Primary Immunodeficiencies in India: Molecular Diagnosis and the Role of Next-Generation Sequencing

Arunachalam, Arun Kumar; Maddali, Madhavi; Aboobacker, Fouzia N.; Korula, Anu; George, Biju; Edison, Eunice Sindhuvi

doi:10.1007/s10875-020-00923-2

Cited by 22 publications

(13 citation statements)

References 60 publications

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“…Molecular diagnosis was obtained in 162 patients— IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9), PNP (3), RFXAP (3), CIITA (2), RFXANK (2), NHEJ1 (2), CD3E (2), CD3D (2), RFX5 (2), ZAP70 (2), STK4 (1), CORO1A (1), STIM1 (1), PRKDC (1), AK2 (1), DOCK2 (1), and SP100 (1). Of the 176 molecular variants, 51 were identified to be novel in this study ( Table 4 , Supplementary Table 3 ) ( 7 , 13 , 17 – 49 ). A novel variant in RAG1 (c.1758_1760delinsGAATC) was identified in 2 unrelated North Indian families.…”

Section: Resultsmentioning

confidence: 89%

“…Eighty-two (82) patients did not undergo a molecular analysis for confirmation of diagnosis due to lack of easy access to molecular diagnostics and financial difficulties. With the establishment of commercial NGS laboratories and reduction in costs involved for genetic sequencing over last few years, NGS-based diagnostics have become feasible in India ( 7 , 13 ). In-house NGS facility for molecular diagnosis of PID is currently available only at PGIMER, Chandigarh (North India) and Christian Medical College, Vellore (South India).…”

Section: Discussionmentioning

confidence: 99%

“…( 7 ). Methodology for NGS at Christian Medical College, Vellore (South India) was described previously ( 13 ).…”

Section: Methodsmentioning

confidence: 99%

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Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India

Vignesh¹,

Rawat²,

Kumrah³

et al. 2021

Front. Immunol.

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BackgroundSevere Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce.ObjectiveTo describe clinical and laboratory features of SCID diagnosed at immunology centers across India.MethodsA detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID.ResultsWe obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9), PNP (3), RFXAP (3), CIITA (2), RFXANK (2), NHEJ1 (2), CD3E (2), CD3D (2), RFX5 (2), ZAP70 (2), STK4 (1), CORO1A (1), STIM1 (1), PRKDC (1), AK2 (1), DOCK2 (1), and SP100 (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%).ConclusionWe document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.

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Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India

Vignesh¹,

Rawat²,

Kumrah³

et al. 2021

Front. Immunol.

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“…Three X-linked carriers of CYBB defect had manifestations of CGD in form of severe infections probably as a result of skewed inactivation (32,33). A carrier of X-linked CGD developed manifestations of severe lupus malar rash, arthritis, positivity for anti-nuclear and anti-double stranded DNA antibodies, seizures, and demyelinating lesions in the brain and spinal cord (21).…”

Section: Molecular Diagnosismentioning

confidence: 99%

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India

et al. 2021

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BackgroundChronic granulomatous disease (CGD) is an inherited defect in phagocytic respiratory burst that results in severe and life-threatening infections in affected children. Single center studies from India have shown that proportion of autosomal recessive (AR) CGD is more than that reported from the West. Further, affected patients have high mortality rates due to late referrals and difficulties in accessing appropriate treatment. However, there is lack of multicentric collaborative data on CGD from India.ObjectiveTo describe infection patterns, immunological, and molecular features of CGD from multiple centers in India.MethodsA detailed proforma that included clinical and laboratory details was prepared and sent to multiple centers in India that are involved in the care and management of patients with inborn errors of immunity. Twelve centers have provided data which were later pooled together and analyzed.ResultsOf the 236 patients analyzed in our study, X-linked and AR-CGD was seen in 77 and 97, respectively. Male female ratio was 172:64. Median age at onset of symptoms and diagnosis was 8 and 24 months, respectively. Common infections documented include pneumonia (71.6%), lymphadenitis (31.6%), skin and subcutaneous abscess (23.7%), blood-stream infection (13.6%), osteomyelitis (8.6%), liver abscess (7.2%), lung abscess (2.9%), meningoencephalitis (2.5%), splenic abscess (1.7%), and brain abscess (0.9%). Forty-four patients (18.6%) had evidence of mycobacterial infection. Results of molecular assay were available for 141 patients (59.7%)—CYBB (44.7%) gene defect was most common, followed by NCF1 (31.9%), NCF2 (14.9%), and CYBA (8.5%). While CYBA variants were documented only in Southern and Western parts of India, a common dinucleotide deletion in NCF2 (c.835_836delAC) was noted only in North Indian population. Of the 174 patients with available outcome data, 67 (38.5%) had expired. Hematopoietic stem cell transplantation was carried out in 23 patients, and 12 are doing well on follow-up.ConclusionsIn India, proportion of patients with AR-CGD is higher as compared to Western cohorts, though regional differences in types of AR-CGD exist. Clinical profile and mortality rates are similar in both X-linked and AR-CGD. However, this may be a reflection of the fact that milder forms of AR-CGD are probably being missed.

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“…The cost of targeted genetic sequencing at our setup is USD 83 per sample. This is much less than the costs incurred at commercial laboratories in India 33 . In addition, infants less than one year are covered under the JSSK (Janani Sishu Suraksha Karyakram) scheme of the Government of India.…”

Section: Discussionmentioning

confidence: 93%

Utility of targeted next generation sequencing for inborn errors of immunity at a tertiary care centre in North India

Rawat

Sharma

Vignesh

et al. 2022

Sci Rep

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Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders that include primary immunodeficiency’s and other disorders affecting different aspects of the immune system. Next-Generation Sequencing (NGS) is an essential tool to diagnose IEI. We report our 3-year experience in setting up facilities for NGS for diagnosis of IEI in Chandigarh, North India. We used a targeted, customized gene panel of 44 genes known to result in IEI. Variant analysis was done using Ion Reporter software. The in-house NGS has enabled us to offer genetic diagnoses to patients with IEI at minimal costs. Of 121 patients who were included pathogenic variants were identified in 77 patients. These included patients with Chronic Granulomatous Disease, Severe Combined Immune Deficiency, leukocyte adhesion defect, X-linked agammaglobulinemia, Ataxia Telangiectasia, Hyper-IgE syndrome, Wiskott Aldrich syndrome, Mendelian susceptibility to mycobacterial diseases, Hyper-IgM syndrome, autoimmune lymphoproliferative syndrome, and GATA-2 deficiency. This manuscript discusses the challenges encountered while setting up and running targeted NGS for IEI in our unit. Genetic diagnosis has helped our patients with IEI in genetic counselling, prenatal diagnosis, and accessing appropriate therapeutic options.

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Primary Immunodeficiencies in India: Molecular Diagnosis and the Role of Next-Generation Sequencing

Cited by 22 publications

References 60 publications

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India

Utility of targeted next generation sequencing for inborn errors of immunity at a tertiary care centre in North India

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