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

TitlePaternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome.
Publication TypeJournal Article
Year of Publication2020
AuthorsArts, P, Garland, J, Byrne, AB, Hardy, TSE, Babic, M, Feng, J, Wang, P, Ha, T, King-Smith, SL, Schreiber, AW, Crawford, A, Manton, N, Moore, L, Barnett, CP, Scott, HS
JournalAm J Med Genet A
Volume182
Issue5
Pagination1273-1277
Date Published2020 May
ISSN1552-4833
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.

DOI10.1002/ajmg.a.61541
Alternate JournalAm. J. Med. Genet. A
PubMed ID32141698
PubMed Central IDPMC7217179
Grant List / / Cancer Council South Australia /
/ / Hospital Research Foundation /
APP1023059 / / National Health and Medical Research Council /
APP1123341 / / National Health and Medical Research Council /
GNT1113531 / / National Health and Medical Research Council /
HG008900 / HG / NHGRI NIH HHS / United States
HG008900 / HG / NHGRI NIH HHS / United States