Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency |
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| Authors: | Rope Alan F Wang Kai Evjenth Rune Xing Jinchuan Johnston Jennifer J Swensen Jeffrey J Johnson W Evan Moore Barry Huff Chad D Bird Lynne M Carey John C Opitz John M Stevens Cathy A Jiang Tao Schank Christa Fain Heidi Deborah Robison Reid Dalley Brian Chin Steven South Sarah T Pysher Theodore J Jorde Lynn B Hakonarson Hakon Lillehaug Johan R Biesecker Leslie G Yandell Mark Arnesen Thomas Lyon Gholson J |
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| Institution: | 1Department of Pediatrics (Medical Genetics), University of Utah School of Medicine, Salt Lake City, UT 84112, USA;2Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA;3Department of Molecular Biology, University of Bergen, N–5020 Bergen, Norway;4Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA;5Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA;6Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA;7ARUP Laboratories, Salt Lake City, UT 84112, USA;8Department of Statistics, Brigham Young University, Provo, UT 84602, USA;9Rady Children's Hospital and University of California, San Diego, Department of Pediatrics, San Diego, CA 92123, USA;10Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT 84112, USA;11Department of Neurology, University of Utah, Salt Lake City, UT 84112, USA;12Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, TN 38163, USA;13BGI-Shenzhen, Shenzhen 518083, China;14Genome Research Institute, Shenzhen University Medical School, Shenzhen 518060, China;15Department of Psychiatry, University of Utah, Salt Lake City, UT 84112, USA;16Huntsman Cancer Institute, Salt Lake City, UT 84112, USA;17Department of Surgery, Haukeland University Hospital, N‐5021 Bergen, Norway;18New York University Child Study Center, New York, NY 10016, USA |
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| Abstract: | We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans. |
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