The global carrier frequency and genetic prevalence of Upshaw-Schulman syndrome

Ting Zhao,Liu Sun,Shanghua Fan

doi:10.1186/s12863-021-01010-0

Abstract

BackgroundUpshaw–Schulman syndrome (USS) is an autosomal recessive disease characterized by thrombotic microangiopathies caused by pathogenic variants in ADAMTS13. We aimed to (1) curate the ADAMTS13 gene pathogenic variant dataset and (2) estimate the carrier frequency and genetic prevalence of USS using Genome Aggregation Database (gnomAD) data.MethodsStudies were comprehensively retrieved. All previously reported pathogenic ADAMTS13 variants were compiled and annotated with gnomAD allele frequencies. The pooled global and population-specific carrier frequencies and genetic prevalence of USS were calculated using the Hardy-Weinberg equation.ResultsWe mined reported disease-causing variants that were present in the gnomAD v2.1.1, filtered by allele frequency. The pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics criteria. The genetic prevalence and carrier frequency of USS were 0.43 per 1 million (95% CI: [0.36, 0.55]) and 1.31 per 1 thousand population, respectively. When the novel pathogenic/likely pathogenic variants were included, the genetic prevalence and carrier frequency were 1.1 per 1 million (95% CI: [0.89, 1.37]) and 2.1 per 1 thousand population, respectively.ConclusionsThe genetic prevalence and carrier frequency of USS were within the ranges of previous estimates.

Highlights

Upshaw–Schulman syndrome (USS) is an autosomal recessive disease characterized by thrombotic microangiopathies caused by pathogenic variants in ADAMTS13
Upshaw–Schulman syndrome (USS) is an ultrarare but life-threatening autosomal recessive disease characterized by the absence or a severe deficiency of plasma von Willebrand factor-cleaving protease; this results in the abnormal presence of ultralarge vWF multimers and subsequent platelet adhesion to these vWF multimers, leading to the formation of circulating platelet microthrombi [1,2,3]
Identification of major functional variants The Genome Aggregation Database (gnomAD) [25] was searched for pathogenic variants that had not yet been reported in patients, and we examined major all-cause functional or structural changes

Summary

Introduction

Upshaw–Schulman syndrome (USS) is an autosomal recessive disease characterized by thrombotic microangiopathies caused by pathogenic variants in ADAMTS13. We aimed to (1) curate the ADAMTS13 gene pathogenic variant dataset and (2) estimate the carrier frequency and genetic prevalence of USS using Genome Aggregation Database (gnomAD) data. Upshaw–Schulman syndrome (USS) is an ultrarare but life-threatening autosomal recessive disease characterized by the absence or a severe deficiency of plasma von Willebrand factor (vWF)-cleaving protease; this results in the abnormal presence of ultralarge vWF multimers and subsequent platelet adhesion to these vWF multimers, leading to the formation of circulating platelet microthrombi [1,2,3]. Disease onset can occur in the USS is the result of homozygous or compound heterozygous variants in the ADAMTS13 gene. USS is extremely rare, and its precise prevalence is uncertain. We hypothesized that the prevalence of USS would vary among different populations or ethnicities

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