PT  - JOURNAL ARTICLE
AU  - Marie F. Smeland
AU  - Pascal Brouillard
AU  - Trine Prescott
AU  - Laurence M Boon
AU  - Bodil Hvingel
AU  - Cecilie V Nordbakken
AU  - Mona Nystad
AU  - Øystein L. Holla
AU  - Miikka Vikkula
TI  - Biallelic ANGPT2 loss-of-function causes severe early-onset non-immune hydrops fetalis
AID  - 10.1136/jmedgenet-2021-108179
DP  - 2021 Dec 07
TA  - Journal of Medical Genetics
PG  - jmedgenet-2021-108179
4099  - http://jmg.bmj.com/content/early/2021/12/06/jmedgenet-2021-108179.short
4100  - http://jmg.bmj.com/content/early/2021/12/06/jmedgenet-2021-108179.full
AB  - Background 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.Methods and results Whole 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.Conclusion Pathogenic 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.All data relevant to the study are included in the article or uploaded as supplementary information.