An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Sacha Ferdinandusse, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands. s.ferdinandusse@amsterdamumc.nl.
Kirsty McWalter, GeneDx, Gaithersburg, MD, USA.
Heleen Te Brinke, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Lodewijk IJlst, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Petra M. Mooijer, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Jos P. Ruiter, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Alida E. van Lint, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Mia Pras-Raves, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Eric Wever, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Francisca Millan, GeneDx, Gaithersburg, MD, USA.
Maria J. Guillen Sacoto, GeneDx, Gaithersburg, MD, USA.
Amber Begtrup, GeneDx, Gaithersburg, MD, USA.
Mark Tarnopolsky, Department of Pediatrics, McMaster University Children's Hospital, Hamilton, ON, Canada.
Lauren Brady, Department of Pediatrics, McMaster University Children's Hospital, Hamilton, ON, Canada.
Roger L. Ladda, Department of Pediatrics, Penn State Children's Hospital, Hershey, PA, USA.
Susan L. Sell, Department of Pediatrics, Penn State Children's Hospital, Hershey, PA, USA.
Catherine B. Nowak, The Feingold Center for Children, Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Jessica Douglas, The Feingold Center for Children, Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Cuixia Tian, Division of Neurology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Elizabeth Ulm, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Seth Perlman, Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
Arlene V. Drack, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
Karen Chong, Mount Sinai Hospital, Department of Obstetrics and Gynecology, Prenatal Diagnosis and Medical Genetics Program, Toronto, ON, Canada.
Nicole Martin, Mount Sinai Hospital, Department of Obstetrics and Gynecology, Prenatal Diagnosis and Medical Genetics Program, Toronto, ON, Canada.
Jennifer Brault, Vanderbilt University Medical Center, Department of Pediatrics, Nashville, TN, USA.
Elly Brokamp, Vanderbilt University Medical Center, Department of Pediatrics, Nashville, TN, USA.
Camilo Toro, NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
William A. Gahl, NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Ellen F. Macnamara, NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Lynne Wolfe, NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.

Abstract

PURPOSE: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). METHODS: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. RESULTS: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. CONCLUSION: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.