title: Whole exome sequencing identifies three recessive FIG4 mutations in an apparently dominant pedigree with Charcot-Marie-Tooth disease.
abstract: Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous and classification based on motor nerve conduction velocity and inheritance is used to direct genetic testing. With the less common genetic forms of CMT, identifying the causative genetic mutation by Sanger sequencing of individual genes can be time-consuming and costly. Next-generation sequencing technologies show promise for clinical testing in diseases where a similar phenotype is caused by different genes. We report the unusual occurrence of CMT4J, caused by mutations in FIG4, in a apparently dominant pedigree. The affected proband and her mother exhibit different disease severities associated with different combinations of compound heterozygous FIG4 mutations, identified by whole exome sequencing. The proband was also shown to carry a de novo nonsense mutation in the dystrophin gene, which may contribute to her more severe phenotype. This study is a cautionary reminder that in families with two generations affected, explanations other than dominant inheritance are possible, such as recessive inheritance due to three mutations segregating in the family. It also emphasises the advantages of next-generation sequencing approaches that screen multiple CMT genes at once for patients in whom the common genes have been excluded.
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, Australia. Electronic address: manoj.menezes@health.nsw.gov.au.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Menezes
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, Australia.
authors.forename: Leigh
authors.initials: L
authors.lastname: Waddell
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Guy M
authors.initials: GM
authors.lastname: Lenk
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Simranpreet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.affiliation: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, Australia.
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
mesh_terms: D000293:Adolescent; D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D018389:Codon, Nonsense; D016189:Dystrophin / Q000235:genetics; D005190:Family; D005260:Female; D005420:Flavoproteins / Q000235:genetics*; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D018389:Codon, Nonsense; D016189:Dystrophin; D005420:Flavoproteins; C522215:FIG4 protein, human; D010744:Phosphoric Monoester Hydrolases
keywords: Autosomal recessive CMT; CMT4J; Charcot–Marie–Tooth; FIG4; Whole exome sequencing