Genomics | Bioinformatics | Medical Genetics
Using VAAST and massively parallel sequencing to characterize a novel disorder caused by protein N-terminal acetyltransferase deficiency
Alan F Rope, Kai Wang, Rune Evjenth, Jinchuan Xing, Jennifer J Johnston, Jeffrey J Swensen, W Evan Johnson, Barry Moore, Chad D Huff, Lynne M Bird, John C Carey, John M Opitz, Cathy A Stevens, Christa Schank, Tao Jiang, Heidi Fain, Reid Robison, Brian Dalley, Steven Chin, Sarah T South, Theodore J Pysher, Lynn B Jorde, Hakon Hakonarson, Johan R Lillehaug, Leslie G Biesecker, Mark Yandell, Thomas Arnesen, Gholson J Lyon*
*Corresponding author: Gholson J Lyon
Utah Foundation for Biomedical Research, University of Utah, Salt Lake City, UT, USA
Children's Hospital of Philadelphia, Philadelphia, PA, USA
F1000Posters 2012, 3: 22 (poster) [English]
2nd Annual Beyond The Genome Conference 2011, 19 - 22 Sep 2011, 13
We have identified two families with a previously undescribed lethal X-linked disorder of infancy comprising a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, cardiac arrhythmia, and cardiomyopathy. We used X-chromosome exon sequencing and the Variant Annotation, Analysis and Search Tool (VAAST), a recently developed probabilistic disease-gene discovery algorithm, to identify a c.109T greater than C (p.Ser37Pro) variant in NAA10 (OMIM 300013), 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 approximately 6000 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.
We conclude that a reduction in acetylation by hNaa10p causes this disease. This is the first evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans. Our study also demonstrates that VAAST can efficiently identify disease-causing variants.
No relevant competing interests disclosed.
Please note that most posters on this site present work that is preliminary in nature and has not been peer reviewed.
This poster is open access subject to the CC BY-NC Creative Commons 3.0 License