Table 2

Guidelines for reporting and interpreting genetic results in the four main HRFs

Report of resultsInterpretation
Patients with symptoms
 Recessive diseases (FMF or MKD)
  Two clearly pathogenic variants
   PhasedThe patient is (homozygote or compound heterozygote) for two clearly pathogenic variants in the (MEFV/MVK) geneThis genotype confirms clinical diagnosis of (FMF/MKD). If relevant add: and is generally associated with a (mild or severe) phenotype
   Not phasedTwo clearly pathogenic variants were identified in the (MEFV/MVK) gene. They have (never/already) been reported in cis (complex allele)This genetic result is consistent with clinical diagnosis of (FMF/MKD). Parental testing should resolve the issue of complex allele. If relevant add: proven homozygosity or compound heterozygosity with these two variants is generally associated with a (mild or severe) phenotype
  One clearly pathogenic and one VUS
   PhasedThe patient is compound heterozygote for one clearly pathogenic variant and one variant of uncertain clinical significance in the (MEFV/MVK) geneThis genotype could be consistent with clinical diagnosis of (FMF/MKD). If relevant add: and is generally associated with a (mild or severe) phenotype
   Not phasedOne clearly pathogenic mutation and one variant of uncertain clinical significance were identified in the (MEFV/MVK) gene. They have (never/already) been reported in cis (complex allele)This genetic result could be consistent with clinical diagnosis of (FMF/MKD). Parental testing should resolve the issue of complex allele. If relevant add: proven homozygosity or compound heterozygosity with these two variants is generally associated with a (mild or severe) phenotype
  Two VUS
   PhasedThe patient is (homozygote or compound heterozygote) for two variants of uncertain clinical significance in the (MEFV/MVK) geneDiagnosis relies on clinical judgement or criteria. If relevant add: possible association with a mild phenotype
   Not phasedTwo variants of uncertain clinical significance were identified in the (MEFV/MVK) geneDiagnosis relies on clinical judgement or criteria. Parental testing should resolve the issue of complex allele. If relevant add: possible association with a mild phenotype
  One clearly pathogenic variantOne clearly pathogenic variant was identified in the (MEFV/MVK) geneRare undetected variants may exist. Diagnosis relies on clinical judgement or criteria
  One VUS or no variantNo pathogenic or one variant of uncertain clinical significance was identified in the (MEFV/MVK)geneRare undetected variants may exist. Diagnosis relies on clinical judgement or criteria. Refer to an expert clinician to consider other HRFs
 Dominant diseases (TRAPS or CAPS)
  One clearly pathogenic variantOne clearly pathogenic variant was identified in the (TNFR1SF1A/NLRP3) geneThis genotype confirms clinical diagnosis of (TRAPS/CAPS). If relevant add: and is generally associated with a (mild/severe) phenotype
  One VUSOne variant of uncertain clinical significance was identified in the (TNFR1SF1A/NLRP3) gene.Diagnosis relies on clinical judgement or criteria. Refer to an expert clinician to consider other HRFs. If rare or new add: (parental testing/familial segregation) may help understanding the clinical significance of this variant
  No variantNo pathogenic variant was identified in the (TNFRSF1A/NLRP3)geneRare undetected variants may exist. Diagnosis relies on clinical judgement or criteria. Refer to an expert clinician to consider other HRFs
 Asymptomatic individuals
  Genotype consistent with HRFAdapt from aboveThe individual is at risk of developing symptoms of HRF. If relevant add: or inaugural renal amyloidosis. It is recommended that acute phase reactants (CRP, SAA) and the kidney function (urine analysis) be regularly monitored
 Recessive diseases (FMF or MKD)
  One sequence variantThe individual is a carrier for a (clearly pathogenic variant/variant of uncertain significance) in the (MEFV/MVK) geneThis individual is not likely to develop (MKD/FMF)
  • CRP, C reactive protein; SAA, serum amyloid A; VUS, variant of uncertain clinical significance (includes debated variants and rare and novel variants with no relevant information).