Whole-exome sequencing for prenatal diagnosis of fetuses with congenital anomalies of the kidney and urinary tract

Lei, Tingying; Fu, Fang; Li, Ru; Wang, Dan; Wang, Rong-Yue; Jing, Xiangyi; Deng, Qing; Li, Zhou-Zhou; Liu, Ze-Qun; Yang, Xin; Li, Dong-Zhi; Liao, Can

doi:10.1093/ndt/gfx031

Cited by 59 publications

(51 citation statements)

References 32 publications

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“…To date, only one recent study applying exome sequencing for CAKUT cases prenatally detected a HNF1B frameshift variant. 55 In conclusion, similar to previous studies, our study indicated no differences in the prenatal renal phenotypic spectrum between intragenic HNF1B aberrations and 17q12DS, and a wide range of postnatal renal and extra-renal abnormalities for both. The most prominent postnatal phenotypic differences, potentially affecting prenatal decision making, are a more severe progress of renal impairment in individuals with intragenic HNF1B variants and the increased NDD risk, which is a confirmed feature in 17q12DS and suspected in HNF1B…”

Section: Discussionsupporting

confidence: 91%

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Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

et al. 2019

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Objective 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. Methods Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B‐related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in‐frame deletion p.(Gly239del) within the HNF1B DNA‐binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B‐associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up‐to‐date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.

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Section: Discussionsupporting

confidence: 91%

“…To date, only one recent study applying exome sequencing for CAKUT cases prenatally detected a HNF1B frameshift variant . Likewise, the herein reported prenatal identification of an intragenic HNF1B variant in individual I1 is likely a consequence of increased availability and demand for such NGS‐based techniques.…”

Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

et al. 2019

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“…Until now, only 18 fetuses with confirmed disease-causing variations in BBS genes have been reported. 20,[25][26][27][28][29][30][31] Most of the clinical signs found in the fetuses and neonates (polydactyly, renal cysts, hepatic fibrosis without bile duct proliferation and situs inversus) overlap with other ciliopathies. This was confirmed by the report of 10 fetuses referred for "Meckel-like cystic kidneys" mutated in 4 BBS genes (BBS2, BBS4 BBS6 and BBS10).…”

Section: Introductionmentioning

confidence: 99%

Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

et al. 2019

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Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses. K E Y W O R D Santenatal presentation, Bardet-Biedl syndrome, BBS, diagnostic strategy

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“…Another paper on application of WES to CAKUT in the setting of normal CMA showed a detection rate of 2/22 (9.1%) for isolated CAKUT and 2/8 (25%) for CAKUT with other abnormalities. However, larger studies are needed to determine the utility of WES when applied to prenatal CAKUT . Serial ultrasonography for fetal surveillance is often utilized, while the approach to antenatal testing and timing of delivery requires individualization.…”

Section: Approach To Evaluationmentioning

confidence: 99%

“…However, larger studies are needed to determine the utility of WES when applied to prenatal CAKUT. 73 Serial ultrasonography for fetal surveillance is often utilized, while the approach to antenatal testing and timing of delivery requires individualization.…”

Section: Approach To Evaluationmentioning

confidence: 99%

Prenatal genetic considerations of congenital anomalies of the kidney and urinary tract (CAKUT)

2019

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Congenital anomalies of the kidney and urinary tract (CAKUT) constitute 20% of all congenital malformations occurring in one in 500 live births. Worldwide, CAKUT are responsible for 40% to 50% of pediatric and 7% of adult end‐stage renal disease. Pathogenic variants in genes causing CAKUT include monogenic diseases such as polycystic kidney disease and ciliopathies, as well as syndromes that include isolated kidney disease in conjunction with other abnormalities. Prenatal diagnosis most often occurs using ultrasonography; however, further genetic diagnosis may be made using a variety of testing strategies. Family history and pathologic examination can also provide information to improve the ability to make a prenatal diagnosis of CAKUT. Here, we provide a comprehensive overview of genetic considerations in the prenatal diagnosis of CAKUT disorders. Specifically, we discuss monogenic causes of CAKUT, associated ultrasound characteristics, and considerations for genetic diagnosis, antenatal care, and postnatal care.

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Whole-exome sequencing for prenatal diagnosis of fetuses with congenital anomalies of the kidney and urinary tract

Cited by 59 publications

References 32 publications

Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

Prenatal genetic considerations of congenital anomalies of the kidney and urinary tract (CAKUT)

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