Challenges in molecular diagnosis of multiple endocrine neoplasia

Abstract

Multiple endocrine neoplasia (MEN) is a group of rare genetic diseases characterized by the occurrence of multiple tumors of the endocrine system in the same patient. The first MEN described was MEN1, followed by MEN2A, and MEN2B. The identification of the genes responsible for these syndromes led to the introduction of family genetic screening programs. More than twenty years later, not all cases of MENs have been resolved from a genetic point of view, and new clinicogenetic entities have been described. In this review, we will discuss the strategies and difficulties of genetic screening for classic and newly described MENs in a clinical setting, from limitations in sequencing, to problems in classifying variants, to the identification of new candidate genes. In the era of genomic medicine, characterization of new candidate genes and their specific tumor risk is essential for inclusion of patients in personalized medicine programs as well as to permit accurate genetic counseling to be proposed for families.

Keywords: MEN1; MEN2; candidate gene; genetic testing; genome; mosaicism.

Figure 1

Flow chart of genetic testing, interpretation and use of sequence variants in a clinical context. CNV, Copy number variation; SNV, single nucleotide variation.

Figure 2

Read alignments produced on an Illumina MiSeq sequencer and visualized using IGV 2.11.3. The reads show a GC-rich region in the second exon of the MEN1 gene. The top bar indicates chromosomal coordinates. Bold letters indicate mismatch bases corresponding to putative variants. Color intensity indicates the sequencing quality values. Clear letters denote poor sequencing quality scores. In these regions, the quality of sequencing is suboptimal leading to potential false-positive results. To avoid this, variants are filtered out based on the quality value, which can also lead to rejection of a true variant if its quality is insufficient. Here the deletion c.249_252del heterozygous of four bases (indicated by the horizontal black line) was filtered out in first-line analysis because the quality value attributed to an absence of signal (deletion) is the quality value of the surrounding region.

Figure 3

Genetic mosaicism. Mosaicism is due to the occurrence of a de novo mutation during postzygotic development, after fertilization. In these cases, only a proportion of the cells will harbor the variation; this feature is termed mosaicism or somatic mosaicism.