Blue Elizabeth E, Huang Samuel J, Khan Alyna, Golden-Grant Katie, Boyd Brenna, Rosenthal Elisabeth A, Gillentine Madelyn A, Fleming Leah R, Adams David R, Wolfe Lynne, Allworth Aimee, Bamshad Michael J, Caruana Nikeisha J, Chanprasert Sirisak, Chen Jingheng, Dargie Nitsuh, Doherty Daniel, Friederich Marisa W, Hisama Fuki M, Horike-Pyne Martha, Lee Jessica C, Donovan Tonia E, Hock Daniella H, Leppig Kathleen A, Miller Danny E, Mirzaa Ghayda, Ranchalis Jane, Raskind Wendy H, Michel Cole R, Reisdorph Richard, Schwarze Ulrike, Sheppeard Sam, Strohbehn Samuel, Stroud David A, Sybert Virginia P, Wener Mark H, Stergachis Andrew B, Lam Christina T, Jarvik Gail P, Dipple Katrina M, Van Hove Johan L K, Glass Ian A
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Institute for Public Health Genetics, University of Washington, Seattle, WA 98195, USA.
Rare. 2024;2. doi: 10.1016/j.rare.2024.100040. Epub 2024 Aug 14.
Biallelic pathogenic variants in underlie a rare form of isolated mitochondrial complex III deficiency associated with lactic acidosis and a distinctive scalp alopecia previously described in two unrelated probands. Here, we describe a participant in the Undiagnosed Diseases Network (UDN) with a dual diagnosis of two autosomal recessive disorders revealed by genome sequencing: -related mitochondrial complex III deficiency and -related cataracts. Both pathogenic variants have been reported before: (NM_006003.3:c.215-1 G>C, p.Val72_Thr81del10) in a case with mitochondrial complex III deficiency and (NM 005267.5:c.736 G>T, p.Glu246*) as a somatic change in aged cornea leading to decreased junctional coupling. A multi-modal approach combining enzyme assays and cellular proteomics analysis provided clear evidence of complex III respiratory chain dysfunction and low abundance of the Rieske iron-sulfur protein, validating the pathogenic effect of the variant. This report extends the genotypic and phenotypic spectrum for these two rare disorders and highlights the utility of deep phenotyping and genomics data to achieve diagnosis and insights into rare disease.
双等位基因致病性变异是一种罕见的孤立性线粒体复合物III缺乏症的基础，该缺乏症与乳酸性酸中毒以及先前在两名无亲缘关系的先证者中描述的一种独特的头皮脱发有关。在此，我们描述了未确诊疾病网络（UDN）中的一名参与者，通过基因组测序揭示其患有两种常染色体隐性疾病的双重诊断：与 相关的线粒体复合物III缺乏症和与 相关的白内障。这两种致病性变异之前均有报道：线粒体复合物III缺乏症病例中的 （NM_006003.3:c.215-1 G>C, p.Val72_Thr81del10）以及老年角膜中作为体细胞变化导致连接偶联减少的 （NM 005267.5:c.736 G>T, p.Glu246*）。结合酶分析和细胞蛋白质组学分析的多模式方法提供了复合物III呼吸链功能障碍以及 Rieske 铁硫蛋白丰度低的明确证据，证实了 变异的致病作用。本报告扩展了这两种罕见疾病的基因型和表型谱，并强调了深度表型分析和基因组学数据在实现罕见病诊断和深入了解方面的效用。
