Human Genetics

, Volume 137, Issue 9, pp 705–716 | Cite as

Whole-exome sequencing identifies rare genetic variations in German families with pulmonary sarcoidosis

  • Amit Kishore
  • Britt-Sabina Petersen
  • Marcel Nutsua
  • Joachim Müller-Quernheim
  • Andre Franke
  • Annegret Fischer
  • Stefan SchreiberEmail author
  • Martin PetrekEmail author
Original Investigation


Genome-wide and candidate gene studies for pulmonary sarcoidosis have highlighted several candidate variants among different populations. However, the genetic basis of functional rare variants in sarcoidosis still needs to be explored. To identify functional rare variants in sarcoidosis, we sequenced exomes of 22 sarcoidosis cases from six families. Variants were prioritized using linkage and high-penetrance approaches, and filtered to identify novel and rare variants. Functional networking and pathway analysis of identified variants was performed using gene ontology based gene–phenotype, gene–gene, and protein–protein interactions. The linkage (n = 1007–7640) and high-penetrance (n = 11,432) prioritized variants were filtered to select variants with (a) reported allele frequency < 5% in databases (1.2–3.4%) or (b) novel (0.7–2.3%). Further selection based on functional properties and validation revealed a panel of 40 functional rare variants (33 from linkage region, 6 highly penetrant and 1 shared by both approaches). Functional network analysis implicated these gene variants in immune responses, such as regulation of pro-inflammatory cytokines including production of IFN-γ and anti-inflammatory cytokine IL-10, leukocyte proliferation, bacterial defence, and vesicle-mediated transport. The KEGG pathway analysis indicated inflammatory bowel disease as most relevant. This study highlights the subsets of functional rare gene variants involved in pulmonary sarcoidosis, such as, regulations of calcium ions, G-protein-coupled receptor, and immune system including retinoic acid binding. The implicated mechanisms in etiopathogenesis of familial sarcoidosis thus include Wnt signalling, inflammation mediated by chemokine and cytokine signalling and cadherin signalling pathways.



Annotate variation


Database for annotation visualization and integrated discovery


NCBI single nucleotide polymorphism database

EASE score

Expression analysis systemic explorer score


Gene multiple association network integration algorithm


Gene ontology


Leucine-rich repeats


Protein annotation through evolutionary relationship


Protein–protein interactions


Search tool for the retrieval of interacting genes/proteins


Whole-exome sequencing



The authors thank Prof. Manfred Schürmann, Institute of Human Genetics, University of Lübeck, for his involvement in the study subject characterisation; Dr. Kumari Neelam, Punjab Agricultural University, Ludhiana, for her helpful suggestions in the manuscript; and to the Sequencing and Genotyping Core Facilities at IKMB for the technical support. The authors were supported by the DFG Cluster of Excellence “Inflammation at Interfaces”, the Deutsche Forschungsgemeinschaft (DFG) Grant EXC 306 (present responsible person: prof. D. Ellinghaus); DFG “Systematic identification and modelling of rare and common genetic risk factors for sarcoidosis” Grant FI 1935/1-1; and the Grants NV18-05-00134, IGA_LF_2018_015 (Czech Republic).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding authors state that there is no conflict of interest.

Supplementary material

439_2018_1915_MOESM1_ESM.docx (2.7 mb)
Supplementary material 1 (DOCX 2787 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Amit Kishore
    • 1
    • 2
  • Britt-Sabina Petersen
    • 1
  • Marcel Nutsua
    • 1
  • Joachim Müller-Quernheim
    • 3
  • Andre Franke
    • 1
  • Annegret Fischer
    • 1
  • Stefan Schreiber
    • 1
    • 4
    Email author
  • Martin Petrek
    • 2
    Email author
  1. 1.Institute of Clinical Molecular BiologyKiel UniversityKielGermany
  2. 2.Department of Pathological Physiology, Faculty of Medicine and DentistryPalacky UniversityOlomoucCzech Republic
  3. 3.Department of Pneumology, Medical Center, Faculty of MedicineUniversity of FreiburgFreiburgGermany
  4. 4.Clinic of Internal Medicine IUniversity Hospital Schleswig-HolsteinKielGermany

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