Sporadic hereditary motor and sensory neuropathies: Advances in the diagnosis using next generation sequencing technology.
Hereditary motor and sensory neuropathies (HMSN) are genetically heterogeneous disorders affecting peripheral motor and sensory functions. Many different pathogenic variants in several genes involved in the demyelinating, the axonal and the intermediate HMSN forms have been identified, for which all inheritance patterns have been described. The mutation screening currently available is based on Sanger sequencing and is time-consuming and relatively expensive due to the high number of genes involved and to the absence of mutational hot spots. To overcome these limitations, we have designed a custom panel for simultaneous sequencing of 28 HMSN-related genes. We have applied this panel to three representative patients with variable HMSN phenotype and uncertain diagnostic classifications. Using our NGS platform we rapidly identified three already described pathogenic heterozygous variants in MFN2, MPZ and DNM2 genes. Here we show that our pre-custom platform allows a fast, specific and low-cost diagnosis in sporadic HMSN cases. This prompt diagnosis is useful for providing a well-timed treatment, establishing a recurrence risk and preventing further investigations poorly tolerated by patients and expensive for the health system. Importantly, our study illustrates the utility and successful application of NGS to mutation screening of a Mendelian disorder with extreme locus heterogeneity.
Medical Genetics, University of Siena, Siena, Italy.
Chiara
C
Fallerini
Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Giulia
G
Carignani
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy; UOC Neurologia e Neurofisiologia Clinica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Giorgio
G
Capoccitti
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Antonio
A
Federico
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Alessandra
A
Rufa
Medical Genetics, University of Siena, Siena, Italy.
Anna Maria
AM
Pinto
Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Caterina Lo
CL
Rizzo
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy; UOC Neurologia e Neurofisiologia Clinica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Alessandro
A
Rossi
Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Francesca
F
Mari
Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Maria Antonietta
MA
Mencarelli
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy; UOC Neurologia e Neurofisiologia Clinica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. Electronic address: gianninif@unisi.it.
Fabio
F
Giannini
Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. Electronic address: alessandra.renieri@unisi.it.
Alessandra
A
Renieri
D000328:Adult; D004252:DNA Mutational Analysis; D034285:Dynamin II; D034281:Dynamins / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D015417:Hereditary Sensory and Motor Neuropathy / Q000175:diagnosis* / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*
D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C000593490:DNM2 protein, human; D034285:Dynamin II; D034281:Dynamins
Custom panel; Hereditary motor and sensory neuropathies; Locus heterogeneity; Low-cost diagnosis; Sporadic next generation sequencing technology