Novel somatic <i>PBX1</i> mosaicism likely masking syndromic CAKUT in an adult with bilateral kidney hypoplasia

Petzold, Friederike; Wu, Jin; Hantmann, Elena; Korbach, Katharina; Schönauer, Ria; Halbritter, Jan

doi:10.1093/ckj/sfac092

Cited by 4 publications

(1 citation statement)

References 23 publications

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“…Renal agenesis, hyperechogenicity, pelvicalyceal dilation, bilateral nephroureters, ectopic kidneys, horseshoe-shaped kidneys, bilateral vesicoureteral reflux, and small urethral valves are common PBX1 mutant renal phenotypes, though renal agenesis is rarer. In the study by Petzold et al (2022), chronic kidney disease stage 3 was observed at the time of the onset except in two adult patients with bilateral renal hypoplasia. Most patients were younger than 5 years of age at the time of their first diagnosis, and their renal functions declined variably.…”

Section: Pbx1 In Renal Developmentmentioning

confidence: 90%

Comprehensive overview of the role of PBX1 in mammalian kidneys

Zou

Liu

Sui

et al. 2023

Front. Mol. Biosci.

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Pre-B-cell leukemia homeobox transcription factor 1 (PBX1) is a member of the TALE (three-amino acid loop extension) family and functions as a homeodomain transcription factor (TF). When dimerized with other TALE proteins, it can act as a pioneer factor and provide regulatory sequences via interaction with partners. In vertebrates, PBX1 is expressed during the blastula stage, and its germline variations in humans are interrelated with syndromic anomalies of the kidney, which plays an important role in hematopoiesis and immunity among vertebrates. Herein, we summarize the existing data on PBX1 functions and the impact of PBX1 on renal tumors, PBX1-deficient animal models, and blood vessels in mammalian kidneys. The data indicated that the interaction of PBX1 with different partners such as the HOX genes is responsible for abnormal proliferation and variation of the embryonic mesenchyme, while truncating variants were shown to cause milder phenotypes (mostly cryptorchidism and deafness). Although such interactions have been identified to be the cause of many defects in mammals, some phenotypic variations are yet to be understood. Thus, further research on the TALE family is required.

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Section: Pbx1 In Renal Developmentmentioning

confidence: 90%

Comprehensive overview of the role of PBX1 in mammalian kidneys

Zou

Liu

Sui

et al. 2023

Front. Mol. Biosci.

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Whole Exome Sequencing Revealing a Novel PBX1 Gene Variant in a Chinese Family Causing Recurrent Neonatal Death

Huang,

Zhang,

Huang

et al. 2024

Birth Defects Research

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BackgroundCausative mutations of PBX1 are associated with congenital abnormalities of the kidney and urinary tract (CAKUT), often accompanied by hearing loss, abnormal ear morphology, or developmental delay. The aim of the present investigation was to introduce a novel variant in the PBX1 gene identified in a Chinese family, leading to recurrent neonatal mortality.MethodsA pregnant woman (gravida 5, para 0), who had experienced recurrent neonatal deaths, sought genetic etiology diagnosis. Whole exome sequencing (WES) was conducted to identify sequence variants and copy number variants in the fetus presenting with posterior nuchal cystic hygroma and fetal hydrops.ResultsA novel NM_002585.4:c.694G>C(p.D232H) in PBX1 was identified in the fetus through trio whole exome sequencing (WES), revealing a paternal mosaic PBX1 variant in blood at 11.54% (6/52 variants reads). Subsequent parental Sanger sequencing confirmed the variant detected by WES. Ultimately, the variant was classified as likely pathogenic, leading the family to elect pregnancy termination at 17 weeks gestation.ConclusionThe novel variant in the PBX1 gene appears to be a significant factor contributing to recurrent neonatal deaths in the Chinese family. Such findings expand the spectrum of PBX1 gene variants and provide valuable perinatal guidance for diagnosing fetuses with PBX1 mutations.

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Relevance of next generation sequencing (NGS) data re-analysis in the diagnosis of monogenic diseases leading to organ failure

Saglia,

Bracciamà,

Trotta

et al. 2023

BMC Med Genomics

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Background In 2018, our center started a program to offer genetic diagnosis to patients with kidney and liver monogenic rare conditions, potentially eligible for organ transplantation. We exploited a clinical exome sequencing approach, followed by analyses of in silico gene panels tailored to clinical suspicions, obtaining detection rates in line with what reported in literature. However, a percentage of patients remains without a definitive genetic diagnosis. This work aims to evaluate the utility of NGS data re-analysis for those patients with an inconclusive or negative genetic test at the time of first analysis considering that (i) the advance of alignment and variant calling processes progressively improve the detection rate, limiting false positives and false negatives; (ii) gene panels are periodically updated and (iii) variant annotation may change over time. Methods 114 patients, recruited between 2018 and 2020, with an inconclusive or negative NGS report at the time of first analysis, were included in the study. Re-alignment and variant calling of previously generated sequencing raw data were performed using the GenomSys Variant Analyzer software. Results 21 previously not reported potentially causative variants were identified in 20 patients. In most cases (n = 19), causal variants were retrieved out of the re-classification from likely benign to variants of unknown significance (VUS). In one case, the variant was included because of inclusion in the analysis of a newly disease-associated gene, not present in the original gene panel, and in another one due to the improved data alignment process. Whenever possible, variants were validated with Sanger sequencing and family segregation studies. As of now, 16 out of 20 patients have been analyzed and variants confirmed in 8 patients. Specifically, in two pediatric patients, causative variants were de novo mutations while in the others, the variant was present also in other affected relatives. In the remaining patients, variants were present also in non-affected parents, raising questions on their re-classification. Conclusions Overall, these data indicate that periodic and systematic re-analysis of negative or inconclusive NGS data reports can lead to new variant identification or reclassification in a small but significant proportion of cases, with benefits for patients’ management.

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Novel somatic PBX1 mosaicism likely masking syndromic CAKUT in an adult with bilateral kidney hypoplasia

Cited by 4 publications

References 23 publications

Comprehensive overview of the role of PBX1 in mammalian kidneys

Comprehensive overview of the role of PBX1 in mammalian kidneys

Whole Exome Sequencing Revealing a Novel PBX1 Gene Variant in a Chinese Family Causing Recurrent Neonatal Death

Relevance of next generation sequencing (NGS) data re-analysis in the diagnosis of monogenic diseases leading to organ failure

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