Against all odds: blended phenotypes of three single-gene defects
| Autor: | Ekkehart Lausch, Bernhard Zabel, Tanja Velten, Sarah C. Grünert, Dieter Lütjohann, Karl Otfried Schwab, Anika Salfelder, Uta Matysiak-Scholze, Yong Li, Anna Köttgen, Pablo Villavicencio-Lorini |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Adolescent Lipoproteins RNA Splicing Hypercholesterolemia TRPM Cation Channels Biology Bioinformatics Thyroglobulin Lipid Metabolism Inborn Errors Article Consanguinity Young Adult 03 medical and health sciences Exon 0302 clinical medicine Hypothyroidism Genetic linkage Molecular genetics TRPM6 Genetics medicine Humans ATP Binding Cassette Transporter Subfamily G Member 5 Gene Genetics (clinical) Phytosterols medicine.disease Human genetics Pedigree Intestinal Diseases Phenotype 030104 developmental biology 030220 oncology & carcinogenesis Mutation Medical genetics Female Magnesium Deficiency Sitosterolemia |
| Zdroj: | European Journal of Human Genetics. 24:1274-1279 |
| ISSN: | 1476-5438 1018-4813 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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