Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency.
BMC Med Genet
; 15: 30, 2014 Mar 06.
Article
in En
| MEDLINE
| ID: mdl-24602372
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. 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 pristanicphytanic acid and arachidonicdocosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation.CONCLUSION:
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ataxia
/
Abnormalities, Multiple
/
Mitochondrial Diseases
/
Peroxisomal Multifunctional Protein-2
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Hearing Loss, Sensorineural
Type of study:
Diagnostic_studies
Limits:
Adult
/
Humans
/
Male
Language:
En
Journal:
BMC Med Genet
Journal subject:
GENETICA MEDICA
Year:
2014
Type:
Article