Two-gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results

Anna Monica Bianco, Flavio Faletra, Diego Vozzi, Martina Girardelli, Alessandra Knowles, Alberto Tommasini, Giorgio Zauli, Annalisa Marcuzzi

Research output: Contribution to journalArticlepeer-review


Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X-chromosome inactivation (XCI) studies on the patient's mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 μg/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient's mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X-linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

Original languageEnglish
Pages (from-to)6128-6132
Number of pages5
JournalMolecular Medicine Reports
Issue number4
Publication statusPublished - Oct 1 2015


  • Genotype-phenotype
  • Mevalonate
  • Mevalonate kinase deficiency
  • RAB40AL
  • Rare disease

ASJC Scopus subject areas

  • Biochemistry
  • Cancer Research
  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Oncology


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