Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome |
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| Authors: | Peer Arts Jessica Garland Alicia B Byrne Tristan SE Hardy Milena Babic Jinghua Feng Paul Wang Thuong Ha Sarah L King‐Smith Andreas W Schreiber April Crawford Nick Manton Lynette Moore Christopher P Barnett Hamish S Scott |
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| Institution: | 1. Genetics and Molecular Pathology Research Laboratory, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia;2. Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, Adelaide, South Australia, Australia;3. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia;4. Australian Genomics Health Alliance, Melbourne, Victoria, Australia;5. Repromed, Dulwich, Australia;6. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia;7. ACRF Cancer Genomics Facility, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia;8. School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia;9. Department of Anatomical Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia;10. Professor Hamish S. Scott, Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, PO Box 14, Rundle Mall, South Australia 5000, Australia.;11. A/Professor Christopher P. Barnett, Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, 72 King William Rd, North Adelaide, South Australia 5006, Australia.;12. https://orcid.org/0000-0002-5813-631X |
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| 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. |
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| Keywords: | paternal mosaicism
PBX1‐related multisystem congenital anomaly syndrome phenotype expansion recurrence risk |
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