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伊朗一个 MUT 基因突变家族的胚胎植入前遗传学诊断。

Pre-implantation genetic diagnosis in an Iranian family with a novel mutation in MUT gene.

机构信息

Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.

出版信息

BMC Med Genet. 2020 Feb 3;21(1):22. doi: 10.1186/s12881-020-0959-8.

Abstract

BACKGROUND

Methylmalonic acidemia (MMA), which is an autosomal recessive metabolic disorder, is caused by mutations in methylmalonyl-CoA mutase (MUT) gene. As a result, the conversion of methylmalonyl-CoA to succinyl-CoA is impaired in this disorder, leading to a wide range of clinical manifestations varying from no signs or symptoms to severe lethargy and metabolic crisis in newborn infants. Since identification of novel mutations in MUT gene can help discover the exact pathogenesis of MMA and also use these disease-causing mutations in prenatal diagnosis, this study was conducted to uncover the possible mutations in an Iranian couple with a deceased offspring clinically diagnosed as having organic acidemia. Moreover, to prevent the occurrence of the mutation in the next pregnancy, we took the advantage of pre-implantation genetic diagnosis (PGD), which resulted in a successful pregnancy.

CASE PRESENTATION

The affected individual was a 15-month-old boy who passed away due to aspiration pneumonia. The child presented at the age of 3 months with lethargy, protracted vomiting, hypotonia, and decreased level of consciousness. To find the mutated gene, Next Generation Sequencing (NGS) was performed as carrier testing for the parents and the results revealed a novel (private) heterozygous missense mutation in MUT gene (c.1055A > G, p.Q352R). After performing PGD on three blastomeres, one was identified as being homozygous wild-type that was followed by successful pregnancy.

CONCLUSIONS

Our study identified a novel, deleterious, heterozygous missense mutation in MUT gene in a couple and helps to consider the genetic counselling and prenatal diagnosis more seriously for this family with clinical phenotypes of organic acidemia.

摘要

背景

甲基丙二酸血症(MMA)是一种常染色体隐性遗传代谢紊乱,由甲基丙二酰辅酶 A 变位酶(MUT)基因突变引起。在这种疾病中,甲基丙二酰辅酶 A 转化为琥珀酰辅酶 A 的过程受损,导致新生儿从无明显症状到严重嗜睡和代谢危象等广泛的临床表现。由于鉴定 MUT 基因中的新突变可以帮助发现 MMA 的确切发病机制,并在产前诊断中使用这些致病突变,因此本研究旨在揭示一对伊朗夫妇中可能存在的突变,他们的一个夭折的后代被临床诊断为有机酸血症。此外,为了防止下一次妊娠中出现该突变,我们利用了胚胎植入前遗传学诊断(PGD),最终成功妊娠。

病例介绍

受影响的个体是一名 15 个月大的男孩,因吸入性肺炎而死亡。该患儿于 3 个月大时出现嗜睡、迁延性呕吐、低张力和意识水平降低。为了寻找突变基因,对父母进行了下一代测序(NGS)作为携带者检测,结果显示 MUT 基因中存在一种新的(私有)杂合错义突变(c.1055A>G,p.Q352R)。对三个卵裂球进行 PGD 后,发现一个为纯合野生型,随后成功妊娠。

结论

本研究在一对夫妇中鉴定出 MUT 基因中的一种新型、有害的杂合错义突变,这有助于更认真地为这个具有有机酸血症临床表型的家庭考虑遗传咨询和产前诊断。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d34f/6998079/239ee9e3b8c6/12881_2020_959_Fig1_HTML.jpg

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