Against all odds: blended phenotypes of three single-gene defects
Against all odds: blended phenotypes of three single-gene defects
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DOI：
10.1038/ejhg.2015.285
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发表时间：
2016-09-01
影响因子：
5.2
通讯作者：
Lausch, Ekkehart
中科院分区：
文献类型：
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作者：
Li, Yong;Salfelder, Anika;Lausch, Ekkehart
全外显子组测序允许公正和全面的突变筛选。虽然成功地用于促进单基因疾病的诊断，但很大一部分假定的单基因疾病的遗传原因仍有待确定。我们使用全外显子组测序来检查具有先天性甲状腺功能减退、低镁血症和高胆固醇血症新组合的近亲婚姻的后代。而不是确定一个致病变异，我们报告的第一个实例，其中三个独立的常染色体隐性单基因疾病在一个病人被确定。总之，这些因果变异产生了一种混合的、看似新颖的表型：我们通过实验表征了甲状腺球蛋白基因（c.638+5G> a）中的一种新的剪接变异，导致外显子5的跳变，并在镁转运基因TRPM6 （c.2667+1G> a）中检测到一种致病性剪接变异，导致家族性低镁血症。基于第三个变体，ABCG5中的一个停止变体（p.(Arg446(star))），我们通过升高的血液植物固醇水平确定了谷固醇血症的诊断，并成功启动了靶向降脂治疗。我们提出，在同一患者中，由几种伴随的单基因疾病导致的混合表型可能占目前未知原因的推定单基因疾病的一部分，并导致可变的基因型-表型相关性。
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(star))), 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.