True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome

Abstract

Purpose Multiple endocrine neoplasia type 1 is a rare tumor syndrome caused by germline mutations of MEN1 gene. Phenotype varies widely, and no definitive correlation with the genotype has been observed. Mutation-negative patients with MEN1-associated tumors represent phenocopies. By comparing mutation-positive and mutation-negative patients, we aimed to identify phenotype features predictive for a positive genetic test and to evaluate the role of MEN1 mutations in phenotype modulation. Methods Mutation screeening of MEN1 gene by Sanger sequencing and assessment of clinical data of 189 consecutively enrolled probands and relatives were performed at our national and European Reference Center. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1 -negative cases. Results Twenty-seven probands and twenty family members carried MEN1 mutations. Five mutations have not been described earlier. Pronouncedly high number of phenocopies (>70%) was observed. Clinical suspicion of MEN1 syndrome emerged at significantly earlier age in MEN1 -positive compared to MEN1 -negative probands. Gastroenteropancreatic neuroendocrine tumors developed significantly earlier and more frequently in carriers compared to non-carriers. Probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers. Conclusions MEN1 phenocopy is common and represents a significant confounder for the genetic testing. GEP-NET under 30 years best predicted a MEN1 mutation. The present study thus confirmed a previous proposal and suggested that GEP-NET under 30 years should be considered as a part of the indication criteria for MEN1 mutational analysis.

Using structural analysis in silico to assess the impact of missense variants in MEN1

“…We conclude that structural analysis provides a useful tool in understanding the impact of missense variants in MEN1, and that integration of proteomic with genomic data could potentially contribute to the classification of novel variants in this disease. collagenomas and meningiomas (11), resulting in a range of clinical symptoms which may overlap with other diseases of different genetic etiology (12)(13)(14). This overlap presents one of the key problems in assessing genetic variants in cases of MEN1.…”

Phenotypes Associated With MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations

“…In keeping with these indications, the novel missense variant herein reported c.836C>A resulting in the amino acid change p.A279D in heterozygous state, leads to a change from alanine to aspartic acid with potential aggressive behavior. At odds with studies minimizing the clinical impact of missense mutations compared to frameshift or non-sense mutations (20,24), the missense variant described in our index case stands out for its aberrant and aggressive clinical manifestations developing long after the first clinical manifestation of MEN1.…”

“…Lack of mutations have been reported in 5-25% of patients with a clinical diagnosis of MEN1, constituting the so-called "phenocopies" (15,22,23). Of note, a recent study on 189 patients with typical MEN1 phenotype described a higher prevalence (74%) of mutation-negative cases than previously reported (24).…”

“…However, genetic testing in MEN1 patients meeting the clinical criteria could be negative (23,89). Some studies demonstrated that negative testing for mutations is frequent in clinical MEN1-like presentations including a combination of pituitary and parathyroid tumors (136,137), while GEP NET appeared more frequently and earlier in MEN1-positive probands, and its development under 30 years seems to be a predictor of a positive genetic test (24).…”

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: Challenges and opportunities in genetic counseling for hereditary endocrine neoplasia syndromes

“…Importantly, though, significant discordance has been recognized between index cases meeting clinical diagnostic criteria and their genetic test results wherein up to 10-30% of index MEN1 cases that meet clinical diagnostic criteria do not have an identifiable germline pathogenic variant in MEN1 (Thakker et al 2012, de Laat et al 2016, Isailovic et al 2019. Furthermore, there have now been several studies published by different groups comparing the phenotypes of gene-positive and gene-negative MEN1 cases, identifying significant differences between these groups (de Laat et al 2016, Pardi et al 2017, Kovesdi et al 2019. Of additional importance, the gene-negative cases often have a weaker or nonexistent family history of MEN1, supporting the idea that these individuals may represent a different entity altogether from highly penetrant MEN1 due to a confirmed germline pathogenic MEN1 variant (Isailovic et al 2019).…”