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

Eur J Hum Genet. 2016 Aug;24(9):1274-9. doi: 10.1038/ejhg.2015.285. Epub 2016 Jan 27.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 5 / genetics
  • Adolescent
  • Consanguinity
  • Female
  • Humans
  • Hypercholesterolemia / complications
  • Hypercholesterolemia / diagnosis
  • Hypercholesterolemia / genetics*
  • Hypothyroidism / complications
  • Hypothyroidism / diagnosis
  • Hypothyroidism / genetics*
  • Intestinal Diseases / complications
  • Intestinal Diseases / diagnosis
  • Intestinal Diseases / genetics*
  • Lipid Metabolism, Inborn Errors / complications
  • Lipid Metabolism, Inborn Errors / diagnosis
  • Lipid Metabolism, Inborn Errors / genetics*
  • Lipoproteins / genetics
  • Magnesium Deficiency / complications
  • Magnesium Deficiency / diagnosis
  • Magnesium Deficiency / genetics*
  • Male
  • Mutation*
  • Pedigree
  • Phenotype*
  • Phytosterols / adverse effects*
  • Phytosterols / genetics
  • RNA Splicing
  • TRPM Cation Channels / genetics
  • Thyroglobulin / genetics
  • Young Adult


  • ABCG5 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • Lipoproteins
  • Phytosterols
  • TRPM Cation Channels
  • TRPM6 protein, human
  • Thyroglobulin

Supplementary concepts

  • Sitosterolemia