Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract

Münch, Johannes; Engesser, Marie; Schönauer, Ria; Hamm, J. Austin; Hartig, Christin; Hantmann, Elena; Akay, Gülsen; Pehlivan, Davut; Mitani, Tadahiro; Akdemir, Zeynep Coban; Tüysüz, Beyhan; Shirakawa, Toshihiko; Dateki, Sumito; Claus, Laura; Eerde, Albertien M. van; Smol, Thomas; Devisme, Louise; Franquet, Hélène; Attié‐Bitach, Tania; Wagner, Timo; Bergmann, Carsten; Höhn, Anne Kathrin; Shril, Shirlee; Pollack, Ari; Wegner, Tara; Scott, Abbey; Paolucci, Sarah; Buchan, Jillian G.; Gabriel, George C.; Posey, Jennifer E.; Lupski, James R.; Petit, Florence; McCarthy, A.A.; Pazour, Gregory J.; Lo, Cecilia; Popp, Bernt; Halbritter, Jan

doi:10.1016/j.kint.2022.01.028

Cited by 11 publications

(4 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The effects in ROBO1 mutant murine models appear much more pronounced in the collecting ducts, with severe cystic dilation thereof, than in the proximal renal tubules. Characterized clinically by markedly variable expressivity and intrafamilial variability, biallelic ROBO1 mutations, similar to ciliopathies, lead to not only URA and BRA but also other renal and (in females) uterine anomalies plus extra‐renal abnormalities: cerebral, pituitary, and ocular abnormalities, cardiac abnormalities, and neurodevelopmental delay 73,74 …”

Section: Resultsmentioning

confidence: 99%

“…Characterized clinically by markedly variable expressivity and intrafamilial variability, biallelic ROBO1 mutations, similar to ciliopathies, lead to not only URA and BRA but also other renal and (in females) uterine anomalies plus extra-renal abnormalities: cerebral, pituitary, and ocular abnormalities, cardiac abnormalities, and neurodevelopmental delay. 73,74 RET encodes for the GDNF receptor which, as mentioned earlier, plays a central role in growth and branching of the ureteric bud in early renal development as the mammalian kidney forms via reciprocal induction between the ureteric bud and the metanephric mesenchyme. 1,69,70 Loss of function mutations in RET have been reported in individuals with CAKUT, including BRA and URA, as well as Hirschsprung disease.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The genetic etiologies of bilateral renal agenesis

Kirschen,

Blakemore,

Al‐Kouatly

et al. 2024

Prenatal Diagnosis

View full text Add to dashboard Cite

ObjectiveThe goal of this study was to review and analyze the medical literature for cases of prenatal and/or postnatally diagnosed bilateral renal agenesis (BRA) and create a comprehensive summary of the genetic etiologies known to be associated with this condition.MethodsA literature search was conducted as a scoping review employing Online Mendeliain Inheritance in Man, PubMed, and Cochrane to identify cases of BRA with known underlying genetic (chromosomal vs. single gene) etiologies and those described in syndromes without any known genetic etiology. The cases were further categorized as isolated versus non‐isolated, describing additional findings reported prenatally, postnatally, and postmortem. Inheritance pattern was also documented when appropriate in addition to the reported timing of diagnosis and sex.ResultsWe identified six cytogenetic abnormalities and 21 genes responsible for 20 single gene disorders associated with BRA. Five genes have been reported to associate with BRA without other renal anomalies; sixteen others associate with both BRA as well as unilateral renal agenesis. Six clinically recognized syndromes/associations were identified with an unknown underlying genetic etiology. Genetic etiologies of BRA are often phenotypically expressed as other urogenital anomalies as well as complex multi‐system syndromes.ConclusionMultiple genetic etiologies of BRA have been described, including cytogenetic abnormalities and monogenic syndromes. The current era of the utilization of exome and genome‐wide sequencing is likely to significantly expand our understanding of the underlying genetic architecture of BRA.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The genetic etiologies of bilateral renal agenesis

Kirschen,

Blakemore,

Al‐Kouatly

et al. 2024

Prenatal Diagnosis

View full text Add to dashboard Cite

show abstract

“…In fact, the strong variable expressivity of these genetic defects underlies the clinical observation that multiple CAKUT phenotypes occur within individual families, and even within the same individual, notwithstanding the fact that all members carry the same genetic mutation. [46][47][48] The finding that the molecular etiology of COU subcategories shows strong similarities is important because the exact clinical definition of COU phenotypes, and CAKUT at large, is often challenging. Therefore, if our capability to ascertain diagnosis, prognosis, and treatment at the individual level is currently limited, this observed genetic heterogeneity and variable expressivity of COU legitimize a genetic first diagnostic approach to these developmental defects, even when extensive (and potentially burdening) clinical and imaging characterization is not completely available or uniform.…”

Section: Discussionmentioning

confidence: 99%

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis

Ahram

Lim

et al. 2023

JASN

View full text Add to dashboard Cite

Background: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. Methods: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction (UPJO; n=321), ureterovesical junction obstruction/congenital megaureter (UVJO; n=178), and congenital hydronephrosis not otherwise specified (COU-NOS; n=234). We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders in 23 (3.1%) cases. No significant differences in the overall diagnostic yield among COU sub-phenotypes nor pathogenic SNVs in several genes were associated with any of the three categories. Discussion: Although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. However, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and genomic disorders suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. Conclusion: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

show abstract

“…Although identifying new CAKUT-causing genes remains challenging due to high genetic heterogeneity, variable expressivity and incomplete penetrance (van der Ven et al 2018b ), gene discovery has been accelerated by the advent and large-scale use of next generation sequencing (NGS) technologies. Dominant genes associated with human CAKUT using NGS include DSTYK (Sanna-Cherchi et al 2013 ), TBX18 (Vivante et al 2015 ), TBC1D1 (Kosfeld et al 2016 ), PBX1 (Heidet et al 2017 ), GREB1L (Brophy et al 2017 ; De Tomasi et al 2017 ), LIFR (Kosfeld et al 2017 ; Christians et al 2020 ), TBX6 (Verbitsky et al 2019 ; Yang et al 2020 ), GDF6 (Martens et al 2020 ), and ZMYM2 (Connaughton et al 2020 ); recessive genes include ITGA8 (Humbert et al 2014 ) and ROBO1 (Münch et al 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes–Brocks syndrome 2

et al. 2022

View full text Add to dashboard Cite

Most patients with congenital anomalies of the kidney and urinary tract (CAKUT) remain genetically unexplained. In search of novel genes associated with CAKUT in humans, we applied whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies, and identified a rare heterozygous missense variant in the DACT1 (dishevelled binding antagonist of beta catenin 1) gene encoding a cytoplasmic WNT signaling mediator. Our patient’s features overlapped Townes–Brocks syndrome 2 (TBS2) previously described in a family carrying a DACT1 nonsense variant as well as those of Dact1-deficient mice. Therefore, we assessed the role of DACT1 in CAKUT pathogenesis. Taken together, very rare (minor allele frequency ≤ 0.0005) non-silent DACT1 variants were detected in eight of 209 (3.8%) CAKUT families, significantly more frequently than in controls (1.7%). All seven different DACT1 missense variants, predominantly likely pathogenic and exclusively maternally inherited, were located in the interaction region with DVL2 (dishevelled segment polarity protein 2), and biochemical characterization revealed reduced binding of mutant DACT1 to DVL2. Patients carrying DACT1 variants presented with kidney agenesis, duplex or (multi)cystic (hypo)dysplastic kidneys with hydronephrosis and TBS2 features. During murine development, Dact1 was expressed in organs affected by anomalies in patients with DACT1 variants, including the kidney, anal canal, vertebrae, and brain. In a branching morphogenesis assay, tubule formation was impaired in CRISPR/Cas9-induced Dact1−/− murine inner medullary collecting duct cells. In summary, we provide evidence that heterozygous hypomorphic DACT1 variants cause CAKUT and other features of TBS2, including anomalies of the skeleton, brain, distal digestive and genital tract.

show abstract

Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract

Cited by 11 publications

References 48 publications

The genetic etiologies of bilateral renal agenesis

The genetic etiologies of bilateral renal agenesis

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis

Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes–Brocks syndrome 2

Contact Info

Product

Resources

About