An investigation into the level of genetic knowledge and family communication regarding genetic risk in parents of children with cystic fibrosis

Includes bibliographical references (leaves 94-103).The aims of the present study were to determine the level of genetic knowledge of parents with a child with cystic fibrosis; to determine the impact of the birth of a child with cystic fibrosis upon subsequent reproductive choices and to investigate family communication about genetic risk. A qualitative approach was selected as it aims to understand, attempts to make sense of and provides descriptions that portray the richness and complexity of ordinary events from the perspective of the participants

Implementation of a breast cancer genetic service in South Africa - lessons learned

CITATION: Schoeman, M., Apffelstaedt, J. P., Baatjes, K. & Urban, M. 2013. Implementation of a breast cancer genetic service in South Africa - lessons learned. South African Medical Journal, 103(8):529-533, doi:10.7196/SAMJ.6814.The original publication is available at http://www.samj.org.zaBackground. Genetic testing for BRCA mutations has been available in the Western Cape of South Africa since 2005, but practical implementation of genetic counselling and testing has been challenging. Objective. To describe an approach to breast cancer genetic counselling and testing developed in a resource-constrained environment at Tygerberg Hospital in Cape Town, Western Cape. Methods. Genetic counselling is offered in a stepwise manner to our diverse patient population, with a focus on affected probands, and subsequent cascade testing. A record review of BRCA testing between 2005 and 2011 was performed. Results. During this period 302 probands received genetic testing, with increasing numbers tested over time. Of 1 520 women treated for breast cancer since 2008, 226 (14.9%) accepted BRCA testing, and 39 tested positive (17.3% of those tested, and 2.6% of all women). Common founder mutations were detected in 11.9% of women (36/302), and comprised 73% (36/49) of mutations detected. Cascade testing increased after 2010: 16 female and 4 male family members of 19 probands accepted testing, with 6 positives being detected. Conclusion. A protocol-driven approach focusing on probands, with initial pre-test counselling by primary care staff has proven effective in establishing the service. Involvement of a clinical geneticist/genetic counsellor has permitted more detailed post-test counselling and increased use of cascade testing.http://www.samj.org.za/index.php/samj/article/view/6814Publisher's versio

When apparent schizophrenia is excluded

CITATION: Fourie, H. F., et al. 2015. When apparent schizophrenia is excluded. South African Journal of Psychiatry, 21(1):31:34, doi:10.4102/sajpsychiatry.v21i1.573.The original publication is available at http://www.sajp.org.zaWhere must a clinician turn when straightforward schizophrenia suddenly turns out to be just the opposite? Fortunately, these days, there are protocols for just about everything. But how much value do these add? This article outlines the journey of our attempt to follow one such protocol.http://www.sajp.org.za/index.php/sajp/article/view/573Publisher's versio

Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency

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. This study describes the use of exome sequencing to identify a homozygous recessive variant in MAP3K14, NIKVal345Met, in a patient with combined immunodeficiency, disseminated BCG-osis, and paradoxically elevated lymphocytes. Laboratory testing confirmed hypogammaglobulinemia with normal CD19, but failed to confirm a definitive diagnosis for targeted treatment decisions. NIKVal345Met is predicted to be deleterious and pathogenic by two in silico prediction tools and is situated in a gene crucial for effective functioning of the non-canonical nuclear factor-kappa B signaling pathway. Functional analysis of NIKVal345Met- versus NIKWT-transfected human embryonic kidney-293T cells showed that this mutation significantly affects the kinase activity of NIK leading to decreased levels of phosphorylated IkappaB kinase-alpha (IKKα), the target of NIK. BCG-stimulated RAW264.7 cells transfected with NIKVal345Met also presented with reduced levels of phosphorylated IKKα, significantly increased p100 levels and significantly decreased p52 levels compared to cells transfected with NIKWT. Ideally, these experiments would have been conducted in patient-derived immune cells, but we were unable to source these cells from the patient. The functional analysis described in this paper supports previous illustrations of the importance of NIK in human immune responses and demonstrates the involvement of function-altering mutations in MAP3K14 in PIDs. The genomic approach used for this patient demonstrates its value in the diagnosis of an unusual PID and as a tool for detecting rarer mutations to help guide treatment approaches

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

CITATION: Kinnear, C., et al. 2017. Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa. BMC Medical Genetics, 18:26, doi:10.1186/s12881-017-0388-5.The original publication is available at https://bmcmedgenet.biomedcentral.comBackground 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.http://scientiamilitaria.journals.ac.za/pub/article/view/190Publisher's versio

Identification of a novel WAS mutation in a South African patient presenting with atypical Wiskott-Aldrich syndrome : a case report

CITATION: Glanzmann, B., et al. 2020. Identification of a novel WAS mutation in a South African patient presenting with atypical Wiskott-Aldrich syndrome : a case report. BMC Medical Genetics, 21:124, doi:10.1186/s12881-020-01054-6.The original publication is available at https://bmcmedgenet.biomedcentral.comBackground: The X-linked recessive primary immunodeficiency disease (PIDD) Wiskott-Aldrich syndrome (WAS) is identified by an extreme susceptibility to infections, eczema and thrombocytopenia with microplatelets. The syndrome, the result of mutations in the WAS gene which encodes the Wiskott-Aldrich protein (WASp), has wide clinical phenotype variation, ranging from classical WAS to X-linked thrombocytopaenia and X-linked neutropaenia. In many cases, the diagnosis of WAS in first affected males is delayed, because patients may not present with the classic signs and symptoms, which may intersect with other thrombocytopenia causes. Case presentation: Here, we describe a three-year-old HIV negative boy presenting with recurrent infections, skin rashes, features of autoimmunity and atopy. However, platelets were initially reported as normal in numbers and morphology as were baseline immune investigations. An older male sibling had died in infancy from suspected immunodeficiency. Uncertainty of diagnosis and suspected severe PIDD prompted urgent further molecular investigation. Whole exome sequencing identified c. 397 G > A as a novel hemizygous missense mutation located in exon 4 of WAS. Conclusion: With definitive molecular diagnosis, we could target treatment and offer genetic counselling and prenatal diagnostic testing to the family. The identification of novel variants is important to confirm phenotype variations of a syndrome.https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-01054-6Publisher's versio

Additional file 1: of Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

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