Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome
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(Published version)
Date
2020
Authors
Arts, P.
Garland, J.
Byrne, A.B.
Hardy, T.S.E.
Babic, M.
Feng, J.
Wang, P.
Ha, T.
King-Smith, S.L.
Schreiber, A.W.
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Journal article
Citation
American Journal of Medical Genetics, Part A, 2020; 182(5):1273-1277
Statement of Responsibility
Tristan S.E. Hardy … Andreas W. Schreiber … Nick Manton, Lynette Moore … Christopher P. Barnett … Hamish S. Scott … et al.
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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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First published:06 March 2020
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© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,provided the original work is properly cited