A Likely Pathogenic Variant of PBX1: Abnormal Renal Morphology and Multiple Cardiac Anomalies Identified By Fetal Ultrasound
Document Type
Conference Proceeding
Publication Date
2024
Publication Title
Genetics in Medicine Open
Abstract
Background: The Pre-B cell leukemia homeobox 1 (PBX1) gene on chromosome 1 encodes a transcription factor belonging to a family of proteins that interact with Hox proteins to regulate cellular proliferation and differentiation. PBX1 is constitutively expressed in many tissues throughout the body, including the bladder, kidneys, heart and brain. During embryonic development, it is crucial in various pathophysiological processes in osteogenesis, renal morphogenesis and morphologic mapping. Several PBX1 variants have been recently reported to be associated with CAKUTHED syndrome, characterized by kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay. Additional case reports demonstrated de novo missense PBX1 variants in patients with congenital cardiac defects such as outflow tract anomalies, septal defects, and great arteries. In this study, we present a case that showed fetal congenital heart defects and renal anomalies and c.863G>A (p.Arg288Gln) identified on exome sequencing (ES), which has not been previously reported in databases. This variant may be indicative of potential pathological variants of the PBX1 gene. Case presentation: A 30-year-old primigravida was referred to genetic counseling at 18 weeks gestation for a suspected cardiac defect involving the great arteries identified on anatomy ultrasound. Maternal past medical history was significant for benign Rolandic childhood epilepsy, not requiring antiepileptics, and ADHD managed with Methylphenidate. Her partner had a history of Hodgkin’s lymphoma treated by radiation. The relationship was non-consanguineous. This pregnancy was conceived with in vitro fertilization and intracytoplasmic sperm injection. Preimplantation genetic testing for aneuploidy demonstrated euploid male. A detailed anatomy ultrasound and fetal echocardiogram revealed overriding aorta, anterior malalignment, large outlet ventricular septal defect, and pulmonary stenosis, suggestive of Tetralogy of Fallot. Additional findings included abnormal renal morphology, empty bilateral renal fossa, and kidney-appearing structures in the lower abdomen traversing the pelvis. The fetal bladder and adrenal glands appeared normal. There was normal amniotic fluid. Amniocentesis was performed for karyotype, chromosomal microarray and exome sequencing (ES). The karyotype was normal male and chromosomal microarray identified a paternally inherited 22q11.23-22q11.23 duplication of unknown significance (1.349Mb) spanning 42 genes. ES indicated a heterozygous de novo, likely pathologic variant in PBX1 with an autosomal dominant mode of inheritance. Specifically, this represents a damaging missense mutation designated c.863G>A not previously reported or classified in population databases. Previously published case reports describing PBX1 deletion and missense variants identified renal and cardiac anomalies on prenatal imaging, including Tetralogy of Fallot, septal defects and ectopic kidney. The couple was counseled that the de novo PBX1 variant was likely the cause of the fetal anomalies and the range of potential neonatal outcomes was described. Although not considered to be contributory to the fetal anomalies, the impact of the 22q11.23 microduplication on neurodevelopment and possible interaction with PBX1 is uncertain. The couple opted for pregnancy termination via dilation and evacuation. No autopsy was performed per the patient's request. Conclusion: Multidisciplinary antenatal discussions remain a vital aspect of patient care when fetal anomalies are identified on ultrasound, especially when the suspected genetic disorders are widely heterogenous such as those described to be associated with PBX1. Phenotype-genotype correlations provide essential information to patients when determining desired clinical management in these situations. Further case reports and specific genetic characterizations are important to provide the tools patients need when developing personal goals of care.
Volume
2
Issue
Suppl 1
Recommended Citation
Perry E, Miller M, Heuerman A, Ahn H. A likely pathogenic variant of PBX1: abnormal renal morphology and multiple cardiac anomalies identified by fetal ultrasound. Genet Med Open. 2024;2(Suppl 1). doi:10.1016/j.gimo.2024.101705
DOI
10.1016/j.gimo.2024.101705
Comments
2024 ACMG (American College of Medical Genetics and Genomics) Annual Clinical Genetics Meeting, March 12-16, 2024, Toronto, Canada