Rare (Jan 2024)
Dual diagnosis of UQCRFS1-related mitochondrial complex III deficiency and recessive GJA8-related cataracts
- Elizabeth E. Blue,
- Samuel J. Huang,
- Alyna Khan,
- Katie Golden-Grant,
- Brenna Boyd,
- Elisabeth A. Rosenthal,
- Madelyn A. Gillentine,
- Leah R. Fleming,
- David R. Adams,
- Lynne Wolfe,
- Aimee Allworth,
- Michael J. Bamshad,
- Nikeisha J. Caruana,
- Sirisak Chanprasert,
- Jingheng Chen,
- Nitsuh Dargie,
- Daniel Doherty,
- Marisa W. Friederich,
- Fuki M. Hisama,
- Martha Horike-Pyne,
- Jessica C. Lee,
- Tonia E. Donovan,
- Daniella H. Hock,
- Kathleen A. Leppig,
- Danny E. Miller,
- Ghayda Mirzaa,
- Jane Ranchalis,
- Wendy H. Raskind,
- Cole R. Michel,
- Richard Reisdorph,
- Ulrike Schwarze,
- Sam Sheppeard,
- Samuel Strohbehn,
- David A. Stroud,
- Virginia P. Sybert,
- Mark H. Wener,
- Andrew B. Stergachis,
- Christina T. Lam,
- Gail P. Jarvik,
- Katrina M. Dipple,
- Johan L.K. Van Hove,
- Ian A. Glass
Affiliations
- Elizabeth E. Blue
- 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; Brotman Baty Institute, Seattle, WA 98195, USA; Correspondence to: Division of Medical Genetics, Department of Medicine, University of Washington, 1959 NE Pacific St, BOX 357720, Seattle, WA 98195-7720, USA
- Samuel J. Huang
- Department of Medical Genetics, Marshfield Clinic, Marshfield, WI 54449, USA
- Alyna Khan
- Institute for Public Health Genetics, University of Washington, Seattle, WA 98195, USA
- Katie Golden-Grant
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Brenna Boyd
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA
- Elisabeth A. Rosenthal
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Madelyn A. Gillentine
- Department of Laboratories, Seattle Children's Hospital, Seattle, WA 98105, USA
- Leah R. Fleming
- Department of Genetics, Saint Luke's Genetics and Metabolic Clinic, Boise, ID 83712, USA
- David R. Adams
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA
- Lynne Wolfe
- NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA
- Aimee Allworth
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Michael J. Bamshad
- Brotman Baty Institute, Seattle, WA 98195, USA; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
- Nikeisha J. Caruana
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
- Sirisak Chanprasert
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Jingheng Chen
- Institute for Public Health Genetics, University of Washington, Seattle, WA 98195, USA
- Nitsuh Dargie
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Daniel Doherty
- Brotman Baty Institute, Seattle, WA 98195, USA; Division of Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
- Marisa W. Friederich
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA
- Fuki M. Hisama
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Martha Horike-Pyne
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Jessica C. Lee
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA
- Tonia E. Donovan
- Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA
- Daniella H. Hock
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia; Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Royal Children’s Hospital, Parkville, VIC, Australia
- Kathleen A. Leppig
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Danny E. Miller
- Brotman Baty Institute, Seattle, WA 98195, USA; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
- Ghayda Mirzaa
- Brotman Baty Institute, Seattle, WA 98195, USA; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
- Jane Ranchalis
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Wendy H. Raskind
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Cole R. Michel
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Richard Reisdorph
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Ulrike Schwarze
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
- Sam Sheppeard
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Samuel Strohbehn
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- David A. Stroud
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia; Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Royal Children’s Hospital, Parkville, VIC, Australia
- Virginia P. Sybert
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
- Mark H. Wener
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA; Department of Rheumatology, University of Washington, Seattle, WA 98195, USA
- Andrew B. Stergachis
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
- Christina T. Lam
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98105, USA
- Gail P. Jarvik
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
- Katrina M. Dipple
- Brotman Baty Institute, Seattle, WA 98195, USA; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA 98105, USA
- Johan L.K. Van Hove
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA
- Ian A. Glass
- Brotman Baty Institute, Seattle, WA 98195, USA; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
- Journal volume & issue
-
Vol. 2
p. 100040
Abstract
Biallelic pathogenic variants in UQCRFS1 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: UQCRFS1-related mitochondrial complex III deficiency and GJA8-related cataracts. Both pathogenic variants have been reported before: UQCRFS1 (NM_006003.3:c.215–1 G>C, p.Val72_Thr81del10) in a case with mitochondrial complex III deficiency and GJA8 (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 UQCRFS1 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.
