Missense mutation in the MEN1 gene discovered through whole exome sequencing co-segregates with familial hyperparathyroidism

Genet Res (Camb). 2013 Aug;95(4):114-20. doi: 10.1017/S0016672313000141.

Abstract

Familial isolated hyperparathyroidism (FIHP) can be encountered in the context of multiple endocrine neoplasia type 1 (MEN1), hyperparathyroidism and jaw tumour syndrome (HPT-JT) and in familial hypocalciuric hypercalcaemia (FHH). In these syndromes, germline mutations in the relevant genes (MEN1, HPRT2 and CaSR, respectively) are detected. In some FIHP cases, the causative gene is still elusive. The objective of this study is to define the genetic basis of FIHP in a Georgian Jewish family with FIHP using whole exome capture and sequencing. DNA extracted from two sibs and one offspring from a single family all affected with multiglandular hyperparathyroidism was subjected to whole exome capturing and sequencing using the Roche NimbleGen V2 chip and the Illumina HiSeq2000 sequencing platform. Genetic variants were detected and annotated using a combination of the Genome Analysis Tool Kit and in-house scripts. Subsequent confirmation of the mutations and co-segregation analyses were carried out by Sanger sequencing in additional affected and unaffected family members. Whole exome capture and sequencing revealed the collection of variations common to the three-sequenced patients, including a very rare previously described missense mutation (c.T1021C: p.W341R) in the MEN1 gene. The p.W341R mutation in the MEN1 gene showed complete co-segregation in the family. Whole exome capture and sequencing led to the discovery of a missense mutation in the MEN1 gene and ruling out of the additional candidates in a single experiment. The limited expressivity of this mutation may imply a specific genotype-phenotype correlation for this mutation.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Exome / genetics
  • Family
  • Female
  • Genome-Wide Association Study
  • Humans
  • Hyperparathyroidism, Primary / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Proto-Oncogene Proteins / genetics*
  • Sequence Analysis, DNA
  • Young Adult

Substances

  • MEN1 protein, human
  • Proto-Oncogene Proteins

Supplementary concepts

  • Hyperparathyroidism 3