RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects

Jeanpierre, C.; Macé, G.; Parisot, Mélanie; Morinière, Vincent; Pawtowsky, A.; Benabou, Marion; Martinovic, Jéléna; Amiel, Jeanne; Attié‐Bitach, Tania; Delezoide, Anne‐Lise; Loget, Philippe; Blanchet, P.; Gaillard, Dominique; Gonzalès, Marie; Carpentier, Wassila; Nitschké, Patrick; Torès, Frédéric; Heidet, Laurence; Antignac, Corinne; Salomon, Rémi

doi:10.1136/jmg.2010.088526

Cited by 59 publications

(45 citation statements)

References 54 publications

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“…These genes were chosen, because (1) they are routinely screened in our laboratory, (2) they have been shown to also be involved in patients with CAKUT without extrarenal anomalies (5,(13)(14)(15), and (3) PAX2 was recently shown to be involved in one case of severe prenatal CAKUT (17). Thirty-one fetuses had been previously screened for RET mutations in another study (11). We identified disease-causing mutations in HNF1B in 12 fetuses from 11 unrelated families and PAX2 in 4 unrelated cases (in addition, we detected a PAX2 variant of unknown significance).…”

Section: Discussionmentioning

confidence: 99%

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Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Madariaga¹,

Morinière²,

Jeanpierre³

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy.Design, setting, participants, & measurements This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy.Results This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family. ConclusionsOur results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.

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Section: Discussionmentioning

confidence: 99%

“…Thirty-one cases had initially been sent for screening of RET mutations in the setting of a research program on renal agenesis (11). None were found to carry an RET mutation.…”

Section: Molecular Analysismentioning

confidence: 99%

Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Madariaga¹,

Morinière²,

Jeanpierre³

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…25,26 Subsequently, inactivating mutations in RET associated with Hirschprung's disease [27][28][29][30][31][32] and renal agenesis were identified. 25,26,[33][34][35][36][37] Mutations in RET Cause MEN2…”

Section: Cancermentioning

confidence: 99%

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma

Krampitz

Norton

2014

Cancer

114

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The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2. Cancer 2014;120:1920-31.

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“…A large range of genetic heterogeneity has been highlighted by the identification of mutations, mostly at the heterozygous state, in more than 50 genes, many of them encoding transcription factors with a crucial role during nephrogenesis (e.g., HNF1B : 191830), and RET (MIM: 164761) in some case subjects with isolated BKA, or in KIF14 (MIM: 616258), FRAS1 (MIM: 219000), and FREM1 (MIM: 608980) in syndromic forms. 5,[8][9][10][11][12] However, in most BKA-affected fetuses, even when a monogenic cause is likely according to the genealogy, the mutated gene is unknown. In order to identify additional genes mutated in CAKUT, 30 case subjects from 15 families were analyzed by wholeexome sequencing (WES).…”

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confidence: 99%

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

Tomasi

David

Humbert

et al. 2017

The American Journal of Human Genetics

130

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RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects

Cited by 59 publications

References 54 publications

Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

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