Genome-Wide Survey for Microdeletions or -Duplications in 155 Patients with Lower Urinary Tract Obstructions (LUTO)

Schierbaum, Luca; Schneider, Sophia; Herms, Stefan; Sivalingam, Sugirthan; Fabian, Julia; Reutter, Heiko; Weber, Stefanie; Merz, Waltraut M.; Tkaczyk, Marcin; Miklaszewska, Monika; Sikora, Przemysław; Szmigielska, Agnieszka; Krzemień, Grażyna; Zachwieja, Katarzyna; Szczepańska, Maria; Taranta-Janusz, Katarzyna; Kroll, Paweł; Polok, Marcin; Zaniew, Marcin; Hilger, Alina C.

doi:10.3390/genes12091449

Cited by 4 publications

(4 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intriguingly, we demonstrated an enrichment of rare duplications and inversions affecting cCREs. Genomic duplications have previously been linked with PUV ( Schierbaum et al, 2021 ; Verbitsky et al, 2019 ) but this is the first study to examine balanced inversions in a PUV cohort. Current understanding of the functional relevance of inversions is limited as the balanced nature and location of breakpoints within complex repeat regions make detection challenging ( Puig et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, a monogenic etiology for isolated PUV has not been identified. Case reports of chromosomal abnormalities resulting in PUV as part of a wider syndrome ( Demirkan, 2021 ; Houcinat et al, 2011 ; Tong et al, 2015 ) and microarray-based studies linking rare copy number variants (CNVs) with PUV ( Boghossian et al, 2016 ; Caruana et al, 2016 ; Faure et al, 2016 ; Schierbaum et al, 2021 ; Verbitsky et al, 2019 ) suggest that structural variation, and in particular duplications ( Schierbaum et al, 2021 ; Verbitsky et al, 2019 ), may be important, but no recurrent CNVs have demonstrated consistent association with PUV. The observation that isolated PUV does not usually follow a classical Mendelian inheritance pattern, and that a monogenic cause has not been identified, suggests that the underlying genetic architecture of this rare disorder is likely to be complex.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves

Chan

Sadeghi-Alavijeh

Lopes

et al. 2022

eLife

Self Cite

View full text Add to dashboard Cite

Posterior urethral valves (PUV) are the commonest cause of end-stage renal disease in children, but the genetic architecture of this rare disorder remains unknown. We performed a sequencing-based genome-wide association study (seqGWAS) in 132 unrelated male PUV cases and 23,727 controls of diverse ancestry, identifying statistically significant associations with common variants at 12q24.21 (P=7.8x10-12; OR 0.4) and rare variants at 6p21.1 (P=2.0x10-8; OR 7.2), that were replicated in an independent European cohort of 395 cases and 4,151 controls. Fine-mapping and functional genomic data mapped these loci to the transcription factor TBX5 and planar cell polarity gene PTK7, respectively, the encoded proteins of which were detected in the developing urinary tract of human embryos. We also observed enrichment of rare structural variation intersecting with candidate cis-regulatory elements, particularly inversions predicted to affect chromatin looping (P=3.1x10-5). These findings represent the first robust genetic associations of PUV, providing novel insights into the underlying biology of this poorly understood disorder and demonstrate how a diverse ancestry seqGWAS can be used for disease locus discovery in a rare disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves

Chan

Sadeghi-Alavijeh

Lopes

et al. 2022

eLife

Self Cite

View full text Add to dashboard Cite

show abstract

“…7 Strong phenotypic variation can occur within a family. 5,8 However, besides disease-causing copy number variations in individual cases [10][11][12] only one monogenic cause has been described so far. 8 During the sampling process for the genetic part of "CaRE for LUTO (Cause and Risk Evaluation for LUTO)" study, we unexpectedly noticed that several parents of LUTO children described discrete lower urinary tract symptoms, possibly in line with mild LUTOs and intrafamilial variable phenotypic expression.…”

Section: Introductionmentioning

confidence: 99%

Familial congenital lower urinary tract obstruction (LUTO) suggested by screening for lower urinary tract dysfunction in parents of patients: A descriptive study

Ebach,

Wagner,

Stein

et al. 2024

Health Science Reports

Self Cite

View full text Add to dashboard Cite

BackgroundCongenital lower urinary tract obstruction (LUTO) describes a heterogeneous group of congenital malformations. Posterior urethral valves (PUV) represent the most common entity. Familial occurrence has been described, suggestive of underlying genetic factors. LUTO can occur in various degrees of severity. In severe forms, oligohydramnios, pulmonary hypoplasia, and renal damage can occur resulting in high pre‐ and postnatal mortality. On the contrary, mild forms may become apparent through recurrent urinary tract infections. Such high phenotypic variability has been described even within the same family. Here, we systematically screened parents of affected children for symptoms of LUTO.MethodsThe study population consisted of parents of LUTO patients. Fathers over 50 years of age were excluded, to avoid inclusion of male phenocopies due to early prostatic hypertrophy. Uroflowmetry, ultrasonography for residual urine and hydronephrosis, and laboratory examination of standard renal retention parameters were assessed, and a detailed patient history was taken, including the assessment of the International Prostate Symptom Score.ResultsTwenty‐nine of 42 LUTO families enrolled were found eligible for the present study. Of these, we identified five families in which the father had already been diagnosed with infravesical obstruction (17%). Of the remaining families, nine agreed to participate in our study. Of these nine families, eight families had a child affected with PUV and one family had a child with urethral stenosis. Here, we found two fathers and one mother with symptoms of LUTO suggestive of mild LUTO and one family, in which the unborn male fetal brother of the affected index patient was also diagnosed prenatally with LUTO.ConclusionOur observations suggest that LUTOs have a higher heritability than previously thought and that first‐degree relatives of the affected should be clinically assessed for symptoms of LUTO.

show abstract

“…Furthermore, Bartels, Schulz, et al, 2012 reported higher concordance rates among monozygotic twin pairs. Over the last decade, molecular karyotyping and sequencing based approaches identified rare disease‐causing copy number variations (Schramm et al, 2011; Brosens et al, 2016; Dworschak et al, 2013; A. Hilger et al, 2013; Schierbaum et al, 2021; Zhang et al, 2017) and putative disease‐causing single nucleotide variants in novel human candidate genes FOXF1 , HSPA6 , HAAO , KYNU , TRAP1 , and ZIC3 (Hilger et al, 2015; Kause et al, 2019; Saisawat et al, 2014; Shi et al, 2017). Up to now, re‐sequencing of larger cohorts was only performed for TRAP1 , ZIC3 , and FOXF1 ( Hilger et al, 2015; Saisawat et al, 2014 ) , confirming TRAP1 and ZIC3 as disease‐genes for VATER/VACTERL phenotypes and isolated ARM.…”

Section: Introductionmentioning

confidence: 99%

Re‐sequencing of candidate genes FOXF1, HSPA6, HAAO, and KYNU in 522 individuals with VATER/VACTERL, VACTER/VACTERL‐like association, and isolated anorectal malformation

Thiem

Stegmann

Hilger

et al. 2022

Birth Defects Research

Self Cite

View full text Add to dashboard Cite

Background The acronym VATER/VACTERL association describes the combination of at least three component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Individuals presenting two CFs have been termed VATER/VACTERL‐like. Recently, FOXF1, HSPA6, HAAO, KYNU, TRAP1, and ZIC3 have been proposed as candidate genes for VATER/VACTERL, VATER/VACTERL‐like, and ARM. Re‐sequencing studies identified disease‐causing variants in TRAP1 and ZIC3, the contribution of other genes was not independently investigated. One affected variant carrier in FOXF1 was previously identified. Here we re‐sequenced FOXF1, HSPA6, HAAO, and KYNU in 522 affected individuals. Methods Using molecular inversion probe (MIP) technology, re‐sequencing was performed in 63 individuals with VATER/VACTERL association, 313 with VATER/VACTERL‐like association, and 146 with ARM. All individuals were of European ethnicity. Variant filtering considered variants with a minor allele frequency (MAF) ≤0.01 for putative recessive disease‐genes HSPA6, HAAO, and KYNU. For the putative dominant disease‐gene FOXF1 we considered variants with a MAF ≤0.0001. In silico prediction tools were used for further prioritization. Results Only two variants in FOXF1 in two independently affected individuals [c.443G>T, p.(Cys148Phe); c.850T>C, p.(Tyr284His)] passed our filter criteria. One individual presented with ARM, the second presented with TE and C comprising atrial and ventricular septal defects. Sanger sequencing confirmed both variants but also their inheritance from the healthy mother. Conclusion Our analysis suggests that FOXF1, HSPA6, HAAO and KYNU do not play a major role in the formation of VACTER/VACTERL phenotypes or ARM.

show abstract

Genome-Wide Survey for Microdeletions or -Duplications in 155 Patients with Lower Urinary Tract Obstructions (LUTO)

Cited by 4 publications

References 26 publications

Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves

Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves

Familial congenital lower urinary tract obstruction (LUTO) suggested by screening for lower urinary tract dysfunction in parents of patients: A descriptive study

Re‐sequencing of candidate genes FOXF1, HSPA6, HAAO, and KYNU in 522 individuals with VATER/VACTERL, VACTER/VACTERL‐like association, and isolated anorectal malformation

Contact Info

Product

Resources

About