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

BMC Medical Genetics

Vamsi K Mootha⁴  Jeremy D Schmahmann¹  Katherine B Sims³  Sarah E Calvo⁵  Nancy G Slate²  Steven G Hershman⁵  Daniel S Lieber⁵ 

[1] 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;Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA;Department of Neurology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA;Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA

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

Others  :  1092285
DOI  :  10.1186/1471-2350-15-30

 received in 2013-11-06, accepted in 2014-02-25,  发布年份 2014

【 摘 要 】

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 pristanic:phytanic acid and arachidonic:docosahexaenoic 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.

【 授权许可】

   
2014 Lieber et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Zeviani M, Simonati A, Bindoff LA: Ataxia in mitochondrial disorders. Handb Clin Neurol 2012, 103:359-372.
• [2]Chinnery PF: Mitochondrial Disorders Overview. In GeneReviews. Edited by Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP. Seattle (WA): University of Washington, Seattle; 1993.
• [3]Lieber DS, Calvo SE, Shanahan K, Slate NG, Liu S, Hershman SG, Gold NB, Chapman BA, Thorburn DR, Berry GT, Schmahmann JD, Borowsky ML, Mueller DM, Sims KB, Mootha VK: Targeted exome sequencing of suspected mitochondrial disorders. Neurology 2013, 80(19):1762-1770.
• [4]Krumm N, Sudmant PH, Ko A, O’Roak BJ, Malig M, Coe BP, Quinlan AR, Nickerson DA, Eichler EE: Copy number variation detection and genotyping from exome sequence data. Genome Res 2012, 22(8):1525-1532.
• [5]Ferdinandusse S, Denis S, Mooyer PA, Dekker C, Duran M, Soorani-Lunsing RJ, Boltshauser E, Macaya A, Gartner J, Majoie CB, Barth PG, Wanders RJ, Poll-The BT: Clinical and biochemical spectrum of D-bifunctional protein deficiency. Ann Neurol 2006, 59(1):92-104.
• [6]Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC: Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet 2010, 87(2):282-288.
• [7]Adamski J, Normand T, Leenders F, Monte D, Begue A, Stehelin D, Jungblut PW, de Launoit Y: Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV. Biochem J 1995, 311(Pt 2):437-443.
• [8]Leenders F, Husen B, Thole HH, Adamski J: The sequence of porcine 80 kDa 17 beta-estradiol dehydrogenase reveals similarities to the short chain alcohol dehydrogenase family, to actin binding motifs and to sterol carrier protein 2. Mol Cell Endocrinol 1994, 104(2):127-131.
• [9]Ferdinandusse S, Ylianttila MS, Gloerich J, Koski MK, Oostheim W, Waterham HR, Hiltunen JK, Wanders RJ, Glumoff T: Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. Am J Hum Genet 2006, 78(1):112-124.
• [10]Paton BC, Sharp PC, Crane DI, Poulos A: Oxidation of pristanic acid in fibroblasts and its application to the diagnosis of peroxisomal beta-oxidation defects. J Clin Invest 1996, 97(3):681-688.
• [11]McMillan HJ, Worthylake T, Schwartzentruber J, Gottlieb CC, Lawrence SE, Mackenzie A, Beaulieu CL, Mooyer PA, Forge Canada C, Wanders RJ, Majewski J, Bulman DE, Geraghty MT, Ferdinandusse S, Boycott KM: Specific combination of compound heterozygous mutations in 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet J Rare Dis 2012, 7(1):90. BioMed Central Full Text
• [12]Perrault M, Klotz B, Housset E: Two cases of Turner syndrome with deaf-mutism in two sisters. Bull Mem Soc Med Hop Paris 1951, 67(3–4):79-84.
• [13]Christakos AC, Simpson JL, Younger JB, Christian CD: Gonadal dysgenesis as an autosomal recessive condition. Am J Obstet Gynecol 1969, 104(7):1027-1030.
• [14]Jenkinson EM, Clayton-Smith J, Mehta S, Bennett C, Reardon W, Green A, Pearce SH, De Michele G, Conway GS, Cilliers D, Moreton N, Davis JR, Trump D, Newman WG: Perrault syndrome: further evidence for genetic heterogeneity. J Neurol 2012, 259(5):974-976.
• [15]Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K, Morell RJ, Drummond MC, Khan SN, Naeem MA, Rauf B, Billington N, Schultz JM, Urquhart JE, Lee MK, Berry A, Hanley NA, Mehta S, Cilliers D, Clayton PE, Kingston H, Smith MJ, Warner TT, Black GC, Trump D, Davis JR, Ahmad W, Leal SM, Riazuddin S, King MC, Friedman TB, et al.: Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 2013, 92(4):605-613.
• [16]Pierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM, Li W, Klevit RE, King MC: Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci USA 2011, 108(16):6543-6548.
• [17]Pierce SB, Gersak K, Michaelson-Cohen R, Walsh T, Lee MK, Malach D, Klevit RE, King MC, Levy-Lahad E: Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in perrault syndrome. Am J Hum Genet 2013.
• [18]Fiumara A, Sorge G, Toscano A, Parano E, Pavone L, Opitz JM: Perrault syndrome: evidence for progressive nervous system involvement. Am J Med Genet A 2004, 128A(3):246-249.
• [19]Huyghe S, Schmalbruch H, De Gendt K, Verhoeven G, Guillou F, Van Veldhoven PP, Baes M: Peroxisomal multifunctional protein 2 is essential for lipid homeostasis in Sertoli cells and male fertility in mice. Endocrinology 2006, 147(5):2228-2236.
• [20]Rasiah KK, Gardiner-Garden M, Padilla EJ, Moller G, Kench JG, Alles MC, Eggleton SA, Stricker PD, Adamski J, Sutherland RL, Henshall SM, Hayes VM: HSD17B4 overexpression, an independent biomarker of poor patient outcome in prostate cancer. Mol Cell Endocrinol 2009, 301(1–2):89-96.
• [21]Breitling R, Marijanovic Z, Perovic D, Adamski J: Evolution of 17beta-HSD type 4, a multifunctional protein of beta-oxidation. Mol Cell Endocrinol 2001, 171(1–2):205-210.
• [22]Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK: A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008, 134(1):112-123.
• [23]Salido EC, Li XM, Lu Y, Wang X, Santana A, Roy-Chowdhury N, Torres A, Shapiro LJ, Roy-Chowdhury J: Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer. Proc Natl Acad Sci USA 2006, 103(48):18249-18254.
• [24]Spinazzola A, Viscomi C, Fernandez-Vizarra E, Carrara F, D’Adamo P, Calvo S, Marsano RM, Donnini C, Weiher H, Strisciuglio P, Parini R, Sarzi E, Chan A, DiMauro S, Rotig A, Gasparini P, Ferrero I, Mootha VK, Tiranti V, Zeviani M: MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 2006, 38(5):570-575.
• [25]Lopez-Erauskin J, Galino J, Ruiz M, Cuezva JM, Fabregat I, Cacabelos D, Boada J, Martinez J, Ferrer I, Pamplona R, Villarroya F, Portero-Otin M, Fourcade S, Pujol A: Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy. Hum Mol Genet 2013, 22(16):3296-3305.