Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Am J Med Genet A. 2019 Apr;179(4):645-649. doi: 10.1002/ajmg.a.61056. Epub 2019 Jan 24.
TBC1D24-related disorders are rare neurodevelopmental disorders that show a broad range of neuropsychiatric deficits and are mostly inherited in an autosomal recessive manner. Here we describe a case with early-onset epileptic encephalopathy, in whom exome sequencing detected a novel pathogenic homozygous c.442G>A, p.(Glu148Lys) variant in TBC1D24. She showed severe developmental delay, congenital sensorineural hearing loss and seizures, but the combination of a high dose phenobarbital and potassium bromide was very effective for the seizures. Sanger sequencing revealed that her mother was a heterozygous carrier of the TBC1D24 variant, but her father showed only wild-type alleles. Homozygosity mapping analysis using exome data showed loss of the heterozygosity region at 16p13.3-p13.13 encompassing TBC1D24. Genotyping analysis using rare variants within loss of the heterozygosity region indicated that the patient has a homozygous haplotype inherited from her mother, indicating maternal segmental uniparental isodisomy (UPiD). These data clearly show that exome sequencing is a powerful tool to perform comprehensive genetic analysis.
TBC1D24 相关疾病是罕见的神经发育障碍，表现出广泛的神经精神缺陷，主要以常染色体隐性方式遗传。在这里，我们描述了一例早发性癫痫性脑病患者，外显子组测序检测到 TBC1D24 中一个新的致病性纯合 c.442G>A，p.(Glu148Lys) 变异。她表现为严重的发育迟缓、先天性感觉神经性耳聋和癫痫发作，但高剂量苯巴比妥和溴化钾的联合治疗对癫痫发作非常有效。Sanger 测序显示，她的母亲是 TBC1D24 变异的杂合携带者，但她的父亲仅显示野生型等位基因。使用外显子数据进行的纯合子作图分析显示 16p13.3-p13.13 缺失杂合区域缺失，包含 TBC1D24。使用缺失杂合区域内罕见变异的基因分型分析表明，患者从母亲那里遗传了纯合子单倍型，表明母源性片段单亲二体性 (UPiD)。这些数据清楚地表明，外显子组测序是进行全面遗传分析的有力工具。
