Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome
Open Access
- 6 March 2020
- journal article
- research article
- Published by Wiley in American Journal of Medical Genetics Part A
- Vol. 182 (5), 1273-1277
- https://doi.org/10.1002/ajmg.a.61541
Abstract
Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post‐zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow‐up studies for presumed de novo and low‐level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.Keywords
Funding Information
- Cancer Council South Australia
- Hospital Research Foundation
- National Health and Medical Research Council (APP1023059, APP1123341, GNT1113531)
- National Human Genome Research Institute (HG008900)
This publication has 21 references indexed in Scilit:
- Providing a Placental Transfusion in Newborns Who Need ResuscitationFrontiers in Pediatrics, 2017
- Analysis of protein-coding genetic variation in 60,706 humansNature, 2016
- Genetic, environmental, and epigenetic factors involved in CAKUTNature Reviews Nephrology, 2015
- Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic VariationAmerican Journal of Human Genetics, 2015
- Stillbirth rates in low-middle income countries 2010 - 2013: a population-based, multi-country study from the Global NetworkReproductive Health, 2015
- Congenital Asplenia in Mice and Humans with Mutations in a Pbx/Nkx2-5/p15 ModuleDevelopmental Cell, 2012
- Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomesProceedings of the National Academy of Sciences of the United States of America, 2012
- Pbx1 Regulates Self-Renewal of Long-Term Hematopoietic Stem Cells by Maintaining Their QuiescenceCell Stem Cell, 2008
- APbx1-dependent genetic and transcriptional network regulates spleen ontogenyDevelopment, 2005
- Pbx1 is essential for adrenal development and urogenital differentiationgenesis, 2003