Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome.
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...
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| Language: | English |
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Public Library of Science (PLoS)
2020-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0237999 |
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| author | Geeta Madathil Govindaraj Abhinav Jain Geetha Peethambaran Rahul C Bhoyar Shamsudheen Karuthedath Vellarikkal Arvind Ganapati Pulukool Sandhya Athulya Edavazhippurath Dhananjayan Dhanasooraj Jayakrishnan Machinary Puthenpurayil Krishnan Chakkiyar Anushree Mishra Arushi Batra Anu Punnen Sathish Kumar Sridhar Sivasubbu Vinod Scaria |
| author_facet | Geeta Madathil Govindaraj Abhinav Jain Geetha Peethambaran Rahul C Bhoyar Shamsudheen Karuthedath Vellarikkal Arvind Ganapati Pulukool Sandhya Athulya Edavazhippurath Dhananjayan Dhanasooraj Jayakrishnan Machinary Puthenpurayil Krishnan Chakkiyar Anushree Mishra Arushi Batra Anu Punnen Sathish Kumar Sridhar Sivasubbu Vinod Scaria |
| author_sort | Geeta Madathil Govindaraj |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T20:32:46Z |
| format | Article |
| id | doaj.art-c8d44fc2ca07459f8f9d973e715de066 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-11T20:32:46Z |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c8d44fc2ca07459f8f9d973e715de0662022-12-22T04:04:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01158e023799910.1371/journal.pone.0237999Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome.Geeta Madathil GovindarajAbhinav JainGeetha PeethambaranRahul C BhoyarShamsudheen Karuthedath VellarikkalArvind GanapatiPulukool SandhyaAthulya EdavazhippurathDhananjayan DhanasoorajJayakrishnan Machinary PuthenpurayilKrishnan ChakkiyarAnushree MishraArushi BatraAnu PunnenSathish KumarSridhar SivasubbuVinod ScariaHyper-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.https://doi.org/10.1371/journal.pone.0237999 |
| spellingShingle | Geeta Madathil Govindaraj Abhinav Jain Geetha Peethambaran Rahul C Bhoyar Shamsudheen Karuthedath Vellarikkal Arvind Ganapati Pulukool Sandhya Athulya Edavazhippurath Dhananjayan Dhanasooraj Jayakrishnan Machinary Puthenpurayil Krishnan Chakkiyar Anushree Mishra Arushi Batra Anu Punnen Sathish Kumar Sridhar Sivasubbu Vinod Scaria Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome. PLoS ONE |
| title | Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome. |
| title_full | Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome. |
| title_fullStr | Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome. |
| title_full_unstemmed | Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome. |
| title_short | Spectrum of clinical features and genetic variants in mevalonate kinase (MVK) gene of South Indian families suffering from Hyperimmunoglobulin D Syndrome. |
| title_sort | spectrum of clinical features and genetic variants in mevalonate kinase mvk gene of south indian families suffering from hyperimmunoglobulin d syndrome |
| url | https://doi.org/10.1371/journal.pone.0237999 |
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