Guidelines for reporting and interpreting genetic results in the four main HRFs
| Report of results | Interpretation | |
|---|---|---|
| Patients with symptoms | ||
| Recessive diseases (FMF or MKD) | ||
| Two clearly pathogenic variants | ||
| Phased | The patient is (homozygote or compound heterozygote) for two clearly pathogenic variants in the (MEFV/MVK) gene | This genotype confirms clinical diagnosis of (FMF/MKD). If relevant add: and is generally associated with a (mild or severe) phenotype |
| Not phased | Two 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 | ||
| Phased | The patient is compound heterozygote for one clearly pathogenic variant and one variant of uncertain clinical significance in the (MEFV/MVK) gene | This genotype could be consistent with clinical diagnosis of (FMF/MKD). If relevant add: and is generally associated with a (mild or severe) phenotype |
| Not phased | One 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 | ||
| Phased | The patient is (homozygote or compound heterozygote) for two variants of uncertain clinical significance in the (MEFV/MVK) gene | Diagnosis relies on clinical judgement or criteria. If relevant add: possible association with a mild phenotype |
| Not phased | Two variants of uncertain clinical significance were identified in the (MEFV/MVK) gene | Diagnosis 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 variant | One clearly pathogenic variant was identified in the (MEFV/MVK) gene | Rare undetected variants may exist. Diagnosis relies on clinical judgement or criteria |
| One VUS or no variant | No pathogenic or one variant of uncertain clinical significance was identified in the (MEFV/MVK)gene | Rare 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 variant | One clearly pathogenic variant was identified in the (TNFR1SF1A/NLRP3) gene | This genotype confirms clinical diagnosis of (TRAPS/CAPS). If relevant add: and is generally associated with a (mild/severe) phenotype |
| One VUS | One 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 variant | No pathogenic variant was identified in the (TNFRSF1A/NLRP3)gene | Rare 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 HRF | Adapt from above | The 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 variant | The individual is a carrier for a (clearly pathogenic variant/variant of uncertain significance) in the (MEFV/MVK) gene | This 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).