Summary
Background 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.
Conclusions Our 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.
Introduction
Congenital anomalies of the kidney and urinary tract (CAKUT) account for 15%–20% of all prenatally detected congenital anomalies (1) and are a frequent cause of renal failure in children (2). They range from renal agenesis to urinary tract malformations and include varying degrees of kidney hypoplasia and dysplasia. Short- and long-term renal prognosis varies with the level of nephron reduction, which is sometimes difficult to appreciate before birth. Most severe cases are associated with perinatal lethality in the context of early anamnios, lung hypoplasia, and renal failure. In cases with very severe renal anomalies and poor prognosis, parents sometimes ask for termination of pregnancy (TOP). The decision to perform a late TOP is complex and raises legal, societal, and ethical questions. In France, each request of TOP is evaluated by a multidisciplinary prenatal committee, and requests for very severe CAKUT are frequently accepted, in accordance with the French law, even at late gestational age.
Except for posterior urethral valves that usually appear as sporadic cases, familial aggregation of CAKUT has been frequently described (3), suggesting a role for genetic factors inherited as complex, nonmonogenic traits in many families. However, in some families, CAKUT is inherited as a Mendelian monogenic disease and frequently transmitted as an autosomal dominant trait with variable expressivity. Although these cases are frequently syndromic and associated with extrarenal anomalies, they can also present as isolated kidney disease, particularly at the prenatal ultrasound (US) screening. Identification of the molecular defect in these cases is very important to provide genetic counseling to the families.
Our laboratory performs routine screening of two genes encoding transcription factors involved in kidney development that, when mutated, cause monogenic syndromic CAKUT transmitted as an autosomal dominant trait: HNF1B and PAX2. HNF1B mutations are associated with the renal cysts and diabetes syndrome that comprise renal cystic dysplasia, maturity onset diabetes of the young, and hepatic, genital, and pancreatic abnormalities, with a variable expression of renal and extrarenal defects (4). HNF1B mutations also represent the first cause of prenatal hyperechogenic kidneys with normal or moderately enlarged size (5). PAX2 mutations are associated with papillorenal syndrome that comprises renal defects (oligomeganephronia, hypodysplasia, vesicoureteral reflux, and cysts) and ocular defects affecting the optic nerve (optic nerve coloboma, optic disc dysplasia, pits, and morning glory syndrome) and/or the retina (retinal coloboma, abnormal retinal pigment epithelium, abnormal retinal vessels, and retinal detachment) (6). In this paper, we report on the analysis of these two genes in a series of fetuses with severe prenatal CAKUT that appeared as isolated at fetal US screening.
Materials and Methods
Fetuses and Phenotypes
This retrospective study included 103 fetuses from 91 unrelated families. All presented with isolated severe renal anomalies at fetal US screening that led to TOP. Fetal renal function and prognosis were evaluated by prenatal US (amniotic fluid volume, kidney size, parenchyma thickness, echogenicity, and differentiation) and in some cases, measurement of the β2 microglobulin in fetal serum and/or urine as described previously (7–9). TOP was conducted after parents’ request and only conducted after a case-by-case evaluation by the multidisciplinary prenatal committee in each center. Autopsy was performed with informed consent in all cases. At histologic examination of the kidney, dysplasia was defined as evidence of aberrant development of metanephric mesenchyme and profound disturbance of the normal patterning of renal tissue; renal hypoplasia was defines as a paucity of nephrons, and renal multicystic dysplasia was defined as the presence of large cysts around interstitial tissue without functional nephrons (10). Urinary tract anomalies as well as extrarenal anomalies were investigated. Family consanguinity and history of renal and extrarenal diseases were recorded when possible, but this information was not always available. Renal US was usually prescribed to the parents but was not always performed.
Molecular Analysis
Fetal DNA or frozen tissue samples were received for molecular screening in the laboratory of the Genetic Department at Necker Hospital in Paris, France, with written informed consents from the parents. 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. Fourteen were collected from the Department of Fetopathology of our hospital between 1996 and 2006. The 58 other samples were sent from fetopathology departments all over the country between January of 2009 and May of 2012. When a mutation was identified, parental DNA from peripheral blood was tested after informed consent. This study was conducted with the approval of the Comité de Protection des Personnes pour la recherche biomédicale Ile de France 2.
Genomic DNA was extracted from frozen fetal tissues or blood by standard methods. HNF1B was tested in 90 unrelated fetuses (one case was not tested, because a PAX2 mutation was identified). Deletion screening was performed using quantitative multiplex PCR amplification of short fluorescent fragments (12) as described (13) or multiplex ligation-dependent probe amplification as previously reported (14). When no deletion was found, the nine exons and all exon–intron boundaries of the gene were screened by direct sequencing as previously described (15). PAX2 was tested in 75 unrelated fetuses (16 families were not tested: 11 families with an HNF1B mutation and 5 cases for which we no longer had DNA) by direct sequencing of the 12 coding exons as described previously (16). Reference sequences (http://www.hgvs.org/mutnomen/) were NM_000458.2 (HNF1B) and NM_003990.3 (PAX2).
Statistical Analyses
Data were analyzed using Fisher exact tests. All tests were two-sided. P values<0.05 were considered significant.
Results
Cases
All 103 cases were fetuses presenting with isolated severe CAKUT at fetal US screening that had led to TOP after parent request and multidisciplinary evaluation in centers for prenatal diagnosis in different cities in France. In nine families, there were two fetuses affected, and in another family, four fetuses were affected. The sex ratio was 1.68 (male/female), and the average gestational age at TOP was 21 weeks. In 95 cases, prenatal US evaluation showed oligoamnios or anamnios. Amniotic fluid volume was normal in six cases and unknown in two cases. Fetal serum β2 microglobulin levels were measured in eight cases and found to be significantly elevated (>6 mg/L) (8) in seven of the cases. Renal phenotypes are shown in Table 1. Kidney size was very large (>+4 SD) in 13 fetuses, corresponding to 10 cases with macrocysts and 3 cases with very large hyperechogenic kidneys, suggesting autosomal recessive polycystic kidney disease, but the histologic findings did not fit that diagnosis (glomerular cysts with or without dysplasia). When present, urinary tract anomalies were always associated with one of the phenotypes affecting the renal parenchyma.
Renal phenotypes
Extrarenal anomalies, not seen at the US level, were systematically searched at fetal autopsy, and 45 extrarenal defects were observed in 39 cases (Table 2). Genital anomalies were observed in 17 females and 4 males and consisted of six findings of total agenesis of the uterus (one of them with associated vaginal agenesis), one finding of partial agenesis of the uterus, nine findings of bicornuate uterus, one finding of clitoral hypertrophy with hydrocolpos, one finding of penoscrotal inversion, one finding of unilateral testicular agenesis, one finding of epididymal hypoplasia, and one finding of epididymal cysts. Hepatic anomalies were found in four cases: three cases with hepatic portal fibrosis without ductal plate anomalies and one case of bile duct hyperplasia. Heart anomalies were observed in four cases (three cases of hypertrophy and one case of tricuspid dystrophy); pancreatic abnormalities were seen in 14 cases. Finally, eye examination was rarely mentioned in the autopsy reports. Two fetuses were diagnosed with retinal focal dysplasia.
Extrarenal phenotypes
The search for family history of CAKUT was recorded in 56 families and found positive in first- or second-degree family member(s) in 30 families. Renal ultrasound was performed in both parents in 51 cases and was abnormal in one parent in 15 cases (3 renal unilateral agenesis cases, 3 duplex kidneys cases, 7 kidney hypoplasia cases [with vesico-ureteral reflux in 2 cases], 1 pyelo-ureteral junction obstruction case, and 1 cystic kidney case). In one case, several members of the maternal family displayed renal multicystic dysplasia, single kidney, and/or pelvi-ureteric junction obstruction, but the mother herself had normal kidney US. The search for family history of extrarenal anomalies was recorded in 52 families and found positive in 12 families (6 cases of diabetes [1 case with associated gout], 5 cases of genital anomalies, and 1 case with pancreatic cyst and liver cholestasis). No case of consanguinity was present in the series.
HNF1B Mutations
Ninety-one fetuses from ninety unrelated families were screened for HNF1B mutations. Eight different mutations were identified in 12 cases from 11 families (Table 3). A heterozygous deletion removing the whole gene was identified in three unrelated fetuses, a partial heterozygous deletion removing exons 5–9 was observed in one case, and six heterozygous point mutations (four frameshift, one nonsense, and one missense mutation) were identified in seven unrelated fetuses [the c.232G>T (p.Glu78*) mutation was detected in two unrelated cases]. The c.827G>A (p.Arg267Gln) mutation has not been previously reported. It affects a conserved amino acid in the DNA binding domain, and it is predicted as possibly damaging by the PolyPhen2 program. It was not present in dbSNP (www.ncbi.nlm.nih.gov/projects/SNP/) or the Exome Variant Server (evs.gs.washington.edu/) databases, and it was found to be a de novo mutation.
Characteristics of the fetuses carrying an HNF1B mutation
Parents were tested in nine families, and the mutations were found to be inherited in six families and de novo in three unrelated fetuses. In two families, we were unable to test the apparently unaffected parents. In addition to these mutations, we identified the p.Gly76Cys variant in one fetus that developed bilateral renal multicystic dysplasia with early anamnios (see Discussion).
Detailed renal and extrarenal phenotypes of the fetuses carrying an HNF1B mutation are shown in Table 3. The mean gestational age at TOP was 23 weeks (range=14–33), and the male/female ratio was 1.4/1. Prenatal renal US showed bilateral hyperechogenic kidneys in five cases, bilateral cystic kidneys in two cases, unilateral cystic kidney with contralateral hyperechogenic kidney in one case, and bilateral renal multicystic dysplasia in four cases. Kidney size was unknown in one case, normal or moderately enlarged (−2 to +3 SD) in five cases, and very enlarged (at least one kidney ≥+4 SD) in six cases, including two cases with cystic kidneys, two cases with renal multicystic dysplasia, and two cases with hyperechogenic kidneys resembling polycystic kidney disease but with renal parenchymal disorganization and glomerular cysts at histology (an example is shown in Figure 1). Three fetuses presented an associated urological malformation (ureteral duplication). Renal histology is detailed in Table 3. In two cases, amniotic fluid volume was normal, whereas oligoamnios or anamnios was present in eight cases. Amniotic fluid volume was unknown in two cases. Fetal serum β2 microglobulin was measured in three fetuses and elevated (>8 mg/L) in all cases. Extrarenal anomalies were found in six cases, affecting pancreas and genital organs. Pancreas malformations were the most frequently observed, with two cases of pancreas hypoplasia, one case of partial agenesis, and two cases with total agenesis. Genital organ malformations were observed in two fetuses: one case of septated uterus and one case of bilateral epididymal cysts.
Histology of the kidney of fetus H3 presenting with very large hyperechogenic kidneys showing dysplasia with renal parenchyma desorganization and cystic dilation involving tubules and glomeruli. Original magnification, ×40.
A positive family history was noted in all cases with inherited mutations, although the phenotype was very variable. The mother of fetus H5 had normal renal function and normal renal US, but various renal anomalies were present in many other members of her family. The mother and aunt of fetus H7 both had unilateral renal agenesis with normal renal function. Many members of the family of fetus H8 had a history of renal abnormalities (including several cases of CAKUT and one case of tubulo-interstitial nephritis), with highly variable degrees of renal dysfunction. The father of fetus H9 had renal hypoplasia, pelviureteric junction obstruction with chronic kidney failure, liver cholestasis, and pancreatic cysts. The mother of fetus H10 had small and hyperechogenic kidneys with multiple lithiasis. Finally, the mother of fetuses H11 and H12 had renal hypoplasia with normal renal function, and their grandmother presented with diabetes and renal hypoplasia.
We compared the frequency of urologic, genital, or pancreatic abnormalities in fetuses with and without HNF1B mutations (Table 4) and found that associated pancreatic and urologic anomalies were significantly higher in cases with an HNF1B mutation.
Comparison of phenotypes between cases with or without HNF1B mutations
PAX2 Mutations
Seventy-five unrelated fetuses were screened for PAX2 mutation (five fetuses were not tested, because DNA was no longer available). Four heterozygous point mutations (one frameshift, one nonsense, one splice, and one missense) were identified in four unrelated cases. The c.350G>C, p.Arg117Pro, mutation, which has not been previously reported, affects a conserved amino acid and is predicted to be probably damaging by the PolyPhen2 program. It was not present in dbSNP (www.ncbi.nlm.nih.gov/projects/SNP/) or the Exome Variant Server (evs.gs.washington.edu/) database. The mutations are shown in Table 5, with the associated renal and extrarenal phenotypes. Of note, postmortem examination of the eye is reported in only two cases, and both display focal retina dysplasia. All mutations were inherited. The father of fetus P4 was mosaic for the mutation in peripheral blood DNA. In addition, we found a variant (c.1284C>G) leading to the change p.Ile428Met in a fetus with unilateral renal agenesis and contralateral renal cystic dysplasia, anamnios, and uterine agenesis (Table 5). This novel variant affects an alternative exon (leading to a putative protein with an extended C terminus) and is predicted to be possibly damaging by the PolyPhen2 program.
Characteristics of the fetuses carrying a PAX2 mutation (P1–P4) or a PAX2 variant of unknown significance (P5)
The mean gestational age at TOP was 20 weeks (range=17–23), and amniotic fluid was reduced in two cases and absent in the other three cases. Fetal renal histologic examination invariably showed severe bilateral hypoplasia, which was associated with dysplasia and cortical microcysts in fetus P2. There was a positive family history of renal anomalies of variable severity in three cases. The mother of case P1 had bilateral renal hypoplasia and reached end stage renal failure at the age of 7 years; she has normal eye fundus. The father of fetus P2 had normal renal US and eye fundus, but the paternal uncle (who received a kidney graft at the age of 6 years) and the paternal grandfather (who currently has stage 2 CKD) both had kidney hypoplasia. In case P3, the mutation was inherited from the mother, who had a renal hypoplasia associated with a vesico-ureteral reflux, a unicornuate uterus, and a history of several miscarriages. She was initially classified as having chronic tubulo-interstitial nephritis and received a kidney transplant from her unaffected mother at the age of 26 years. At optic fundus examination, she had a very small optic disc pit. The father of fetus P4, who was mosaic for the mutation in peripheral blood DNA, had normal renal function and ultrasound. His eyes have not been examined. No other extrarenal anomalies apart from the mentioned ocular defect were found.
Discussion
We tested a large cohort of fetuses with severe renal anomalies for mutations in HNF1B (the gene involved in renal cyst and diabetes syndrome) and PAX2 (the gene involved in papillorenal syndrome). 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 (5,13–15), 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). Altogether, this result represents a mutation detection rate of 17% (16/91). It is interesting to note that the prevalence of HNF1B mutations in this series of very severe prenatal CAKUT (12%) is not very different from the 19% prevalence that we previously reported in a series of children and adults with CAKUT (14). The same holds true for PAX2, because 7 of 99 cases of patients with CAKUT were found to carry a PAX2 mutation in a recent study (18). All cases tested here presented with isolated renal disease at fetal US, but extrarenal anomalies were diagnosed at fetal autopsy in 38% (39/103) of cases, underscoring the importance of autopsy examination in case of TOP. Pancreas hypoplasia/agenesis was associated with HNF1B mutation, and eye defects were associated with PAX2 mutation; altogether, the finding of an extrarenal defect was not significantly different in cases with (8/16) or without (31/87) an identified mutation, and a mutation was identified in 8 cases without any extrarenal defect. The association of genital anomalies with renal disease was more frequent in females (17 cases). However, genital abnormalities were not more common in cases with HNF1B mutations than cases without HNF1B mutations, a finding previously reported by others (19). This finding indicates that other factors, involved in both renal and genital development, remain to be identified. Interestingly, none of the six cases with complete uterus agenesis was carrying an HNF1B mutation in our series. This finding confirms that 17q12 deletion removing HNF1B is not a major cause of Mayer–Rokitansky–Kuster–Hauser syndrome (congenital aplasia of the uterus and the upper part of vagina) (20).
The frequency of a family history of renal disease was high (53%) in our cohort. Interestingly, this result was not more common in cases with an identified mutation (9/13) than cases without an identified mutation (21/43). Moreover, a mutation was identified in only 1 of 10 families with more than one affected fetus. This result illustrates the role of other genetic factors in the pathogenesis of CAKUT. Although we did not test other genes known to be involved in monogenic syndromic CAKUT (e.g., EYA1, SIX1, SALL1, FRAS1, and KAL1 among others), it is likely that additional genes remain to be identified, particularly in the numerous cases without extrarenal defects. Finally, mutations were also identified in five cases that seemed sporadic, a finding of importance for genetic counseling in these families.
Regarding the renal phenotype, we searched for genotype–phenotype correlations that may help to guide molecular screening. The presence of kidney macrocysts was frequent in fetuses carrying an HNF1B mutation, although this result was not constant, and some cases presented with enlarged hyperechogenic kidneys resembling polycystic kidney disease at fetal US. No HNFIB or PAX2 mutations were identified in fetuses with bilateral renal agenesis, suggesting a different genetic mechanism for this specific defect. Although the RET gene, encoding the glial derived neurotrophic factor receptor, had been highlighted as a promising candidate for renal agenesis, we recently showed that RET mutations are not a major cause of bilateral renal agenesis (11). Not taking into account cases with bilateral agenesis, the rate of HNF1B/PAX2 mutations in our series would increase to 23% (16/70).
As previously reported, all HNF1B missense mutations were located within the region encoding the DNA binding domain. In addition, we found the c.226G>T p.G76C variant in one fetus with bilateral multicystic dysplasia and early anamnios with Potter syndrome from North African parents. That variant, which was previously reported in three probands in the literature (13,21), is predicted to be probably damaging by the PolyPhen2 program. However, it was recently identified in up to 8.5% (10/117 individuals) of a control population originating from North Africa (C. Bellanné-Chantelot et al., personal communication). Thus, it is not likely a disease-causing variant.
We observed a very important intrafamilial variability in cases with an inherited mutation, particularly with respect to severity of renal disease. This finding was independent of the gene involved and illustrates the lack of genotype–phenotype correlation. This finding may be because of the effect of modifier genes. However, fetuses with an HNF1B mutation had a high frequency of severe pancreas malformations (two complete agenesis, one partial agenesis, and two hypoplasia) not usually reported in series of children or adults with mutations in this gene. This finding may suggest a correlation between the severity of the renal defect and the severity of the extrarenal defect. Because many of the HNF1B mutations identified in the fetuses are similar to those mutations observed in children and adults, it would be interesting to test whether the severity of the defect is caused by, in addition to the identified mutation, variants affecting the HNF1B wild-type allele in trans or other genes involved in cystic disease or CAKUT and/or whether the level of expression of the wild-type allele plays a role in the severity of the phenotype affecting different organs in the same individual.
It is important to note that HNF1B mutations occurred de novo in at least three cases. This result shows that molecular testing must be performed, even when there is no known family history. In these cases, families can be reassured regarding the risk of recurrence for future pregnancies, which is limited to the low risk of germinal mosaicism (22).
All PAX2 mutations were inherited. Interestingly, the father of the fetus carrying the PAX2 p.Arg117Pro mutation, who was not known to have renal, ocular, or ear disease, seems to carry the mutation at a level of about 30% in leukocyte DNA. This result is well fitting with the fact that this couple underwent another TOP for severe renal hypoplasia in a second fetus (whose DNA was not available). Interestingly, this report is the second report of somatic mosaicism for a PAX2 mutation (16). Finally, the PAX2 p.Ile428Met missense change identified in one fetus with cystic dysplasia of a single kidney and uterine agenesis may not be responsible for this phenotype, but we were unable to obtain DNA from the unaffected parents to determine inheritance.
In conclusion, we report, for the first time, a high rate of mutation in two genes known to be involved in monogenic syndromic CAKUT in a large series of severe prenatal CAKUT, including sporadic cases. These results illustrate the importance of molecular screening in these cases to provide the best genetic counseling to the families. Our data also confirm the large clinical heterogeneity associated with mutations in these genes and the lack of genotype–phenotype correlations, because the severity of renal disease was extremely variable, even for a given mutation within a single family.
Disclosures
None.
Acknowledgments
We thank the families for their participation. We are grateful to the following physicians for contribution of material and clinical data: Dr. Aziza (Hôpital Purpan, Toulouse, France), Dr. Blesson (Hôpital de Tours, France), Dr. Cambon (Hôpital de Poitiers, France), Dr. Carles (Hôpital Pellegrin, Bordeaux, France), Dr. Cartault (Hôpital Sud Région, La Réunion), Dr. Delezoide (Assistance Publique-Hôpitaux de Paris Hôpital Robert Debré, Paris, France), Dr. Esperandieu (Hôpital d’Orleans, France), Pr. Foliguet (Hôpital de Nancy, France), Dr. Francannet (Hôpital de Clermont-Ferrand, France), Dr. Fuchs (Assistance Publique-Hôpitaux de Paris Hôpital Bicêtre, Paris, France), Dr. Gilbert-Dussardier (Hôpital de Poitiers, France), Dr. Gonzales (Assistance Publique-Hôpitaux de Paris Hôpital de Armand Trousseau, Paris, France), Dr. Holder (Hôpital de Lille, France), Pr. Jouk (Hôpital de Grenoble, France), Dr. Journel (Hôpital Bretagne Atlantique, Vannes, France), Dr. Marcorelles (Hôpital de Brest, France), Dr. Mathieu (Hôpital d’Amiens, France), Dr. Odent (Centre Hospitalo-Universitaire de Rennes, France), Dr. Picone (Assistance Publique Hôpitaux de Paris Hôpital Antoine Béclère, Paris, France), Dr. Pommeruy (Hôpital de Limoges, France), Dr. Poussou (Hôpital de Cahors, France), Dr. Roume (Hôpital de Poissy, France), Dr. Sigaudy (Hôpital La Timone, Marseille), Dr. Sinico (Hôpital de Créteil, France), Dr. Taque (Hôpital de Rennes, France), and Dr. Touraine (Hôpital de St Etienne, France). We thank Scott J. Harvey for editorial assistance.
Part of the project was funded by the French Agence Nationale de la Recherche (ANR07-MRAR-010-01).
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.10221012/-/DCSupplemental.
- Received October 7, 2012.
- Accepted February 19, 2013.
- Copyright © 2013 by the American Society of Nephrology
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