Neurofibromatosis type 1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis: what should be offered?

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in NF1 Recently, NF1 testing has been included as a clinical criterion for NF1 diagnosis. Additionally, preconception genetic counselling in patients with NF1 focuses on a 50% risk of transmitting the familial variant as the risk of having a sporadic NF1 is considered the same as the general population. METHODS: 829 individuals, 583 NF1 sporadic cases and 246 patients with NF1 with documented family history, underwent genetic testing for NF1. Genotyping and segregation analysis of NF1 familial variants was determined by microsatellite analysis and NF1 sequencing. RESULTS: The mutational analysis of NF1 in 154 families with two or more affected cases studied showed the co-occurrence of two different NF1 germline pathogenic variants in four families. The estimated mutation rate in those families was 3.89×10-3, 20 times higher than the NF1 mutation rate (~2×10-4) (p=0.0008). Furthermore, the co-occurrence of two different NF1 germline pathogenic variants in these families was 1:39, 60 times the frequency of sporadic NF1 (1:2500) (p=0.003). In all cases, the de novo NF1 pathogenic variant was present in a descendant of an affected male. In two cases, variants were detected in the inherited paternal wild-type allele. CONCLUSIONS: Our results, together with previous cases reported, suggest that the offspring of male patients with NF1 could have an increased risk of experiencing de novo NF1 pathogenic variants. This observation, if confirmed in additional cohorts, could have relevant implications for NF1 genetic counselling, family planning and NF1 genetic testing.

Revisiting the UK Genetic Severity Score for NF2: a proposal for the addition of a functional genetic component.

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by the development of multiple schwannomas, especially on vestibular nerves, and meningiomas. The UK NF2 Genetic Severity Score (GSS) is useful to predict the progression of the disease from germline NF2 pathogenic variants, which allows the clinical follow-up and the genetic counselling offered to affected families to be optimised. METHODS: 52 Spanish patients were classified using the GSS, and patients' clinical severity was measured and compared between GSS groups. The GSS was reviewed with the addition of phenotype quantification, genetic variant classification and functional assays of Merlin and its downstream pathways. Principal component analysis and regression models were used to evaluate the differences between severity and the effect of NF2 germline variants. RESULTS: The GSS was validated in the Spanish NF2 cohort. However, for 25% of mosaic patients and patients harbouring variants associated with mild and moderate phenotypes, it did not perform as well for predicting clinical outcomes as it did for pathogenic variants associated with severe phenotypes. We studied the possibility of modifying the mutation classification in the GSS by adding the impact of pathogenic variants on the function of Merlin in 27 cases. This revision helped to reduce variability within NF2 mutation classes and moderately enhanced the correlation between patient phenotype and the different prognosis parameters analysed (R2=0.38 vs R2=0.32, p>0001). CONCLUSIONS: We validated the UK NF2 GSS in a Spanish NF2 cohort, despite the significant phenotypic variability identified within it. The revision of the GSS, named Functional Genetic Severity Score, could add value for the classification of mosaic patients and patients showing mild and moderate phenotypes once it has been validated in other cohorts.

[Predictive ability of the BRCAPro model compared to nursing professionals in the selection of candidates for the genetic study of hereditary breast or ovarian cancer]. / Capacidad predictiva del modelo BCRAPro frente al profesional de enfermería en la selección de candidatos a estudio genético de cáncer de mama u ovario hereditario.

OBJECTIVE: To compare the predictive skills of the BRCAPro predictive model and nurses with different training/experience levels in identifying families with a personal and family history of breast cancer as likely candidates to being studied genetically. METHOD: Descriptive study in which 2 nurses with different levels of training in genetic counselling have estimated the probability of being carrier of a mutation in the BRCA1/BRCA2 genes of 157 families. The Sensitivity, Specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of both nurses and the BRCAPro model were calculated. RESULTS: The nurse with less experience demonstrated more specificity (N2:0.84) compared to the nurse with more experience (N1:0.23) and to BRCAPro model (0.47). The sensitivity of the nurses was 0.95 (N1) and 0.28 (N2), whereas that of BRCAPro was 0.74. The PPV was similar in the three cases. The NPV of the nurse with more experience (0.93) was higher than that of BRCAPro model (0.85) and the nurse with less experience (0.72). CONCLUSIONS: Clinical experience contributes to obtaining a high sensitivity, but with a significant decrease of specificity. The BRCAPro predictive model obtains intermediate values between both nurses. The BRCAPro predictive model could be a useful tool to help improve those values with lower scores, that is, the specificity and PPV for nurses with more experience and the sensitivity and NPV for those with less experience.