title: Novel PEX11B Mutations Extend the Peroxisome Biogenesis Disorder 14B Phenotypic Spectrum and Underscore Congenital Cataract as an Early Feature.
abstract: Peroxisomes perform complex metabolic and catabolic functions essential for normal growth and development. Mutations in 14 genes cause a spectrum of peroxisomal disease in humans. Most recently, PEX11B was associated with an atypical peroxisome biogenesis disorder (PBD) in a single individual. In this study, we identify further PEX11B cases and delineate associated phenotypes.
  
  
  
  Probands from three families underwent next generation sequencing (NGS) for diagnosis of a multisystem developmental disorder. Autozygosity mapping was conducted in one affected sibling pair. ExomeDepth was used to identify copy number variants from NGS data and confirmed by dosage analysis. Biochemical profiling was used to investigate the metabolic signature of the condition.
  
  
  
  All patients presented with bilateral cataract at birth but the systemic phenotype was variable, including short stature, skeletal abnormalities, and dysmorphism-features not described in the original case. Next generation sequencing identified biallelic loss-of-function mutations in PEX11B as the underlying cause of disease in each case (PEX11B c.235C>T p.(Arg79Ter) homozygous; PEX11B c.136C>T p.(Arg46Ter) homozygous; PEX11B c.595C>T p.(Arg199Ter) heterozygous, PEX11B ex1-3 del heterozygous). Biochemical studies identified very low plasmalogens in one patient, whilst a mildly deranged very long chain fatty acid profile was found in another.
  
  
  
  Our findings expand the phenotypic spectrum of the condition and underscore congenital cataract as the consistent primary presenting feature. We also find that biochemical measurements of peroxisome function may be disturbed in some cases. Furthermore, diagnosis by NGS is proficient and may circumvent the requirement for an invasive skin biopsy for disease identification from fibroblast cells.
authors.affiliation: Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, The University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Taylor
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Handley
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Waller
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Campbell
authors.affiliation: Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, The University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Urquhart
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Meynert
authors.affiliation: Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, The University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Ellingford
authors.affiliation: Northern Ireland Regional Genetics Service (NIRGS), Belfast City Hospital, Belfast, United Kingdom.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Donnelly
authors.affiliation: Adult Inherited Metabolic Disorders, The Mark Holland Metabolic Unit, Salford Royal Foundation NHS Trust, Salford, United Kingdom.
authors.forename: Gisela
authors.initials: G
authors.lastname: Wilcox
authors.affiliation: Paediatric Ophthalmology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom 7Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester Foundation Trust, Manchester, United Kingdom.
authors.forename: I Chris
authors.initials: IC
authors.lastname: Lloyd
authors.affiliation: Centre for Inherited Metabolic Disease, Evelina London Children's Healthcare, London, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Mundy
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, Institute of Genetic and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.affiliation: Department of Genetics, Guy's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, The University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom 3Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, The University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom 3Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, United Kingdom.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
mesh_terms: D000293:Adolescent; D000328:Adult; D002386:Cataract / Q000151:congenital / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D018901:Peroxisomal Disorders / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D013997:Time Factors; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C490453:PEX11B protein, human; D004247:DNA