Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT)

Wu, Chen‐Han Wilfred; Mann, Nina; Nakayama, Makiko; Connaughton, Dervla M.; Dai, Rufeng; Kolvenbach, Caroline M.; Kause, Franziska; Ottlewski, Isabel; Wang, Chunyan; Klämbt, Verena; Seltzsam, Steve; Lai, Ethan; Selvin, Aravind; Senguttuva, Prabha; Bodamer, Olaf A.; Stein, Deborah R.; Desoky, Sherif El; Kari, Jameela A.; Tasić, Velibor; Bauer, Stuart B.; Shril, Shirlee; Hildebrandt, Friedhelm

doi:10.1038/s41436-020-0844-z

Cited by 16 publications

(14 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This abnormal splicing was also shown to be the etiology of brain malformations and neurodevelopmental disorders in patients with SON mutations (Kim et al, 2016). This mechanism is the most likely cause of the renal anomalies seen in the five patients with deletions of the SON gene there are other reports of genes causing CAKUT with reduced penetrance and variable expressivity (Kitzler et al, 2019;Wu et al, 2020).…”

Section: To the Editormentioning

confidence: 87%

“…Concerning the fact that not all patients with LoF variants or deletions of the SON gene have renal anomalies, we suggest similarly to Kim et al (2019) that heterogeneity of the renal phenotypes is likely due to the presence of multiple downstream targets of SON‐mediated splicing, stochastic functional compensation by other splicing factors, and/or the varying levels of functional efficiency of the nonsense‐mediated RNA decay machinery in each patient. Further, there are other reports of genes causing CAKUT with reduced penetrance and variable expressivity (Kitzler et al, 2019; Wu et al, 2020). As the cardiac defects found in our patient have also been described in patients with ZTTK syndrome, it is likely SON haploinsufficiency is a candidate for many of the congenital abnormalities found in patients with deletions at 21q22.11.…”

Section: Figurementioning

confidence: 98%

See 1 more Smart Citation

Lethal renal anomalies in a fetus with 21q22.11‐q22.12 deletion

Dinh

Mark

2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Section: To the Editormentioning

confidence: 87%

Section: Figurementioning

confidence: 98%

Lethal renal anomalies in a fetus with 21q22.11‐q22.12 deletion

Dinh

Mark

2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

“…Wu et al looked for and found FOXC1 variants enriched in congenital anomalies of kidney and urinary tract 1 (CAKUT1) in affected families. Interestingly, FOXC1 variants linked to the ocular phenotypes clustered in the Forkhead domain (FH) while variants linked to CAUTHED were identified outside of the FH domain (Wu et al, 2020). This observed phenotype overlap for PBX1 and FOXC1 variants alludes to a shared regulatory pathway.…”

Section: Discussionmentioning

confidence: 99%

De novo PBX1 variant in a patient with glaucoma, kidney anomalies, and developmental delay: An expansion of the CAKUTHED phenotype

Safgren

Olson

Vairo

et al. 2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

An infant was referred for evaluation of congenital glaucoma and corneal clouding. In addition, he had a pelvic kidney, hypotonia, patent ductus arteriosus, abnormal pinnae, and developmental delay. Exome sequencing identified a previously unpublished de novo single nucleotide insertion in PBX1 c.400dupG (NM_002585.3), predicted to cause a frameshift resulting in a truncated protein with loss of function (p.Ala134Glyfs*65). Identification of this loss of function variant supports the diagnosis of congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED). Here, we propose glaucoma as an extra‐renal manifestation associated with PBX1‐related disease due to the relationship of PBX1 with MEIS1, MEIS2, and FOXC1 transcription factors associated with eye development.

show abstract

“…The earliest reports on the biologic role and function of the FOXC1 TF implicated it in abnormal pathologic conditions like glaucoma (16)(17)(18)(19)(20)(21)(22)(23), congenital hydrocephalus (24), congenital renal defects (25,26), congenital heart defects (21,(27)(28)(29) and Axenfeld-Rieger Syndrome (21,30,31), a congenital disorder characterized by glaucoma and congenital heart defects.…”

Section: Foxc1: a Prognostic Biomarker Of Cancer Progression And Metastasismentioning

confidence: 99%

Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis

Ray¹,

Ryusaki²,

Ray³

2021

Front. Oncol.

View full text Add to dashboard Cite

Metastasis accounts for more than 90% of cancer related mortality, thus the most pressing need in the field of oncology today is the ability to accurately predict future onset of metastatic disease, ideally at the time of initial diagnosis. As opposed to current practice, what would be desirable is that prognostic, biomarker-based detection of metastatic propensity and heightened risk of cancer recurrence be performed long before overt metastasis has set in. Without such timely information it will be impossible to formulate a rational therapeutic treatment plan to favorably alter the trajectory of disease progression. In order to help inform rational selection of targeted therapeutics, any recurrence/metastasis risk prediction strategy must occur with the paired identification of novel prognostic biomarkers and their underlying molecular regulatory mechanisms that help drive cancer recurrence/metastasis (i.e. recurrence biomarkers). Traditional clinical factors alone (such as TNM staging criteria) are no longer adequately prognostic for this purpose in the current molecular era. FOXC1 is a pivotal transcription factor that has been functionally implicated to drive cancer metastasis and has been demonstrated to be an independent predictor of heightened metastatic risk, at the time of initial diagnosis. In this review, we present our viewpoints on the master regulatory role that FOXC1 plays in mediating cancer stem cell traits that include cellular plasticity, partial EMT, treatment resistance, cancer invasion and cancer migration during cancer progression and metastasis. We also highlight potential therapeutic strategies to target cancers that are, or have evolved to become, “transcriptionally addicted” to FOXC1. The potential role of FOXC1 expression status in predicting the efficacy of these identified therapeutic approaches merits evaluation in clinical trials.

show abstract

Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT)

Cited by 16 publications

References 40 publications

Lethal renal anomalies in a fetus with 21q22.11‐q22.12 deletion

Lethal renal anomalies in a fetus with 21q22.11‐q22.12 deletion

De novo PBX1 variant in a patient with glaucoma, kidney anomalies, and developmental delay: An expansion of the CAKUTHED phenotype

Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis

Contact Info

Product

Resources

About