Sriwattanapong Kanokwan, Rojnueangnit Kitiwan, Theerapanon Thanakorn, Srichomthong Chalurmpon, Porntaveetus Thantrira, Shotelersuk Vorasuk
Genomics and Precision Dentistry Research Unit, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.
Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand.
Int J Neonatal Screen. 2021 Feb 5;7(1):9. doi: 10.3390/ijns7010009.
A variant in the gene is the leading cause of a heterogeneous group of mitochondrial disorders. No definitive treatment is currently available. Prenatal and newborn screening have the potential to improve clinical outcome of patients affected with -related disorders. We reported a 4-month-old infant who presented with developmental delay, fever, and diarrhea. Within two weeks after hospital admission, the patient developed hepatic failure and died. Liver necropsy demonstrated an extensive loss of hepatocytes and bile duct proliferations. Trio-whole exome sequencing identified that the patient was compound heterozygous for a novel frameshift variant c.3102delG (p.Lys1035Serfs59) and a common variant c.3286C>T (p.Arg1096Cys) in (NM_002693.3) inherited from the mother and father, respectively. The c.3102delG (p.Lys1035Serfs59) was a null variant and classified as pathogenic according to the American College of Medical Genetics and Genomics Standards and Guidelines. Prenatal genetic screenings using rapid whole exome sequencing successfully detected the heterozygous c.3286C>T variant in the following pregnancy and the normal alleles in the other one. Both children had been healthy. We reviewed all 34 cases identified with the c.3286C>T variant and found that all 15 compound heterozygous cases had two missense variants except our patient who had the truncating variant and showed the earliest disease onset, rapid deterioration, and the youngest death. All homozygous cases had disease onset before age 2 and developed seizure. Here, we report a novel variant expanding the genotypic spectrum, demonstrate the successful use of exome sequencing for prenatal and neonatal screenings of -related disorders, and show the genotype-phenotype correlation of the common c.3286C>T variant.
该基因的一个变异是一组异质性线粒体疾病的主要病因。目前尚无确切的治疗方法。产前和新生儿筛查有可能改善患有相关疾病患者的临床结局。我们报告了一名4个月大的婴儿，其表现出发育迟缓、发热和腹泻。入院两周内，该患者出现肝衰竭并死亡。肝脏尸检显示肝细胞广泛丧失和胆管增生。三联全外显子测序确定该患者在 （NM_002693.3） 基因上分别从母亲和父亲遗传了一个新的移码变异c.3102delG（p.Lys1035Serfs59）和一个常见变异c.3286C>T（p.Arg1096Cys），为复合杂合子。根据美国医学遗传学与基因组学学会的标准和指南，c.3102delG（p.Lys1035Serfs59）是一个无效变异，被归类为致病性变异。在接下来的妊娠中，使用快速全外显子测序进行的产前基因筛查成功检测到杂合的c.3286C>T变异，而另一次妊娠检测到正常等位基因。两个孩子均健康。我们回顾了所有34例被鉴定为携带c.3286C>T变异的病例，发现所有15例复合杂合子病例均有两个错义变异，除了我们的患者有截短变异，且疾病发作最早、病情迅速恶化且死亡时年龄最小。所有纯合子病例在2岁前发病并出现癫痫发作。在此，我们报告一个新的变异，扩展了基因型谱，证明外显子测序在与 相关疾病的产前和新生儿筛查中的成功应用，并展示了常见的c.3286C>T变异的基因型-表型相关性。
