title: Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child.
abstract: Charcot-Marie-Tooth disease (CMT) refers to a genetically heterogeneous group of disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is 1 in 2500 individuals. Mutations in the MFN2 gene are the commonest cause for the axonal (CMT2) type. We describe a Caucasian 5-year old girl affected by CMT2A since the age of 2 years. She presented with unsteady gait, in-turning of the feet and progressive foot deformities. Nerve conduction studies suggested an axonal neuropathy and molecular testing identified a previously reported pathogenic variant c.1090C > T, p.(Arg364Trp) in the MFN2 gene. This variant was also detected in a mosaic state in blood and saliva by Sanger sequencing in her subjectively healthy father. Next generation sequencing showed that the level of mosaicism was 21% in blood and 24% in saliva. A high recurrence risk was given because the father had proven somatic mosaicism and an affected child implying gonadal mosaicism. The parents were referred for pre-implantation genetic diagnosis. To the best of our knowledge, this is the first reported case of somatic mosaicism for MFN2. This study has important implications for genetic counselling in families with CMT2A.
authors.affiliation: East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK. Katherine.schon@addenbrookes.nhs.uk.
authors.forename: Katherine
authors.identifier: 0000-0001-8054-8954
authors.initials: K
authors.lastname: Schon
authors.affiliation: East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
authors.forename: Olivera
authors.initials: O
authors.lastname: Spasic-Boskovic
authors.affiliation: East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Brugger
authors.affiliation: Department of Neurology, Hinchingbrooke Hospital, Hinchingbrooke Park, Huntingdon, PE29 6NT, UK.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Graves
authors.affiliation: East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.affiliation: East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
authors.forename: Gautam
authors.initials: G
authors.lastname: Ambegaonkar
authors.affiliation: East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Armstrong
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology*; D002675:Child, Preschool; D005219:Father-Child Relations; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D009030:Mosaicism; D020125:Mutation, Missense; D009679:Nuclear Family; D010290:Parents; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index
chemical_list: D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
keywords: CMT2A; Charcot-Marie-tooth disease; MFN2; Mosaicism