title: Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency.
abstract: BACKGROUND
  D-bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe, infantile-onset disorder of peroxisomal fatty acid oxidation. Few affected patients survive past two years of age. Compound heterozygous mutations in HSD17B4 have also been reported in two sisters diagnosed with Perrault syndrome (MIM # 233400), who presented in adolescence with ovarian dysgenesis, hearing loss, and ataxia.
  
  
  METHODS
  An adult male presented with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia. The clinical presentation, in combination with biochemical findings in serum, urine, and muscle biopsy, suggested a mitochondrial disorder. Commercial genetic testing of 18 ataxia and mitochondrial disease genes was negative. Targeted exome sequencing followed by analysis of single nucleotide variants and small insertions/deletions failed to reveal a genetic basis of disease. Application of a computational algorithm to infer copy number variants (CNVs) from exome data revealed a heterozygous 12 kb deletion of exons 10-13 of HSD17B4 that was compounded with a rare missense variant (p.A196V) at a highly conserved residue. Retrospective review of patient records revealed mildly elevated ratios of pristanic:phytanic acid and arachidonic:docosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation.
  
  
  CONCLUSIONS
  Our case expands the phenotypic spectrum of HSD17B4-deficiency, representing the first male case reported with infertility. Furthermore, it points to crosstalk between mitochondria and peroxisomes in HSD17B4-deficiency and Perrault syndrome.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lieber
authors.forename: Steven G
authors.initials: SG
authors.lastname: Hershman
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Slate
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Calvo
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Sims
authors.affiliation: Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology,  Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114 USA, jschmahmann@partners.org
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Schmahmann
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D000328:Adult; D001259:Ataxia / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D053713:Azoospermia / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D001483:Base Sequence; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D025202:Molecular Diagnostic Techniques; D008969:Molecular Sequence Data; D064029:Peroxisomal Multifunctional Protein-2 / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human