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

Background And Objectives: Variants in the gene have been associated with normal pressure hydrocephalus (NPH). We aimed to replicate these findings, identify additional variants, and further define the clinical phenotype associated with variants.

Methods: We determined the prevalence of variants by whole-genome sequencing (WGS) in 94 patients with NPH. The odds of having 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 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, = 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 variant carriers compared with that for noncarriers (unadjusted OR 5.67, 95% CI 0.96-108.55, = 0.0), and this was consistent after adjusting for sex and height (OR 5.42, 95% CI 0.87-106.37, = 0.073 DESH was present in 56.7% of noncarriers and only 21.4% of carriers ( = 0.016), while sulcal trapping was also more prevalent among noncarriers (67.2% vs 35.7%, = 0.030). All 8 of the 15 variant carriers who underwent ventriculoperitoneal shunting at our institution experienced ambulatory improvements.

Discussion: 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 -related NPH clinical syndrome.