Journal Article

Biallelic ANGPT2 loss-of-function causes severe early-onset non-immune hydrops fetalis

Holla, Øystein L., Nordbakken, Cecilie V, Vikkula, Miikka, Prescott, Trine, Smeland, Marie F., Brouillard, Pascal, Hvingel, Bodil, Nystad, Mona, Boon, Laurence M

2023

Overview

BackgroundHydrops 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.Methods and resultsWhole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 (ANGPT2) 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.ConclusionPathogenic heterozygous ANGPT2 missense variants were recently shown to cause autosomal dominant primary lymphoedema. ANGPT2 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 ANGPT2-related disorder in humans.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Age / Angiopoietin / Angiopoietin-2 - genetics / Animals / Ascites / Biopsy / Chromosomes / Codon, Nonsense - genetics / Developmental Defects / Epidermal growth factor / Etiology / Female / female urogenital diseases and pregnancy complications / Fetuses / Fibroblasts / Genes / genetics / Genomes / Genomics / Growth factors / Hereditary diseases / Heterozygote / Humans / Hydrops fetalis / Hydrops Fetalis - genetics / Hydrops Fetalis - metabolism / Infant, Newborn / loss of function mutation / Lymphatic system / Lymphedema / medical / Mice / mRNA turnover / Mutation, Missense / Nonsense mutation / Nonsense-mediated mRNA decay / Nucleotides / Pregnancy / Protein-tyrosine kinase / Skin / Software / Stop codon