title: Expanding the phenotype associated with the NEFL mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings.
abstract: OBJECTIVE
  Newer sequencing technologies in combination with traditional gene mapping techniques, such as linkage analysis, can help identify the genetic basis of disease for patients with rare disorders of uncertain etiology. This approach may expand the phenotypic spectrum of disease associated with those genetic mutations.
  
  
  OBJECTIVE
  To elucidate the molecular cause of a neuromuscular disease among a family in which 4 members, a mother and her 3 sons, were affected.
  
  
  METHODS
  Two of 4 affected members manifested nemaline myopathy, a common subtype of congenital myopathy, while the other 2 had a nonspecific myopathy. Single-nucleotide polymorphism-based linkage analysis was performed on DNA samples from the 4 affected family members, and whole-genome sequencing was performed in the proband. Real-time quantitative reverse transcription-polymerase chain reaction, immunofluorescence, and Western blot analysis were performed on muscle biopsy specimens.
  
  
  METHODS
  Whole-genome sequencing and linkage analysis identified a variant in a gene that explains the phenotype.
  
  
  RESULTS
  We identified a novel neurofilament light polypeptide (NEFL) nonsense mutation in all affected members. NEFL mutations have been previously linked to Charcot-Marie-Tooth disease in humans. This led us to reevaluate the diagnosis, and we recognized that several of the findings, especially those related to the muscle biopsy specimens and electromyography, were consistent with a neurogenic disease.
  
  
  CONCLUSIONS
  NEFL mutations are known to cause Charcot-Marie-Tooth disease in humans and motor neuron disease in mice. We report the identification of an NEFL mutation in a family clinically manifesting congenital myopathy. We also describe potential overlap between myopathic and neurogenic findings in this family. These findings expand the phenotypic spectrum of diseases associated with NEFL mutations. This study is an example of the power of genomic approaches to identify potentially pathogenic mutations in unsuspected genes responsible for heterogeneous neuromuscular diseases.
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts2Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts3Manton Center for Orphan Disease Research.
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Agrawal
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts3Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts3Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Marinakis
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts3Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts4Department of Pathology, Bost.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitz-Abe
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts5Broad Institute, Massachusetts Institute of Technology, Cambridge.
authors.forename: Pedro D S C
authors.initials: PD
authors.lastname: Ciarlini
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sargent
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts3Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Markianos
authors.affiliation: Broad Institute, Massachusetts Institute of Technology, Cambridge.
authors.forename: Umberto
authors.initials: U
authors.lastname: De Girolami
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: David A
authors.initials: DA
authors.lastname: Chad
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts3Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009135:Muscular Diseases / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D016900:Neurofilament Proteins / Q000235:genetics*; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D016900:Neurofilament Proteins; C044882:neurofilament protein L