What is FUO?

FUO is acronym for Fever of Unknown Origin. FUO has been first defined by Petersdorf and Beeson in 1961 as a fever lasting more than 3 weeks, with a temperature over 38.3 °C on several occasions.

FUO still represents a challlenge for Diagnostics in several clinical cases.

Apart from infective, autoimmune and other frequent cases, FUO may actually be genetic as well! 

In this post we’ll review the genes which are most commonly associated to FUO. These genes can all be tested by Whole Exome Sequencing (WES), that can help identifying well known genetic causes of fever, as well as other conditions with an occasionally atypical presentation characterized by fever.

Genes associated with FUO

There are some genetic conditions which are typically characterized by episodes of fever and other conditions where fever is less common, so they may go underdiagnosed or misdiagnosed.

Let’s have a look to some genes:

CFTR: in rare cases, especially if combined with the 5T allele (here’s our LinkedIn post on 5T), a classic heterozygous mutation (severe mutation) in the CFTR gene may cause non-classic cystic fibrosis, causing bronchiectasis and other respiratory symptoms, sometimes with fever.

MEFV: familial Mediterranean fever is another genetic disorder, characterized by recurrent short episodes of inflammation and serositis including fever.

ADGRV1: this is a candidate gene for familial febrile seizures type 4 and variants have been already detected in patients with FUO.

THBD: the gene is associated to thrombophilia 12, which might predispose to pulmonary embolism.

GATA2: mutations cause Immunodeficiency 21.

TYK2: known for the susceptibility to mycobacterial disease.

RIPK1: Autoinflammation with episodic fever and lymphadenopathy.

ADA2: Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome.

Then we have the genes associated with AutoInflammatory Disease – AID (PSMB4, PSMB8, PSMB9, POMP, PSMB10, and PSMG2) and with genetic Immunodeficiencies.

Then we have NTRK1, associated to congenital insensitivity to pain with anhidrosis (CIPA), where recurrent episodes of unexplained fever are possible. Then Hyper-IgD syndrome (MVK gene mutations).

Finally a surprise: Fabry disease! Yes, Fabry disease (GLA mutations, X-linked) may be misdiagnosed for years and, in some cases, it may present with intermittent fever in association with acrodynia or arthralgia.

Other genes?

The aforementioned list of genes is probably incomplete, that’s why the whole exome sequencing (o whole genome sequencing – WGS) approach is recommeded in identifying the causes of FUO. Also of note: in addition to the known genes, new genetic loci may be identified in future as being associated twith FUO. Because, once sequenced, a patient’s WES and WGS can also be reanalyzed in the years to come, the search for a final diagnosis may be repeated also inthose cases where the first run of analyses was negative.

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Wanru Guo et al. The Application of Whole-Exome Sequencing in Patients With FUO – Front Cell Infect Microbiol. 2022 Jan 12;11:783568. doi: 10.3389/fcimb.2021.783568. eCollection 2021.

Yuting Tan et al. Clinical features and outcomes of patients with fever of unknown origin: a retrospective study – BMC Infect Dis. 2019 Feb 27;19(1):198. doi: 10.1186/s12879-019-3834-5.

Ti Luo et al. Recurrent fever of unknown origin: An overlooked symptom of Fabry disease – Mol Genet Genomic Med. 2020 Oct;8(10):e1454. doi: 10.1002/mgg3.1454.

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Genereviews at large (https://www.ncbi.nlm.nih.gov/books/NBK1116/?term=)


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