Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
Human Molecular Genetics, de Duve Institute, Universite catholique de Louvain, Brussels, Belgium.
J Med Genet. 2023 Jan;60(1):57-64. doi: 10.1136/jmedgenet-2021-108179. Epub 2021 Dec 7.
Hydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with recurrent pregnancy loss due to severe early-onset non-immune hydrops fetalis.
Whole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 () variant Chr8 (GRCh37/Hg19): 6385085T>C, NM_001147.2:c.557A>G. The substitution introduces a cryptic, exonic splice site predicted to result in loss of 10 nucleotides with subsequent shift in reading frame, leading to a premature stop codon. RNA analysis in the heterozygous parents demonstrated loss of detectable mutant allele, indicative of loss-of-function via nonsense-mediated mRNA decay. Serum ANGPT2 levels were reduced in the parents. In a pregnancy with a healthy, heterozygous child, transiently increased fetal nuchal translucency was noted.
Pathogenic heterozygous missense variants were recently shown to cause autosomal dominant primary lymphoedema. is a ligand of the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) pathway. It is critical to the formation and remodelling of blood and lymphatic vessels and is involved in vessel maintenance. ANGPT2 knockout mice die from generalised lymphatic dysfunction. We show here that a homozygous pathogenic variant causes loss-of-function and results in severe early-onset hydrops fetalis. This is the first report of an autosomal recessive -related disorder in humans.
胎儿水肿是指两个或多个身体腔室病理性积液，病因具有异质性。我们研究了一个有血缘关系的家族，该家族因严重的早发性非免疫性胎儿水肿而反复发生妊娠丢失。
对 4 例胎儿水肿进行全外显子组测序，发现他们均为血管生成素-2（）变异 Chr8（GRCh37/Hg19）：6385085T>C，NM_001147.2:c.557A>G 的纯合子。该取代引入了一个隐蔽的外显子剪接位点，预计会导致 10 个核苷酸的缺失，并随后导致阅读框移位，从而产生一个过早的终止密码子。杂合父母的 RNA 分析表明，突变等位基因的检测丢失，表明通过无意义介导的 mRNA 降解导致功能丧失。父母的血清 ANGPT2 水平降低。在一次怀有健康杂合子孩子的妊娠中，胎儿颈后透明带暂时增加。
最近发现致病性杂合错义变体可导致常染色体显性原发性淋巴水肿。是 TIE1-TIE2（含免疫球蛋白样和表皮生长因子样结构域的酪氨酸激酶 1 和 2）通路的配体。它对血液和淋巴管的形成和重塑至关重要，并且参与血管维持。ANGPT2 敲除小鼠因全身淋巴功能障碍而死亡。我们在这里表明，纯合致病性变体导致功能丧失，并导致严重的早发性胎儿水肿。这是人类首例报道的常染色体隐性相关疾病。
