Against all odds: blended phenotypes of three single-gene defects

European Journal of Human Genetics : EJHG
Yong LiEkkehart Lausch

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 se...Continue Reading

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Citations

Apr 30, 2016·Human Genetics·Anne H O'Donnell-Luria, David T Miller
Aug 31, 2016·Expert Review of Molecular Diagnostics·Anna Maria PintoAlessandra Renieri
Mar 3, 2017·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Dustin BaldridgeMarwan Shinawi
Mar 23, 2017·European Journal of Human Genetics : EJHG·Alistair T PagnamentaUsha Kini
Jan 26, 2018·The British Journal of Ophthalmology·Marta de Castro-MiróRoser Gonzàlez-Duarte
Jul 11, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Natasha T StrandeJonathan S Berg
Aug 9, 2019·JIMD Reports·Lara VeitJohannes Häberle
Jun 14, 2021·Molecular and Cellular Endocrinology·Mauricio Gomes PioHéctor M Targovnik
Jul 27, 2021·Journal of Clinical Lipidology·Zühre KayaAziz Tekin

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