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Case Reports
. 2017 Nov 14;18(1):129.
doi: 10.1186/s12881-017-0490-8.

COPA Syndrome in an Icelandic Family Caused by a Recurrent Missense Mutation in COPA

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Free PMC article
Case Reports

COPA Syndrome in an Icelandic Family Caused by a Recurrent Missense Mutation in COPA

Brynjar O Jensson et al. BMC Med Genet. .
Free PMC article

Abstract

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: Arthritis; COPA syndrome; Case report; Immune dysregulation; Lung disease.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the National Bioethics Committee in Iceland. Written, informed consent to participate was obtained for all participants, or their guardians, before blood samples were drawn.

Consent for publication

All participants, or their guardians, provided written informed consent for publication of medical data, medical imaging and genetic data.

Competing interests

The authors affiliated with deCODE Genetics are employed by the company, which is owned by Amgen, Inc.: BOJ, GAA, GS, RPK, AO, SB, HJ, AH, GM, GAT, JS, OTM, ADJ, AJ, AS, IJ, DFG, UT, PS, and KS. The following authors declare no conflict of interest: SH, VP, JRK, RA, and GG.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Illustration of the COPA protein. Previously reported mutations in COPA (Watkin et al., 2015) all cluster within a 14 amino acid stretch in the COPA protein. The mutation detected in the Icelandic pedigree is listed in red. The current report marks the second observation of the p.Glu241Lys mutation
Fig. 2
Fig. 2
The three-generation family. Shown are genotypes of the COPA mutation (W: wild-type allele, M: mutated allele). Blackened symbols denote affected individuals, unblackened symbols denote unaffected individuals, and the slashed line denotes deceased. The genotypes of the siblings of the index case (II-3) were obtained with Sanger sequencing and the other six family members were whole-genome sequenced

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