The Evaluation of Genetic Diagnosis on High-Risk Fetal CAKUT

Abstract

Background: It is challenging to make an accurate prenatal diagnosis for congenital anomalies of the kidney and urinary tract (CAKUT) because of its pathologic diversity. This study aims to evaluate the performance of whole-exome sequencing (WES) combined with karyotype analysis and copy number variations (CNVs) in diagnosing high-risk fetal CAKUT.Methods: We conducted a retrospective study on prenatal diagnoses of CAKUT in our hospital from January 2020 to April 2021. The research studied 24 high-risk fetuses with CAKUT who were scanned by ultrasonography at the prenatal diagnosis center of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. The likely pathogenic gene variants were screened for the patients and their parents by multiple approaches, including karyotype analysis, CNVs and WES, and further verified with Sanger sequencing.Results: ①We detected abnormal CNVs in 20.8% (5/24) of the fetuses but only 8.3% (2/24) fetuses had abnormal karyotypes. ②Of the 15 CAKUT fetuses, positive findings (40%) were detected by WES. Of the 9 high-risk fetuses with CAKUT (negative findings in ultrasound scan but with family history), we found abnormal variants (77.8%) through WES.Conclusion: The application of CNVs and WES showed advance in prenatal diagnosis of CAKUT and the pathogenic gene variants were detectable especially for high-risk fetuses with negative ultrasound findings on CAKUT in the preliminary study. The applied strategy could be used to improve the accuracy of prenatal diagnosis for CAKUT in the future.

Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT

“…It was thus proposed that a balanced level of functional PKD1 protein is important to maintain tubular architecture 48 . Although PKD1 could have a possible role in the development of CAKUT 49 , we did not notice the difference in PKD1 mRNA levels in MIR484 +/− KO compared to HEK293 WT. By taking into account the previously described regulation of the FIS1 which is depicted in the inhibition of translation 41 there is a need for further functional studies to clarify the role of PKD1 in CAKUT regarding hsa-miR-484 downregulation.…”

When should we offer antenatal sequencing for urinary tract malformations? A systematic review, cohort study and meta‐analysis

“…42,43 Of relevance to the current report, it can be associated with genetic syndromes such as PKD and other ciliopathies, as well as the renal cysts and diabetes syndrome. 6,13 With the lower yield for all other anomalies pooled together excluding BEK being less than 10% collectively, it appears that the most common prenatal presentation for a single gene disorder affecting the urinary tract is that of BEK. This would, furthermore, justify this as inclusion criteria for the NHSE PES case selection.…”

“…There is currently no universally agreed upon classification system for CAKUT or prenatal UTMs. 12,29 Older anatomically based classification systems of 13 and future classifications of UTMs, as will be true in other organ systems, are sure to be classified by the disorders as defined by their underlying genetic etiologies. The most significant study limitation as evident from the emerging dominant subgroup of BEKs, is that of selection bias of cases within all studies, including the NHSE cohort, hence the incremental yield of non-BEKs should be interpreted with caution as it represents a potential under-representation as such cases may not have been selected for PES in the first instance.…”

“…12 In recent decades, with advances in human genomics, attention has begun to focus on defining potential genetic causes of UTMs, including those detected before birth. 5,7,13,14 Such information, in turn, can give families a reason as to why the UTM occurred to inform genetic counseling and to help plan clinical management because the postnatal clinical trajectory of specific diseases, for example, kidney dysplasia versus ARPKD, may differ. 15 Aneuploidy or pathogenic copy number variants are detected in 40% of prenatally detected anomalies using standard diagnostic methods, G-banding karyotyping and chromosomal microarray (CMA), respectively.…”

“…When fetal UTMs are detected, it is imperative to allow parents to make informed decisions about the pregnancy, including the decision to terminate, planning for postnatal care or to inform future pregnancies 12 . In recent decades, with advances in human genomics, attention has begun to focus on defining potential genetic causes of UTMs, including those detected before birth 5,7,13,14 . Such information, in turn, can give families a reason as to why the UTM occurred to inform genetic counseling and to help plan clinical management because the postnatal clinical trajectory of specific diseases, for example, kidney dysplasia versus ARPKD, may differ 15 …”