RESUMO
Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.
Assuntos
Cardiopatias Congênitas , Peixe-Zebra , Animais , Humanos , Polaridade Celular/genética , Células Germinativas/metabolismo , Mutação em Linhagem Germinativa/genética , Cardiopatias Congênitas/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genéticaRESUMO
Paraduodenal hernia is an uncommon cause of acute abdominal pain; however, it is the commonest of internal herniation. Computer tomography of the abdomen is diagnostic. Although it is a rare cause of intestinal obstruction, it is estimated that more than half of paraduodenal hernias develop symptoms. We present a case of left paraduodenal hernia that presented with acute abdominal pain and a left upper abdominal mass. Symptoms resolved spontaneously and a planned Laparoscopic repair was performed. The malpositioned small intestine was reduced from the hernia sac and the hernial orifice was closed. The patient made a rapid recovery with no recurrence of symptoms at 3-year follow-up.