title: Two‑gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results.
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.
authors: Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health ‑ IRCCS 'Burlo Garofolo', Trieste, Trieste 34137, Italy.
authors: Anna Monica
authors: AM
authors: Bianco
authors: Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health ‑ IRCCS 'Burlo Garofolo', Trieste, Trieste 34137, Italy.
authors: Flavio
authors: F
authors: Faletra
authors: Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health ‑ IRCCS 'Burlo Garofolo', Trieste, Trieste 34137, Italy.
authors: Diego
authors: D
authors: Vozzi
authors: Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health ‑ IRCCS 'Burlo Garofolo', Trieste, Trieste 34137, Italy.
authors: Martina
authors: M
authors: Girardelli
authors: Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health ‑ IRCCS 'Burlo Garofolo', Trieste, Trieste 34137, Italy.
authors: Alessandra
authors: A
authors: Knowles
authors: Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health ‑ IRCCS 'Burlo Garofolo', Trieste, Trieste 34137, Italy.
authors: Alberto
authors: A
authors: Tommasini
authors: Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health ‑ IRCCS 'Burlo Garofolo', Trieste, Trieste 34137, Italy.
authors: Giorgio
authors: G
authors: Zauli
authors: Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health ‑ IRCCS 'Burlo Garofolo', Trieste, Trieste 34137, Italy.
authors: Annalisa
authors: A
authors: Marcuzzi
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D002648:Child; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics; D005819:Genetic Markers; D014644:Genetic Variation; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D008297:Male; D054078:Mevalonate Kinase Deficiency / Q000175:diagnosis* / Q000235:genetics; D008798:Mevalonic Acid / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009035:Mothers; D020125:Mutation, Missense; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D024101:Mitochondrial Proteins; D011944:Receptors, Androgen; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; C466300:RAB40AL protein, human; D018631:ras Proteins; D008798:Mevalonic Acid