- Letter to the Editor
- Open Access
Genetics of chronic nonbacterial osteomyelitis in the irish population: no significant association with rare FBLIM1 variants
Pediatric Rheumatology volume 19, Article number: 32 (2021)
We read with interest the recent article by d’Adamo et al. demonstrating a high prevalence of rare FBLIM1 gene variants in an Italian cohort with CNO . This showed 22 % of 80 patients with CNO carried at least one rare variant in FBLIM1 with a gnomAD global minor allele frequency (MAF) less than 0.02. The FBLIM1 gene was first implicated in the pathogenesis of CNO by Cox et al. who identified rare variants in 2 patients of South East Asian descent, one of whom had consanguineous parents resulting in a recessively inherited form of the disease . In addition, there was statistically significant enrichment of a nonsynonymous missense variant rs114077715 (p.Gly311Arg) in a European-American population with CNO . These findings in the context of Fblim1 expression of in the cmo murine model suggested a role either for these FBLIM1 variants or a variant in close linkage disequilibrium to them in the pathogenesis of CNO. In the Italian cohort, the MAF of rs114077715 was 0.013, which was not significantly enriched compared to the gnomAD global MAF of 0.019 (odds ratio 0.64, p = 0.77). The MAF of the synonymous variant rs140170023 was 0.063, which was statistically significantly enriched compared to the gnomAD global allele count of 2993/253,068 or MAF of 0.012 (odds ratio 5.64, p = 2.2 × 10− 5).
Sporadic forms of chronic nonbacterial osteomyelitis (CNO) demonstrate significant clinical heterogeneity between cohorts; from unifocal, non-recurrent disease to recurrent multifocal disease and disease associated with extraosseous inflammatory manifestations similar to synovitis acne hyperostosis osteitis (SAPHO) syndrome . This clinical heterogeneity may reflect a similar genetic heterogeneity. Assmann et al. demonstrated that FBLIM1 variants do not appear to play a significant role in the pathogenesis of SAPHO syndrome in a European population which also included a small number of patients with CNO ; disease heterogeneity may explain the lack of association in this cohort .
In order to ascertain the frequency of variants in FBLIM1 in an Irish cohort of patients with CNO compared to the gnomAD non-Finnish European (gnomAD NFE) population, we have recruited 43 Irish children and adolescents with CNO currently attending paediatric rheumatology services. Ethical approval for this study was obtained from Children’s Health Ireland (CHI) at Crumlin (GEN/572/17) and CHI at Temple St (17.075). All participants met the Bristol criteria for diagnosis of CNO  and all were ethnically Irish. Whole exome sequencing was performed using Agilent SureSelect XT Human All Exon V6 kits and Illumina HiSeq 3000 with 150 bp paired-end reads. Reads were aligned to the hg19 reference genome using BWA software , duplicates removed using Picard tools and GATK software  used to realign indels and call variants. The resulting VCF files were annotated using wAnnovar. Rarer variants with a gnomAD NFE minor allele frequency (MAF) </= 0.05, were hard filtered for mapping quality (MQ > 40) and depth of coverage (QD > 2). A MAF of < 0.05 was selected in order to include previously published candidate variants. Statistical analysis was performed in RStudio (version 1.1.456) using Fisher exact test.
Only 5/43 (11.62 %) individuals had variants in FBLIM1 with MAF < 0.02 each of whom carried a single variant in a heterozygous state. Four carried the missense variant rs114077715 (p.Gly311Arg) indicating a MAF in this population of 0.0465 with no significant enrichment (gnomAD NFE MAF = 0.0264, OR 1.79, p = 0.29). One carried the synonymous minor allele rs140170023 indicating a similar MAF to that reported in gnomAD (NFE MAF = 0.017). No variants were present with a MAF between 0.03 and 0.05.
In conclusion, variants in FBLIM1 do not occur at a significantly higher prevalence than expected in the Irish paediatric population with CNO compared to gnomAD non-Finnish European allele frequencies. This does not exclude a role for FBLIM1 variants in the pathogenesis of CNO in certain populations but may suggest genetic differences related to ethnicity or clinical phenotype.
Availability of data and materials
The data and materials from this study can be made available on request.
Chronic nonbacterial osteomyelitis
Synovitis acne hyperostosis osteitis
Minor allele frequency
Depth of coverage
d’Adamo AP, Bianco AM, Ferrara G, La Bianca M, Insalaco A, Tommasini A, et al. High prevalence of rare FBLIM1 gene variants in an Italian cohort of patients with Chronic Non-bacterial Osteomyelitis (CNO). Pediatr Rheumatol Online J. 2020 Jul 10;18(1):55.
Cox AJ, Darbro BW, Laxer RM, Velez G, Bing X, Finer AL, et al. Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO). PLoS One. 2017;12(3):e0169687.
Girschick H, Finetti M, Orlando F, Schalm S, Insalaco A, Ganser G, et al. The multifaceted presentation of chronic recurrent multifocal osteomyelitis: A series of 486 cases from the Eurofever international registry. Rheumatol (United Kingdom). 2018;57(7).
Assmann G, Köhm M, Schuster V, Behrens F, Mössner R, Magnolo N, et al. Genetic variants in FBLIM1 gene do not contribute to SAPHO syndrome and chronic recurrent multifocal osteomyelitis in typical patient groups. BMC Med Genet. 2020 Dec 12;21(1):102.
Roderick MR, Ramanan AV. Chronic recurrent multifocal osteomyelitis. Adv Exp Med Biol. 2013;764:99–107.
Li H, Durbin R. Fast and accurate long-read alignment with Burrows–Wheeler transform. Bioinformatics. 2010 Mar 1;26(5):589–95.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010 Sep 1;20(9):1297–303.
The authors wish to acknowledge the participants and their parents for agreeing to participate in this study.
Funding was received from the National Children’s Research Centre (grant number G/17/1) and the UCD Foundation AbbVie SOBI Nordic Pharma Newman Fellowship in Rheumatology.
Ethics approval and consent to participate
Ethical approval for this study was obtained from Children’s Health Ireland (CHI) Research and Ethics committees at Crumlin (REC GEN/572/17) and Temple Street (Reference 17.075).
Consent for publication
Written consent was obtained from all parents/guardians and participants age > 18 years of age. Written assent was obtained from all participants age < 18 years.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
O’Leary, D., Killeen, O.G. & Wilson, A.G. Genetics of chronic nonbacterial osteomyelitis in the irish population: no significant association with rare FBLIM1 variants. Pediatr Rheumatol 19, 32 (2021). https://doi.org/10.1186/s12969-021-00533-1
- Chronic nonbacterial osteomyelitis
- Chronic recurrent multifocal osteomyelitis
- FBLIM1 gene