Browsing by Author "Schlechter, Nikola"

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    Exome sequencing identifies a novel MAP3K14 mutation in recessive atypical combined immunodeficiency
    (Frontiers, 2017-11) Schlechter, Nikola; Glanzmann, Brigitte; Hoal, Eileen Garner; Schoeman, Mardelle; Petersen, Britt-Sabina; Franke, Andre; Lau, Yu-Lung; Urban, Michael; Van Helden, Paul David; Esser, Maria Esser; Moller, Marlo; Kinnear, Craig
    ENGLISH ABSTRACT: Primary immunodeficiency disorders (PIDs) render patients vulnerable to infection with a wide range of microorganisms and thus provide good in vivo models for the assessment of immune responses during infectious challenges. Priming of the immune system, especially in infancy, depends on different environmental exposures and medical practices. This may determine the timing and phenotype of clinical appearance of immune deficits as exemplified with early exposure to Bacillus Calmette-Guérin (BCG) vaccination and dissemination in combined immunodeficiencies. Varied phenotype expression poses a challenge to identification of the putative immune deficit. Without the availability of genomic diagnosis and data analysis resources and with limited capacity for functional definition of immune pathways, it is difficult to establish a definitive diagnosis and to decide on appropriate treatment.
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    Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa
    (BioMed Central, 2017-03-14) Kinnear, Craig; Glanzmann, Brigitte; Banda, Eric; Schlechter, Nikola; Durrheim, Glenda; Neethling, Annika; Nel, Etienne; Schoeman, Mardelle; Johnson, Glynis; Van Helden, Paul D.; Hoal, Eileen G; Esser, Monika; Urban, Michael; Moller, Marlo
    Background Trichohepatoenteric syndrome (THE-S) or phenotypic diarrhoea of infancy is a rare autosomal recessive disorder characterised by severe infantile diarrhoea, facial dysmorphism, immunodeficiency and woolly hair. It was first described in 1982 in two infants with intractable diarrhoea, liver cirrhosis and abnormal hair structure on microscopy. We report on two siblings from a consanguineous family of Somali descent who, despite extensive clinical investigation, remained undiagnosed until their demise. The index patient died of fulminant cytomegalovirus pneumonitis at 3 months of age. Methods Whole exome sequencing (WES) was performed on a premortem DNA sample from the index case. Variants in a homozygous recessive state or compound heterozygous state were prioritized as potential candidate variants using TAPER™. Sanger sequencing was done to genotype the parents, unaffected sibling and a deceased sibling for the variant of interest. Results Exome sequencing identified a novel homozygous mutation (c.4507C > T, rs200067423) in TTC37 which was confirmed by Sanger sequencing in the index case. The identification of this mutation led to the diagnosis of THE-S in the proband and the same homozygous variant was confirmed in a male sibling who died 4 years earlier with severe chronic diarrhoea of infancy. The unaffected parents and sister were heterozygous for the identified variant. Conclusions WES permitted definitive genetic diagnosis despite an atypical presentation in the index case and suggests that severe infection, likely secondary to immunodeficiency, may be a presenting feature. In addition definitive molecular diagnosis allows for genetic counseling and future prenatal diagnosis, and demonstrates the value of WES for post-mortem diagnosis of disorders with a non-specific clinical presentation in which a Mendelian cause is suspected.
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    Identification of novel candidate genes for susceptibility to tuberculosis by identifying disease-causing mutations in individuals with Primary Immunodeficiency disorders
    (Stellenbosch : Stellenbosch University, 2017-03) Schlechter, Nikola; Kinnear, Craig; Moller, Marlo; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human Genetics.
    ENGLISH ABSTRACT: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency disorder believed to affect less than 1:1 000 000 individuals globally. It is characterized by increased susceptibility to weakly virulent mycobacterial infections, such as Bacille Calmette Guerin, and in some cases more virulent agents, such as Mycobacterium tuberculosis, possibly implying a monogenic predisposition to tuberculosis (TB). TB claimed the lives of ~1.5 million people worldwide in 2014, making it the leading cause of death due to a single infectious agent and a very high-priority health problem. Ten genes have been associated with MSMD, five of which are also involved in TB susceptibility. In half of all MSMD patients, however, no mutations are found in these genes, highlighting the need to identify yet undiscovered MSMD-causing genes. The present study aimed to identify novel MSMD-causing mutations by using whole exome sequencing (WES), and to determine whether the genes containing these variants are associated with increased TB susceptibility. It also investigated a potential link between MSMD and tuberculosis meningitis (TBM) by investigating variants identified in known MSMD-causing genes in TBM cases. Three MSMD patients and five of their healthy parents, as well as 10 TBM patients and 10 controls, were recruited. WES was performed on the Illumina HiSeq and produced ~60 000 - 75 000 variants per individual. Numerous filtering and variant prioritization tools were used to identify three plausible MSMD-causing variants in the MSMD patients based on in silico predictions of their potential to be disease-causing and the function of the genes they are situated in. These include two variants in transporter associated with antigen processing 1 (TAP1) and one in mitogen-activated protein kinase kinase kinase 14 (MAP3K14). In vitro functional studies verified their involvement in disease. Case-control association studies were performed using known single nucleotide polymorphisms in these two genes in a cohort of TB cases and controls. Four variants in three MSMD-causing genes were also identified in four of the TBM patients, which were absent from controls, and predicted to cause disease. One variant was identified in each MSMD patient. The heterozygous I296M variant in TAP1 was absent from ethnically matched controls and has not been previously identified according to ExAC Browser, the 1000 Genomes Project and ESP6500. The variant is predicted to be deleterious and may alter antigen presentation to molecules of the type I major histocompatibility complex. The homozygous V345M variant in MAP3K14 was absent from the above-mentioned databases, and predicted to be deleterious. It can potentially inhibit effective nuclear factor-kappa B signaling and thus lead to aberrant lymphoid immunity. The P67S variant in TAP1 has not previously been identified in homozygous form, although it has been recorded in the heterozygous state in three Asians and one European. This heterozygous variant is predicted to be a benign polymorphism. However, homozygous variants can have more severe effects on protein function, and could influence different ethnic populations dissimilarly. In summary, these results identify three novel putative variants involved in MSMD and thus increased TB susceptibility. It also hints at a potential link between MSMD and TBM, which should be investigated further. Identification of MSMD-causing mutations can inform treatment strategies by aiding in the implementation of patient-specific vaccine strategies and treatment regimes. It can lead to identification of at-risk relatives, and also provide novel candidate genes to be evaluated for increased TB susceptibility in the general population.