH), microvascular changes on MRI quantified by the Fazekas scale, and ambulatory response to ventriculoperitoneal shunting. Results: We identified rare (MAF <0.05) coding CWH43 variants in 15 patients with NPH. Ten patients (Leu533Terfs, n = 8; Lys696Asnfs, n = 2) harbored previously reported predicted loss-of-function variants, and combined burden analysis confirmed risk association with NPH (OR 2.60, 95% CI 1.12-6.03, p = 0.027). Additional missense variations observed included Ile292Thr (n = 2), Ala469Ser (n = 2), and Ala626Val (n = 1). Though not quite statistically significant, in single variable analysis, the odds of having a head circumference above the 75th percentile of normal controls was more than 5 times higher for CWH43 variant carriers compared with that for noncarriers (unadjusted OR 5.67, 95% CI 0.96-108.55, p = 0.0 57 ), and this was consistent after adjusting for sex and height (OR 5.42, 95% CI 0.87-106.37, p = 0.073 ). DESH was present in 56.7% of noncarriers and only 21.4% of carriers ( p = 0.016), while sulcal trapping was also more prevalent among noncarriers (67.2% vs 35.7%, p = 0.030). All 8 of the 15 variant carriers who underwent ventriculoperitoneal shunting at our institution experienced ambulatory improvements. Discussion: CWH43 variants are frequent in patients with NPH. Predicted loss-of-function mutations were the most common; we identified missense mutations that require further study. Our findings suggest that congenital factors, rather than malabsorption or vascular dysfunction, are primary contributors to the CWH43 -related NPH clinical syndrome. Competing Interests: B.D. Elder: Consulting for Depuy Synthes and SI Bone, medical advisory board and stock in Injectsense, and institutional funding as site PI for clinical trials for Stryker and SI Bone. The other authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
Databáze:	MEDLINE
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