A single-center pilot study in Malaysia on the clinical utility of whole-exome sequencing for inborn errors of immunity.

Primary immunodeficiency diseases refer to inborn errors of immunity (IEI) that affect the normal development and function of the immune system. The phenotypical and genetic heterogeneity of IEI have made their diagnosis challenging. Hence, whole-exome sequencing (WES) was employed in this pilot study to identify the genetic etiology of 30 pediatric patients clinically diagnosed with IEI. The potential causative variants identified by WES were validated using Sanger sequencing. Genetic diagnosis was attained in 46.7% (14 of 30) of the patients and categorized into autoinflammatory disorders (n = 3), diseases of immune dysregulation (n = 3), defects in intrinsic and innate immunity (n = 3), predominantly antibody deficiencies (n = 2), combined immunodeficiencies with associated and syndromic features (n = 2) and immunodeficiencies affecting cellular and humoral immunity (n = 1). Of the 15 genetic variants identified, two were novel variants. Genetic findings differed from the provisional clinical diagnoses in seven cases (50.0%). This study showed that WES enhances the capacity to diagnose IEI, allowing more patients to receive appropriate therapy and disease management.

A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation.

Autoinflammatory disorders are characterized by dysregulated innate immune response, resulting in recurrent uncontrolled systemic inflammation and fever. Gain-of-function mutations in NLRC4 have been described to cause a range of autoinflammatory disorders. We report a twelve-year-old Malay girl with recurrent fever, skin erythema, and inflammatory arthritis. Whole exome sequencing and subsequent bidirectional Sanger sequencing identified a heterozygous missense mutation in NLRC4 (NM_001199138: c.1970A > T). This variant was predicted to be damaging in silico, was absent in public and local databases and occurred in a highly conserved residue in the leucine-rich repeat (LRR) domain. Cytokine analysis showed extremely high serum IL-18 and IL-18/CXCL9 ratio, consistent with other NLRC4-MAS patients. In summary, we identified the first patient with a novel de novo heterozygous NLRC4 gene mutation contributing to autoinflammatory disease in Malaysia. Our findings reinforce the likely pathogenicity of specific LRR domain mutations in NLRC4 and expand the clinical spectrum of NLRC4 mutations.

Demographic, clinical and laboratory features of leptospirosis and dengue co-infection in Malaysia.

Purpose. In this study, we aim to describe and compare the demographical, clinical and laboratory features of leptospirosis and dengue co-infections (LDCI) against single leptospirosis infections in Malaysia.Methodology. Data of patients admitted to various hospitals in Malaysia from 2011 to 2015 diagnosed with leptospirosis in our laboratory were obtained from their admission records. Co-infection with dengue was determined by collecting dengue serology results. Multivariate analysis and multiple logistic regression were used to differentiate features between single leptospirosis infection and confirmed LDCI.Results/Key findings. Only 602 (29.11 %) out of 2068 leptospira-positive patients were concurrently tested for dengue during their admission in which 44 (7.31 %) patients had positive non-structural protein 1 (confirmed LDCI) while 140 (23.26 %) were positive for dengue IgM (probable LDCI) with the highest number of cases recorded in high-density suburban districts. Myalgia and arthralgia were the only significant distinguishing clinical feature of LDCI while significant laboratory features were thrombocytopenia and high levels of alanine and aspartate transaminases. Only thrombocytopenia displayed a predictive value for LDCI from analysis of multiple logistic regression. Death occurred in 19 (3.16 %) patients in this dataset studied but only three (0.50 %) were attributed to LDCI.Conclusion. There is a considerable prevalence of LDCI in this country of which overlapping demographic, clinical and laboratory presentations pose diagnostic and therapeutic challenges. Efforts to raise awareness regarding LDCI, better access to diagnostic services and further prospective studies are warranted.