title: Against all odds: blended phenotypes of three single-gene defects.
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.
authors.affiliation: Renal Division, Department of Internal Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Salfelder
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Karl Otfried
authors.initials: KO
authors.lastname: Schwab
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Sarah Catharina
authors.initials: SC
authors.lastname: Grünert
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Velten
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Clinics of Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Pablo
authors.initials: P
authors.lastname: Villavicencio-Lorini
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Matysiak-Scholze
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.affiliation: Renal Division, Department of Internal Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
authors.affiliation: Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5 / Q000235:genetics; D000293:Adolescent; D003241:Consanguinity; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D007037:Hypothyroidism / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D007410:Intestinal Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008052:Lipid Metabolism, Inborn Errors / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008074:Lipoproteins / Q000235:genetics; D008275:Magnesium Deficiency / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010840:Phytosterols / Q000009:adverse effects* / Q000235:genetics; D012326:RNA Splicing; D050053:TRPM Cation Channels / Q000235:genetics; D013954:Thyroglobulin / Q000235:genetics; D055815:Young Adult
chemical_list: C416945:ABCG5 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D008074:Lipoproteins; D010840:Phytosterols; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D013954:Thyroglobulin
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