Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome.

Geeta Madathil Govindaraj,Dhananjayan Dhanasooraj,Krishnan Chakkiyar,Geetha Peethambaran,Sathish Kumar,Arushi Batra,Vinod Scaria,Athulya Edavazhippurath,Arvind Ganapati,Anushree Mishra,Rahul C Bhoyar,Anu Punnen,Pulukool Sandhya,Shamsudheen Karuthedath Vellarikkal,Sridhar Sivasubbu,Jayakrishnan Machinary Puthenpurayil,Abhinav Jain

doi:10.1371/journal.pone.0237999

Abstract

Hyper-IgD syndrome (HIDS, OMIM #260920) is a rare autosomal recessive autoinflammatory disorder caused by pathogenic variants in the mevalonate kinase (MVK) gene. HIDS has an incidence of 1:50,000 to 1:5,000, and is thought to be prevalent mainly in northern Europe. Here, we report a case series of HIDS from India, which includes ten patients from six families who presented with a wide spectrum of clinical features such as recurrent fever, oral ulcers, rash, arthritis, recurrent diarrhea, hepatosplenomegaly, and high immunoglobulin levels. Using whole exome sequencing (WES) and/or Sanger capillary sequencing, we identified five distinct genetic variants in the MVK gene from nine patients belonging to six families. The variants were classified as pathogenic or likely pathogenic as per the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for annotation of sequence variants. Over 70% of patients in the present study had two recurrent mutations in MVK gene i.e. a nonsynonymous variant p.V377I, popularly known as the 'Dutch mutation', along with a splicing variant c.226+2delT in a compound heterozygous form. Identity by descent analysis in two patients with the recurrent variants identified a 6.7 MB long haplotype suggesting a founder effect in the South Indian population. Our analysis suggests that a limited number of variants account for the majority of the patients with HIDS in South India. This has implications in clinical diagnosis, as well as in the development of cost-effective approaches for genetic diagnosis and screening. To our best knowledge, this is the first and most comprehensive case series of clinically and genetically characterized patients with HIDS from India.

Highlights

Autoinflammatory disorders are rare disorders characterized by dysfunction of the innate immune system, resulting in unprovoked inflammation
Hyper-immunoglobulin D (IgD) syndrome (HIDS) is one of the several autoinflammatory disorders and has an autosomal recessive mode of inheritance caused by pathogenic variants in the mevalonate kinase (MVK) gene [1]
We describe a case series of ten patients with HIDS from six South Indian families identified by clinical suspicion and confirmed in nine of the patients with genetic testing

Summary

Introduction

Autoinflammatory disorders are rare disorders characterized by dysfunction of the innate immune system, resulting in unprovoked inflammation. Hyper-IgD syndrome (HIDS) is one of the several autoinflammatory disorders and has an autosomal recessive mode of inheritance caused by pathogenic variants in the mevalonate kinase (MVK) gene [1]. MA is associated with neurological features like developmental delay, cerebellar atrophy, ataxia, psychomotor retardation and dysmorphic features, apart from autoinflammatory symptoms The clinical presentation largely depends on the residual activity of mevalonate kinase ranging from virtually undetectable in MA to a range of detectable, but clearly deficient in HIDS and possibly resulting in premature death [5]. Mevalonate kinase phosphorylates mevalonic acid, which is required for the formation of non-sterol isoprenoids and cholesterol. This in turn is necessary for prenylation of proteins for protein [2]. Due to decreased level of mevalonate kinase, RhoA remains unprenylated and increased secretion of proinflammatory cytokines such as IL-1β results in the development of autoinflammatory symptoms [2,6]

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