Abstract
Whole-exome sequencing allows for an unbiased and comprehensive mutation screening. Although successfully used to facilitate the diagnosis of single-gene disorders, the genetic cause(s) of a substantial proportion of presumed monogenic diseases remain to be identified. We used whole-exome sequencing to examine offspring from a consanguineous marriage featuring a novel combination of congenital hypothyroidism, hypomagnesemia and hypercholesterolemia. Rather than identifying one causative variant, we report the first instance in which three independent autosomal-recessive single-gene disorders were identified in one patient. Together, the causal variants give rise to a blended and seemingly novel phenotype: we experimentally characterized a novel splice variant in the thyroglobulin gene (c.638+5G>A), resulting in skipping of exon 5, and detected a pathogenic splice variant in the magnesium transporter gene TRPM6 (c.2667+1G>A), causing familial hypomagnesemia. Based on the third variant, a stop variant in ABCG5 (p.(Arg446*)), we established a diagnosis of sitosterolemia, confirmed by elevated blood plant sterol levels and successfully initiated targeted lipid-lowering treatment. We propose that blended phenotypes resulting from several concomitant single-gene disorders in the same patient likely account for a proportion of presumed monogenic disorders of currently unknown cause and contribute to variable genotype-phenotype correlations.
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Acknowledgements
YL and AK were funded by the Emmy Noether Programme of the German Research Foundation (KO 3598/2–1). EL and BZ are supported by national and EU-funded Rare Disease Network Programmes FACE (agreement no. 01GM1109A, TP1); SYBIL (FP7 grant agreement no. 602300) and INTERREG IV project A27 to EL. The work of AK and EL was additionally funded through the German Research Foundation (CRC 1140). We thank Anja Kerksiek for excellent technical assistance. We thank the patients and their family members for the participation in this study.
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Li, Y., Salfelder, A., Schwab, K. et al. Against all odds: blended phenotypes of three single-gene defects. Eur J Hum Genet 24, 1274–1279 (2016). https://doi.org/10.1038/ejhg.2015.285
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DOI: https://doi.org/10.1038/ejhg.2015.285
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