engleski

The Challenges of Genetic Testing in Children with Suspected Periodic Fever Syndromes

Objectives: Establishing a genetic diagnosis in children with periodic fever syndromes can be challenging. Availability of genetic testing is variable, different testing panels are used, and majority of patients have negative testing or a variant of unclear significance (VUS). We describe genetic testing results of a prospective cohort of children with suspected periodic fever syndromes seen in a provincial pediatric Auto-Inflammatory Diseases clinic in British Columbia (BC). Methods: Auto-Inflammatory Diseases clinic was established in 2016 in Rheumatology, BC Children’s Hospital (BCCH), Vancouver, BC. Until September 2018, 94 patients have been evaluated and enrolled in a longitu- dinal registry, collecting clinical and laboratory data. Gene screening for MEFV, MVK, and TNFRSP1A was available at BCCH Molecular Genetics Laboratory (MGL) ; more extensive gene testing was limited, out of-province and funding dependent, done at GeneDX, MNG labs and Hospital for Sick Children (HSC). Summary results of genetic testing performed in BCCH MGL is reported here. Results: Genetic testing was performed in three quarter of patients (71/94). Mean age of tested patients was 8.2 years (IQR 4.9-11.9 years) and 67.6% were female. Out-of-province testing, including whole exome sequencing and gene panels, was performed in 10 patients, while three patients came to the clinic with out-of-country results of the single gene sequencing. Total of 66 patients were tested in BCCH MGL ; MEFV was sequenced in 61, TNFSR1 in 48 and MVK in 45 patients. In those patients, sequencing of MEFV revealed one homozygous (p.Met694Val) and four heterozygous (p.Met694Val, p.Lys695Arg, p.Glu148Gln, p.Val726Ala) pathogenic or likely pathogenic variants in nine patients, two compound heterozygous VUS (Pro369Ser/Arg408Gln and p.Glu148Gln/p.Leu110Pro) in four patients and two heterozygous VUS (p.Val469Ala and p.Glu248Gln) in two patients. The most common pathogenic variants in MEFV gene were p.Glu148Gln and p.Met694Val seen in three patients each. Sequencing of TNFSR1 revealed one heterozygous pathogenic variant (p.Cys72Tyr) in one patient, three heterozygous VUS (p.Arg121Gln, pThr276Ser and p.Leu359=) in five patients and one heterozygous likely benign variant (p.Pro75Leu) in one patient. Finally, sequencing of MVK revealed two compound heterozygous pathogenic variants (p.Trp188/p.val377Ile and p.Val377Ile/p.Arg215Ter) in one patient each and heterozygous VUS (p.Leu308=) in two patients. Conclusion: Pathogenic variants causing three most common autoinflam- matory diseases (FMF, MKD and TRAPS) were discovered in 18.2% of tested patients. Additionally, 19.7% of patients had VUS in associated genes. The majority of patients did not have an identified pathologic variant, although they had clinical symptoms of a periodic fever syndrome.

Periodic Fever Syndroms

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