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COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA

COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA

Title: COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA
Author: Jensson, Brynjar Örn
Hansdottir, Sif   orcid.org/0000-0002-8485-1106
Arnadottir, Gudny   orcid.org/0000-0001-6571-423X
Sulem, Gerald
Kristjansson, Ragnar   orcid.org/0000-0002-3678-5693
Oddsson, Asmundur   orcid.org/0000-0002-4606-5163
Benonisdottir, Stefania   orcid.org/0000-0001-5019-514X
Jónsson, Hákon   orcid.org/0000-0001-6197-494X
Helgason, Agnar
Sæmundsdóttir, Jóna
... 15 more authors Show all authors
Date: 2017-11-14
Language: English
Scope: 129
University/Institute: Háskóli Íslands
University of Iceland
School: Félagsvísindasvið (HÍ)
School of Social Sciences (UI)
Verkfræði- og náttúruvísindasvið (HÍ)
School of Engineering and Natural Sciences (UI)
Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Félags- og mannvísindadeild (HÍ)
Faculty of Social and Human Sciences (UI)
Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: BMC Medical Genetics;18(1)
ISSN: 1471-2350
DOI: 10.1186/s12881-017-0490-8
Subject: Genetics; Erfðagreining; Lungnasjúkdómar; Erfðafræði; Rannsóknir
URI: https://hdl.handle.net/20.500.11815/470

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Jensson, B. O., Hansdottir, S., Arnadottir, G. A., Sulem, G., Kristjansson, R. P., Oddsson, A., . . . Stefansson, K. (2017). COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA. BMC Medical Genetics, 18(1), 129. doi:10.1186/s12881-017-0490-8


Background: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. Case presentation: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. Conclusions: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome. Keywords: COPA syndrome, Lung disease, Arthritis, Immune dysregulation, Case report


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