Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India

Aluri, Jahnavi; Gupta, Maya; Dalvi, Aparna; Mhatre, Snehal; Kulkarni, Manasi; Hule, Gouri; Desai, Mukesh; Shah, Nitin; Taur, Prasad; Vedam, Ramprasad; Madkaikar, Manisha

doi:10.3389/fimmu.2018.00188

Cited by 31 publications

(21 citation statements)

References 23 publications

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“…The molecular findings in five cases of MHC class II deficiency from our cohort has been recently described (20). Additionally, we have identified another patient with a defect in RFXANK gene.…”

Section: Discussionmentioning

confidence: 80%

Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

et al. 2019

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Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/μL <2,500) was noted in 63% of the patients. Based on immunophenotypic pattern, majority of the cases were T−B− SCID (39%) followed by T−B+ SCID (28%). MHC class II deficiency accounted for 10.5% of our patient group. A total of 49 patients were molecularly characterized in this study and 32 novel variants were identified in our cohort. The spectrum of genetic defects in our cohort revealed a wide genetic heterogeneity with the major genetic cause being RAG1/2 gene defect (n = 12) followed by IL2RG (n = 9) and JAK3 defects (n = 9). Rare forms of SCID like Purine nucleoside phosphorylase (PNP) deficiency, reticular dysgenesis, DNA-Protein Kinase (DNA-PKcs) deficiency, six cases of MHC class II deficiency and two ZAP70 deficiency were also identified in our cohort. Fourteen percent of the defects still remained uncharacterized despite the application of next generation sequencing. With the exception of MHC class II deficiency and ZAP70 deficiency, all SCID patients had extremely low T cell receptor excision (TRECs) (<18 copies/μL).

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Section: Discussionmentioning

confidence: 80%

Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

et al. 2019

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“…Newborn screening has enabled prompter diagnosis and earlier transplantation, entailing a higher survival rate, for patients with severe combined immunodeficiencies (SCID), 11‐13 but it is important to note that patients with MCH II deficiency may present with detectable levels of TRECs, and thus can be missed by newborn screening 1,14 …”

Section: Discussionmentioning

confidence: 99%

Meta‐analysis of hematopoietic stem cell transplantation in major histocompatibility complex class II deficiency

Castaño-Jaramillo¹,

Bareño‐Silva²,

Tobón

et al. 2020

Pediatric Transplantation

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Major histocompatibility complex class II deficiency is a rare case of PID. Specific recommendations for hematopoietic stem cell transplant, the only curative treatment option, are still lacking. This meta‐analysis aims to identify the factors associated with better prognosis in these patients. Thirteen articles reporting 63 patients with major histocompatibility complex class II deficiency that underwent hematopoietic stem cell transplant were included. The median age for hematopoietic stem cell transplant was 18 months. The most common source of transplant was bone marrow, with alternative sources as umbilical cord blood emerging during recent years. The highest proportion of engraftment was seen with umbilical cord. Engraftment was higher in patients with matched donors, with better overall survival in patients with reduced‐intensity conditioning. Graft‐vs‐host disease developed in 65% of the patients, with grades I‐II being the most frequently encountered. There was a higher mortality in patients with myeloablative conditioning and no engraftment. There was an inverse correlation between survival and stage of graft‐vs‐host disease. The main cause of mortality was infectious disease, mostly secondary to viral infections. Ideally, matched grafts should be used, and reduced‐intensity conditioning should be considered to reduce early post‐transplant complications. GVHD and viral prophylaxis are fundamental.

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“…The utmost challenging facet of PIDs is under diagnosis, owing to the high incidence of infectious diseases in countries like India [175]. Whole exome sequencing approach has proved to be instrumental in identifying mutations in capillary sequencing negative cases of X-linked agammaglobulinemia (XLA) [149], severe combined immunodeficiency (SCID) [148], B cell expansion with NF-κB, and T cell anergy (BENTA) [176], apart from targeted next generation sequencing in SCID [177] and major histocompatibility complex class II deficiency [178].…”

Section: Main Textmentioning

confidence: 99%

Genomics of rare genetic diseases—experiences from India

Sivasubbu

Scaria

2019

Hum Genomics

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Home to a culturally heterogeneous population, India is also a melting pot of genetic diversity. The population architecture characterized by multiple endogamous groups with specific marriage patterns, including the widely prevalent practice of consanguinity, not only makes the Indian population distinct from rest of the world but also provides a unique advantage and niche to understand genetic diseases. Centuries of genetic isolation of population groups have amplified the founder effects, contributing to high prevalence of recessive alleles, which translates into genetic diseases, including rare genetic diseases in India. Rare genetic diseases are becoming a public health concern in India because a large population size of close to a billion people would essentially translate to a huge disease burden for even the rarest of the rare diseases. Genomics-based approaches have been demonstrated to accelerate the diagnosis of rare genetic diseases and reduce the socio-economic burden. The Genomics for Understanding Rare Diseases: India Alliance Network (GUaRDIAN) stands for providing genomic solutions for rare diseases in India. The consortium aims to establish a unique collaborative framework in health care planning, implementation, and delivery in the specific area of rare genetic diseases. It is a nation-wide collaborative research initiative catering to rare diseases across multiple cohorts, with over 240 clinician/scientist collaborators across 70 major medical/research centers. Within the GUaRDIAN framework, clinicians refer rare disease patients, generate whole genome or exome datasets followed by computational analysis of the data for identifying the causal pathogenic variations. The outcomes of GUaRDIAN are being translated as community services through a suitable platform providing low-cost diagnostic assays in India. In addition to GUaRDIAN, several genomic investigations for diseased and healthy population are being undertaken in the country to solve the rare disease dilemma. In summary, rare diseases contribute to a significant disease burden in India. Genomics-based solutions can enable accelerated diagnosis and management of rare diseases. We discuss how a collaborative research initiative such as GUaRDIAN can provide a nation-wide framework to cater to the rare disease community of India.

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Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India

Cited by 31 publications

References 23 publications

Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

Clinical, Immunological, and Molecular Findings in 57 Patients With Severe Combined Immunodeficiency (SCID) From India

Meta‐analysis of hematopoietic stem cell transplantation in major histocompatibility complex class II deficiency

Genomics of rare genetic diseases—experiences from India

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