Clinical, immunological and genomic characteristics of children with X-linked agammaglobulinemia from Kerala, South India.

X-linked agammaglobulinemia (XLA) is an X-linked recessive primary immunodeficiency disorder caused due to a pathogenic variant in the Bruton tyrosine (BTK) gene with an incidence of 1:379,000 live births and 1:190,000 male births. Patients affected with XLA present with recurrent infections of the gastrointestinal and respiratory tracts. Here we report the first case series of 17 XLA patients of 10 South Indian families with a wide spectrum of clinical and genetic features. In our cohort, patients presented mainly with recurrent pneumonia, gastrointestinal infection, otitis media, pyoderma, abscesses, empyema, arthritis, and osteomyelitis. Using next-generation and Sanger sequencing we have identified 10 unique pathogenic and likely pathogenic variants in 17 patients. This encompasses three nonsynonymous, two stop-gain, two frameshifts, two structural, and one splicing variant, out of which two of them are novel. Based on the type of variant, patients had variable clinical features and treatment responses. We have also evaluated Btk protein expression for six patients in comparison to the healthy individuals and determined mosaic Btk expression patterns in four mothers. We have also performed family screening in 6 families using Sanger sequencing and identified 19 carriers for the variant. The diagnosis for the patients led to the proper treatment i.e. 15 patients were on intravenous immunoglobulin (IVIG) and the other two had successful hematopoietic stem cell transplantation (HSCT). Unfortunately, two of our patients died due to sepsis, while on IVIG. We envision the present study could help in better understanding of patients with XLA and help in family screening and prenatal diagnosis. To the best of our knowledge, this is the largest case series of patients affected with XLA from South India.

Baseline cell proliferation rates and response to UV differ in lymphoblastoid cell lines derived from healthy individuals of extreme constitution types.

Differences in human phenotypes and susceptibility to complex diseases are an outcome of genetic and environmental interactions. This is evident in diseases that progress through a common set of intermediate patho-endophenotypes. Precision medicine aims to delineate molecular players for individualized and early interventions. Functional studies of lymphoblastoid cell line (LCL) model of phenotypically well-characterized healthy individuals can help deconvolute and validate these molecular mechanisms. In this study, LCLs are developed from eight healthy individuals belonging to three extreme constitution types, deep phenotyped on the basis of Ayurveda. LCLs were characterized by karyotyping and immunophenotyping. Growth characteristics and response to UV were studied in these LCLs. Significant differences in cell proliferation rates were observed between the contrasting groups such that one type (Kapha) proliferates significantly slower than the other two (Vata, Pitta). In response to UV, one of the fast growing groups (Vata) shows higher cell death but recovers its numbers due to an inherent higher rates of proliferation. This study reveals that baseline differences in cell proliferation could be a key to understanding the survivability of cells under UV stress. Variability in baseline cellular phenotypes not only explains the cellular basis of different constitution types but can also help set priors during the design of an individualized therapy with DNA damaging agents. This is the first study of its kind that shows variability of intermediate patho-phenotypes among healthy individuals with potential implications in precision medicine.