Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome.

Autor: Arts P; 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., Garland J; Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, Adelaide, South Australia, Australia., Byrne AB; 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.; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.; Australian Genomics Health Alliance, Melbourne, Victoria, Australia., Hardy TSE; 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.; Repromed, Dulwich, Australia.; School of Medicine, University of Adelaide, Adelaide, South Australia, Australia., Babic M; 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., Feng J; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.; ACRF Cancer Genomics Facility, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia., Wang P; ACRF Cancer Genomics Facility, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia., Ha T; 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., King-Smith SL; 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.; Australian Genomics Health Alliance, Melbourne, Victoria, Australia., Schreiber AW; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.; ACRF Cancer Genomics Facility, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.; School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia., Crawford A; Department of Anatomical Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia., Manton N; Department of Anatomical Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia., Moore L; School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.; Department of Anatomical Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia., Barnett CP; Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, Adelaide, South Australia, Australia.; School of Medicine, University of Adelaide, Adelaide, South Australia, Australia., Scott HS; 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.; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.; School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.; ACRF Cancer Genomics Facility, Centre for Cancer Biology, An Alliance Between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.; Australian Genomics Health Alliance, Melbourne, Victoria, Australia.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2020 May; Vol. 182 (5), pp. 1273-1277. Date of Electronic Publication: 2020 Mar 06.
DOI: 10.1002/ajmg.a.61541
Abstrakt: 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.
(© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
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