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Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency

Daniel S Lieber1234, Steven G Hershman1234, Nancy G Slate12, Sarah E Calvo1234, Katherine B Sims25, Jeremy D Schmahmann6* and Vamsi K Mootha12347*

Author Affiliations

1 Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA

2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA

3 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA

4 Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA

5 Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA

6 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

7 Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA

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BMC Medical Genetics 2014, 15:30  doi:10.1186/1471-2350-15-30

Published: 6 March 2014



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.

Case presentation

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.


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.

HSD17B4; DBP; D-bifunctional protein deficiency; Perrault syndrome; Next-generation sequencing; Exome sequencing; Copy number variants; CNV; Mitochondria; Mitochondrial disorders; Mitochondrial disease; Mendelian disorders; Human genetics; Ataxia; Multi-system disorders; Peroxisomal defects