Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency.
Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency.
复制标题
DOI：
10.1186/1471-2350-15-30
复制
发表时间：
2014-03-06
影响因子：
--
通讯作者：
Mootha VK
中科院分区：
文献类型：
--
作者：
Lieber DS;Hershman SG;Slate NG;Calvo SE;Sims KB;Schmahmann JD;Mootha VK
由HSD 17 B4隐性突变引起的D-双功能蛋白缺乏症是一种严重的过氧化物酶体脂肪酸氧化障碍。很少有受影响的患者存活超过2岁。在两名被诊断为Perrault综合征（MIM # 233400）的姐妹篇中也报告了HSD 17 B4的复合杂合突变，她们在青春期出现卵巢发育不全、听力损失和共济失调。一名成年男性表现为小脑共济失调、周围神经病变、听力丧失和无精子症。临床表现，结合血清，尿液和肌肉活检的生化结果，提示线粒体疾病。18个共济失调和线粒体疾病基因的商业基因检测结果为阴性。有针对性的外显子组测序，然后分析单核苷酸变异和小的插入/缺失，未能揭示疾病的遗传基础。应用计算算法从外显子组数据推断拷贝数变体（CNV）揭示了HSD 17 B4的外显子10-13的杂合12 kb缺失，其在高度保守的残基处与罕见的错义变体（p.A196V）复合。患者记录的回顾性审查显示降植烷酸：植烷酸和花生四烯酸：二十二碳六烯酸的比例轻度升高，与功能失调的过氧化物酶体脂肪酸氧化一致。我们的病例扩大了HSD 17 B4缺乏症的表型谱，代表了第一例男性不育症的报道。此外，它指出了HSD 17 B4缺乏症和Perrault综合征中线粒体和过氧化物酶体之间的串扰。
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. 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.