3 research outputs found
Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing
Background: Multiple sclerosis is a disorder related to demyelination of axons. Iron is an essential cofactor in myelin synthesis. Previously, we described two children (males of mixed ancestry) with relapsing-remitting multiple sclerosis (RRMS) where long-term remission was achieved by regular iron supplementation. A genetic defect in iron metabolism was postulated, suggesting that more advanced genetic studies could shed new light on disease pathophysiology related to iron. Methods: Whole exome sequencing (WES) was performed to identify causal pathways. Blood tests were performed over a 10 year period to monitor the long-term effect of a supplementation regimen. Clinical wellbeing was assessed quarterly by a pediatric neurologist and regular feedback was obtained from the schoolteachers. Results: WES revealed gene variants involved in iron absorption and transport, in the transmembrane protease, serine 6 (TMPRSS6) and transferrin (TF) genes; multiple genetic variants in CUBN, which encodes cubilin (a receptor involved in the absorption of vitamin B12 as well as the reabsorption of transferrin-bound iron and vitamin D in the kidneys); SLC25A37 (involved in iron transport into mitochondria) and CD163 (a scavenger receptor involved in hemorrhage resolution). Variants were also found in COQ3, involved with synthesis of Coenzyme Q10 in mitochondria. Neither of the children had the HLA-DRB1*1501 allele associated with increased genetic risk for MS, suggesting that the genetic contribution of iron-related genetic variants may be instrumental in childhood MS. In both children the RRMS has remained stable without activity over the last 10 years since initiation of nutritional supplementation and maintenance of normal iron levels, confirming the role of iron deficiency in disease pathogenesis in these patients. Conclusion: Our findings highlight the potential value of WES to identify heritable risk factors that could affect the reabsorption of transferrin-bound iron in the kidneys causing sustained iron loss, together with inhibition of vitamin B12 absorption and vitamin D reabsorption (CUBN) and iron transport into mitochondria (SLC25A37) as the sole site of heme synthesis. This supports a model for RRMS in children with an apparent iron-deficient biochemical subtype of MS, with oligodendrocyte cell death and impaired myelination possibly caused by deficits of energy- and antioxidant capacity in mitochondria. Keywords: Pediatric onset multiple sclerosis, Genetic variants, Whole exome sequencing, Iron deficiency, Oxidative stress, Mitochondri
Genomic medicine and risk prediction across the disease spectrum
Genomic medicine is based on the knowledge that virtually every medical condition, disease
susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic
testing may therefore add value across the disease spectrum, ranging from single-gene
disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical
factors for genomic risk prediction are to determine: (1) where the genomic footprint of a
particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the
genetic determinants are modified by environmental exposures. Regarding the small subset of
highly penetrant monogenic disorders, a positive family history and early disease onset are
mostly sufficient to determine the appropriateness of genetic testing in the index case and to
inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic noncommunicable
diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a
balance between benefit and risk. An additional screening step may therefore be necessary to
identify individuals most likely to benefit from genetic testing. This need provided the stimulus
for the development of a pathology-supported genetic testing (PSGT) service as a new model
for the translational implementation of genomic medicine in clinical practice. PSGT is linked to
the establishment of a research database proven to be an invaluable resource for the validation
of novel and previously described gene-disease associations replicated in the South African
population for a broad range of NCDs associated with increased cardio-metabolic risk. The
clinical importance of inquiry concerning family history in determining eligibility for
personalized genotyping was supported beyond its current limited role in diagnosing or
screening for monogenic subtypes of NCDs. With the recent introduction of advanced
microarray-based breast cancer subtyping, genetic testing has extended beyond the genome
of the host to also include tumor gene expression profiling for chemotherapy selection. The
decreasing cost of next generation sequencing over recent years, together with improvement
of both laboratory and computational protocols, enables the mapping of rare genetic disorders
and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic
boundaries. This article reviews the challenges, successes, increasing inter-disciplinary
integration and evolving strategies for extending PSGT towards exome and whole genome
sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighte