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

Abstract

Abstract. 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.

The Challenge of Next Generation Sequencing in a Boy With Severe Mononucleosis and EBV-related Lymphoma

“…Serologic investigation showed that both subjects had developed memory antibodies against EBV. The maternal X-chromosome inactivation (XCI) performed in peripheral blood lymphocytes, as already described, 4 and in selected RTE population isolated using CD4+ recent thymic emigrant isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) showed a random inactivation (Fig. 3).…”

A Rab-bit hole: Rab40 GTPases as new regulators of the actin cytoskeleton and cell migration

“…Investigation found that the D59G mutation reduced Rab40AL protein level and altered Rab40AL cytoplasmic localization ( Jirair Krikor et al, 2012 ). However, the role of the D59G Rab40AL mutation in causing MPS has been contested as multiple healthy individuals have also been found to carry the D59G Rab40AL mutation ( Ołdak et al, 2014 ; Bianco et al, 2015 ; Ołdak et al, 2015 ).…”