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

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

Genetic Landscape of Rare Autoinflammatory Disease Variants in Qatar and Middle Eastern Populations Through the Integration of Whole-Genome and Exome Datasets

“…A number of studies have shown that this variant was present in homozygous or compound heterozygous states in multiple patients affected by HIDS with different ethnic backgrounds. Various in-vitro and in-vivo functional studies have proved that p.V377I is disease-causing with a very low allele frequency in control databases ( Drenth et al, 1999 ; Houten et al, 1999 , 2001 ; Cuisset et al, 2001 ; Levy et al, 2013 ; Govindaraj et al, 2020 ). The fourth nonsynonymous likely pathogenic variant has been found in RAB27A i.e., Arg82Cys (R82C), and had been predicted as a causal variant for hemophagocytic lymphohistiocytosis (HLH) (OMIM number 267700).…”

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience

“…13–14). Three patients were found to have the V377I Dutch founder variant and 2 had c.1129G>A variant which is fairly common in South India particularly Kerala ( 15 ).…”

“…Further, molecular insights of these disorders have provided the basis for new therapeutic interventions leading to improved outcomes and long-term survivals. There is paucity of data on SAID from India with published literature comprising of only anecdotal case reports (14)(15)(16)(17)(18)(19)(20)(21). In this manuscript we describe clinical features, molecular profile, treatment and outcome in patients with monogenic SAID from six centers in our country.…”

Rad52 mediates class-switch DNA recombination to IgD

“…Serum IgD have been suggested to increase in patients with inflammatory autoimmune diseases, such as systemic lupus erythematosus (SLE) 29 and rheumatoid arthritis 30 , and in hereditary autoinflammatory syndromes, most notably the hyper-IgD syndrome (HIDS) [31][32][33][34] . In healthy humans, many B cells with CSR to IgD react with components of the self 35 .…”

“…Serum IgD have been suggested to increase in patients with inflammatory autoimmune diseases, such as systemic lupus erythematosus (SLE) 29 and rheumatoid arthritis 30 , and in hereditary autoinflammatory syndromes, most notably the hyper-IgD syndrome (HIDS) [31][32][33][34] . While in healthy humans, many B cells make IgD that react with components of the self 35 , we found patients with systemic lupus to display significantly higher levels of circulating IgD, including IgD specific for nuclear antigens, than their healthy subject controls (Fig.…”