Inherited intragenic <scp><i>PBX1</i></scp> deletion: Expanding the phenotype

Fitzgerald, K.; Powell-Hamilton, Nina; Shillingford, Amanda J.; Robinson, Bradley; Gripp, Karen W.

doi:10.1002/ajmg.a.61932

Cited by 5 publications

(7 citation statements)

References 12 publications

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“…Remarkably, genetic PBX1 alterations are rarely found to be familial. In the literature, only two instances of parental transmission have been reported [ 9 , 10 ], whereas all other cases are described as being de novo (29/31) (Table 1 ), although low-grade mosaicism in the parents cannot fully be excluded without more sensitive sequencing techniques, such as NGS.…”

Section: Discussionmentioning

confidence: 99%

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

Petzold

Hantmann

et al. 2022

Clinical Kidney Journal

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Background Congenital abnormalities of the kidney and urinary tract (CAKUT) are characterized by vast phenotypic heterogeneity and incomplete penetrance. Although CAKUT represent the main cause of pediatric chronic kidney disease, only around 20% can be explained by single-gene disorders to date. While pathogenic alterations of PBX1 were recently associated with a severe form of syndromic CAKUT, most CAKUT-patients survive childhood and adolescence to reach end-stage kidney disease later in life. Although somatic mosaicism is known to attenuate severity in other kidney diseases, it has rarely been described nor systematically been assessed in CAKUT. Methods In-depth phenotypic characterization of the index patient and his family. Targeted next-generation sequencing (NGS), segregation analysis, and work-up of mosaicism with DNA isolated from peripheral blood cells, oral mucosa, and cultured urinary renal epithelial cells (URECs). Results Somatic mosaicism was identified in a 20-year-old male with sporadic but mild syndromic renal hypoplasia. He was found to carry a novel de novo truncating variant in PBX1 (c.992C > A, p.(Ser331*)). This variant was detected in 26% of sequencing reads from blood cells, 50% from oral mucosa, and 20% from cultured URECs. Conclusions PBX1 associated CAKUT is characterized by a wealth of de novo mutations. As in de novo cases, mutations can occur intra- or post-zygotically, genetic mosaicism might represent a more common phenomenon in PBX1-disease, accounting for variable expressivity on a general basis. Consequently, we suggest ruling out somatic mosaicism in sporadic CAKUT, notably in attenuated and atypical clinical courses.

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Section: Discussionmentioning

confidence: 99%

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

Petzold

Hantmann

et al. 2022

Clinical Kidney Journal

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“…Thirty patients with heterozygous pathogenic mutations and partial or complete heterozygous deletions of PBX1 have been reported in the literature (Alankarage et al, 2020; Bertoli‐Avella et al, 2021; Eozenou et al, 2019; Fitzgerald et al, 2021; Fromer et al, 2014; Heidet et al, 2017; Le Tanno et al, 2017; Riedhammer et al, 2017; Slavotinek et al, 2017), and 10 additional patients are reported in the ClinVar, DECIPHER, and HGMD databases. Their clinical data are summarized in Table 2.…”

Section: Pbx1 Variations In Humansmentioning

confidence: 99%

Section: Pbx1 Variations In Humansmentioning

confidence: 99%

“…To date, 17 patients have been reported with whole or partial deletions of PBX1 (Fitzgerald et al, 2021; Heidet et al, 2017; Le Tanno et al, 2017) of whom 3 were siblings (Fitzgerald et al, 2021). The size of these deletions ranged from 37 kb (Fitzgerald et al, 2021) to 18 Mb (patient 398083 from DECIPHER). Nine patients were described as presenting LOF variations (nonsense, splice, or frame‐shift variations, including indels) and six had documented phenotypes.…”

Section: Pbx1 Variations In Humansmentioning

confidence: 99%

Section: Pbx1 Loss-of-function (Lof)mentioning

confidence: 99%

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The TALE never ends: A comprehensive overview of the role of PBX1, a TALE transcription factor, in human developmental defects

et al. 2022

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PBX1 is a highly conserved atypical homeodomain transcription factor (TF) belonging to the TALE (three amino acid loop extension) family. Dimerized with other TALE proteins, it can interact with numerous partners and reach dozens of regulating sequences, suggesting its role as a pioneer factor. PBX1 is expressed throughout the embryonic stages (as early as the blastula stage) in vertebrates. In human, PBX1 germline variations are linked to syndromic renal anomalies (CAKUTHED). In this review, we summarized available data on PBX1 functions, PBX1‐deficient animal models, and PBX1 germline variations in humans. Two types of genetic alterations were identified in PBX1 gene. PBX1 missense variations generate a severe phenotype including lung hypoplasia, cardiac malformations, and sexual development defects (DSDs). Conversely, truncating variants generate milder phenotypes (mainly cryptorchidism and deafness). We suggest that defects in PBX1 interactions with various partners, including proteins from the HOX (HOXA7, HOXA10, etc.), WNT (WNT9B, WNT3), and Polycomb (BMI1, EED) families are responsible for abnormal proliferation and differentiation of the embryonic mesenchyme. These alterations could explain most of the defects observed in humans. However, some phenotype variability (especially DSDs) remains poorly understood. Further studies are needed to explore the TALE family in greater depth.

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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

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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.

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Inherited intragenic PBX1 deletion: Expanding the phenotype

Cited by 5 publications

References 12 publications

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

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

The TALE never ends: A comprehensive overview of the role of PBX1, a TALE transcription factor, in human developmental defects

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

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