Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Hepatology & Nutrition
Prenatal Molecular Diagnosis of Inherited Cholestatic Diseases
Jung, Camille*; Driancourt, Catherine†; Baussan, Christiane‡; Zater, Mokhtar‡; Hadchouel, Michelle*,†; Meunier-Rotival, Michèle†; Guiochon-Mantel, Anne§; Jacquemin, Emmanuel*,†
*Pediatric Hepatology and National Reference Centre for Biliary Atresia
†INSERM U347, E0020, and U804
‡Departments of Biochemistry
§Molecular Genetics, Pharmacogenetics and Hormonology, Bicêtre Hospital, University of Paris-South XI, AP-HP, Paris, France
Received 16 October, 2006
Accepted 27 December, 2006
Address correspondence and reprint requests to Prof Emmanuel Jacquemin, Hépatologie Pédiatrique, Centre de Référence National de l'Atrésie des Voies Biliaires, Centre Hospitalier Universitaire de Bicêtre, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre Cedex, France (e-mail: email@example.com).
Objectives: Progressive familial intrahepatic cholestasis (PFIC) and to a lesser extent, Alagille syndrome, often lead to end-stage liver disease during childhood. We report our experience of DNA-based prenatal diagnosis of PFIC1–3 and Alagille syndrome.
Patients and Methods: Four molecular antenatal diagnoses were performed in 3 PFIC families and 17 in 11 Alagille syndrome families. DNA was isolated from chorionic villus or cultured amniocyte samples from women, without pregnancy complications.
Results: All four foetuses with a family history of PFIC1, 2, or 3 were heterozygous for an ATP8B1, ABCB11, or ABCB4 mutation and pregnancies were continued. Three of the infants were healthy after birth, and 1 premature infant, who had an ABCB4 mutation, experienced transient neonatal cholestasis. Among the families with a history of de novo JAG1 mutation, none of the foetuses was mutated, versus 40% of those with a history of familial mutation. Of 4 pregnant women with a JAG1-mutated foetus, 3 cut short their pregnancy and 1 gave birth to a child with overt Alagille syndrome.
Conclusions: Molecular antenatal diagnosis of PFIC1–3 and Alagille syndrome is reliable because clinical outcome after birth corresponded to molecular foetal data.
Progressive familial intrahepatic cholestasis (PFIC) includes a heterogeneous group of autosomal recessive liver disorders, of which hepatocellular cholestasis is often present in the first months of life and leads to liver failure at ages ranging from infancy to adolescence. Molecular and genetic studies have allowed the identification of the genes responsible for 3 types of PFIC and have shown that PFIC is caused by mutations in hepatocellular transport system genes involved in bile formation (1). The first type of PFIC, PFIC1, is caused by mutation of the ATP8B1 gene (2–4). This gene codes for a P-type adenosine triphosphatase (ATPase) (FIC1), which is expressed in several organs but whose function is not precisely known. The second type of PFIC, PFIC2, is caused by mutation of the ABCB11 gene that codes for the ATP-dependent canalicular bile salt export pump (5,6). The third type of PFIC, PFIC3, is caused by mutation of the ABCB4 gene (7,8). ABCB4 codes for a P-glycoprotein of class III multidrug resistance (MDR3), involved in biliary phospholipid excretion. Thus far, the data available show that there is no predominant mutation of these 3 genes among PFIC patients (3,4,6,7). The autosomal recessive inheritance of PFIC includes a recurrence risk of 25% for subsequent pregnancies, assuming that each parent has an affected allele.
Alagille syndrome is an autosomal dominant disorder whose expression varies, and is defined by the presence of at least 3 of the 5 following features: chronic cholestasis caused by paucity of interlobular bile ducts, pulmonary artery branch stenosis, butterfly-like vertebrae, typical facies, and posterior embryotoxon (9). Hepatic and cardiac symptoms usually predominate, but the main symptoms may sometimes be renal (10,11). Most cases of Alagille syndrome are caused by mutations of the JAGGED 1 (JAG1) gene that codes for a cell surface protein that binds the Notch transmembrane receptors involved in cell differentiation (12–16). In the event of an autosomal dominant inheritance the recurrence risk is around 50% for subsequent pregnancies if 1 parent has a mutated allele, but expression of the syndrome may vary (17–19). Nevertheless, de novo JAG1 mutations are present in 60% to 70% of cases, and parental mosaicism has been reported in about 8% of cases (15,16,20). Therefore, it is recognized that genetic testing is indicated in both familial and sporadic cases (21,22). PFIC1–3 and Alagille syndrome are considered disabling rare diseases. In PFIC1–3 the treatments proposed include ursodeoxycholic acid therapy or biliary diversion, but they are often ineffective, and in most cases do not prevent liver transplantation, which often remains the ultimate solution during childhood (1,3,4,6–8,23). In Alagille syndrome it has been shown that with native liver, 10-year survival is <50% in children presenting with neonatal cholestasis, and that one third of these patients need liver transplantation at a median age of 6 years (11). Therefore, the gravity of these diseases justifies the development of antenatal molecular diagnosis, which is now possible because the genes responsible for the diseases have been identified. This diagnosis constitutes a new tool for the management of these diseases and may be useful for genetic counselling of affected families. There are few publications on the prenatal molecular diagnosis of inherited cholestatic diseases (22). We report here our experience of DNA-based prenatal diagnosis of PFIC1, PFIC2, and PFIC3 and of Alagille syndrome.
PATIENTS AND METHODS
Between 1999 and 2006, 14 families with a propositus severely affected by PFIC1, PFIC2, PFIC3, or Alagille syndrome asked for prenatal molecular diagnosis after genetic counselling had been provided. Briefly, the information given to the parents during the counselling concerned the risk of disease recurrence, clinical manifestations, the possible outcomes for an affected foetus, and the effectiveness and risks of available therapies. Among the Alagille syndrome families the propositus was an affected mother in 3 cases and an affected father in 1 case. To make the DNA-based prenatal diagnoses we used the knowledge we had acquired regarding the mutational status of these unrelated families with a history of PFIC1 (n = 1), PFIC2 (n = 1), PFIC3 (n = 1), or Alagille syndrome (n = 11). This knowledge was as follows: In the PFIC families (families 1–3) each parent had transmitted an ATP8B1, ABCB11, or ABCB4 mutated allele. Of the Alagille syndrome families (families 4–14) JAG1 heterozygous mutations were de novo in 5 and familial in 6. In 4 cases the mutation was present in the mother and in 2 cases in the father. Initial sequencing analysis of the ATP8B1, ABCB11, ABCB4, and JAG1 genes was performed in each propositus as previously described (7,15,23,24). Briefly, the genomic DNA of all of the coding regions and intron-exon boundaries was amplified by polymerase chain reaction, using specific primers. The amplified products were directly sequenced using a Taq dideoxyterminator sequencing kit and an ABI PRISM 3100 sequencer (Applied Biosystems, Foster City, CA). Double-strand sequencing was systematically performed. Mutations were confirmed separately on a second polymerase chain reaction product. For prenatal diagnosis, genomic DNA was isolated from chorionic villus or cultured amniocyte samples, obtained between 11 and 18 weeks of pregnancy and without complications. For each DNA sample, maternal DNA contamination was excluded by short tandem repeat typing at 15 loci distributed throughout the human genome, using the PowerPlex16 system (Promega, Madison, WI). The amplified fragments were detected with the ABI PRISM 3100 genetic analyser. Foetal genomic DNA was amplified in the known mutated region, using primers that encompassed the mutation. In 1 case (family 3, foetus 1), the entire ABCB4 gene was sequenced after childbirth. All nonmutated children were clinically examined at birth and at least once during the first year of life. Depending on the disease type, appropriate investigations were scheduled after birth in the cases of JAG1 mutation, biallelic ATP8B1, ABCB11, or ABCB4 mutations, or in cases of unexpected manifestations among the patients without these mutations. Written informed consent was obtained from all of the families and the protocol conformed to the ethical guidelines of our institution's Human Research Committee.
The results of the 4 molecular antenatal diagnoses performed in PFIC families are shown in Table 1. In family 1 the propositus was compound heterozygous for ATP8B1 mutations. The foetus was heterozygous for a nucleotide substitution in the splice donor site of intron 9. The pregnancy was continued. The child, a boy, did not experience cholestasis after birth and is healthy at age 1 year. In family 2 the propositus was compound heterozygous for ABCB11 mutations. The foetus was heterozygous for a deletion and pregnancy was continued. The child, a girl, did not experience neonatal cholestasis and is healthy at age 3 months. In family 3 the propositus was carrying a homozygous ABCB4 deletion leading to protein truncation, and 2 antenatal diagnoses were performed. At the time of the first diagnosis, the foetus was found to be heterozygous for the ABCB4 deletion and the pregnancy was continued. Unfortunately, this premature newborn girl, whose birth was scheduled at 31 weeks of gestation because of recurrent intrahepatic cholestasis of pregnancy, developed neonatal cholestasis. At 3.5 months of age, the child had hepatomegaly and serum liver tests showed 837 IU/L γ-glutamyltranspeptidase (n < 25), 44 μmol/L conjugated bilirubin (n < 10), and 429 IU/L alanine aminotransferase (n < 40). Liver biopsy showed cholestasis, portal fibrosis with ductular proliferation, but no picture of giant cell hepatitis. Percutaneous cholangiography was normal. Investigations performed to identify another cause of cholestasis were negative. Ursodeoxycholic acid (UDCA) treatment was started, cholestasis resolved, and liver test results returned to normal. A control liver biopsy performed at 3.5 years, before UDCA was stopped, showed no cholestasis or ductular proliferation, but slight portal fibrosis. After UDCA was stopped clinical status and serum liver tests remained normal until the last follow-up at age 7 years. Despite this favourable evolution, the entire ABCB4 gene downstream of the deletion was sequenced to exclude the possible presence of another mutation on the second allele. We identified a homozygous missense mutation, 1986A>G (R652G), believed to constitute a polymorphism (7). Subsequently, this family asked for another antenatal diagnosis. The second foetus's DNA was negative for the ABCB4 deletion and heterozygous for the R652G mutation. Pregnancy was continued. The male child who was born at 31 weeks of gestation in the same context as his sister, never developed cholestasis and is healthy at the age of 5.5 years.
The results of the 17 antenatal molecular diagnoses performed in 11 Alagille syndrome families are shown in Table 2. Seven families asked for 1 antenatal diagnosis, 2 families for 2 diagnoses, and 2 families for 3. In 12 cases the foetus was not mutated and the pregnancy was continued, and we know that in 10 of these cases, the child was healthy after birth, after at least 1 year of follow-up. For the 2 others (families 13 and 14) we have no postnatal information. In 1 case (family 8) the foetus was not mutated, but the family decided to terminate the pregnancy. In 3 cases (families 10 and 12) the foetus was mutated and the family decided to terminate the pregnancy. Pathological analysis of 1 foetus (family 12) at 23 weeks of gestation showed facial dismorphy, cardiopathy and kidney cysts, which are signs compatible with Alagille syndrome (25). In 1 case (family 10, second foetus), prenatal ultrasonography suggested the tetralogy of Fallot (21). The foetus was mutated, but the family decided to continue the pregnancy. At birth, the child, a girl, exhibited clinical signs of Alagille syndrome, with neonatal cholestasis. Cardiac ultrasonography confirmed the presence of the tetralogy of Fallot.
Hereditary cholestasis such as PFIC1–3 and Alagille syndrome are rare genetic disorders that have high morbidity and mortality rates and may lead to liver transplantation during childhood (1,11). The genes responsible for these diseases have now been identified (1,12,13), enabling us to develop a method of antenatal diagnosis for these genetic disorders. The present results concern our experience of DNA-based prenatal diagnosis in 14 families with PFIC1, PFIC2, PFIC3, or Alagille syndrome.
When genetic counselling and molecular prenatal diagnosis based on mutation screening are proposed to a family, it is important to have strong arguments in favour of the disease-causing effect of the mutation(s) identified in the propositus. Even when this is the case, the family must be informed that certain diseases carry the risk of a discrepancy between genotype and phenotype, or in other words, that a given genotype may lead to different phenotypes whose intensity of expression may vary from absent or mild to severe. Because this variability is unpredictable, final family decisions concerning the outcome of an ongoing pregnancy are usually based on the absence or presence of the known mutation(s) in the foetus, with the information acquired thanks to genetic counselling.
Although variability of phenotypic expression for a given genotype is not a typical characteristic of PFIC, it may in fact exist (1). This was shown in patients with benign recurrent intrahepatic cholestasis (BRIC) type 1 harbouring a common ATP8B1 mutation, and in PFIC1 patients whose expression of an extrahepatic phenotype may only become evident after liver transplantation (3,4,23). In PFIC3 certain genotype-phenotype correlations have been established showing that different mutations were associated with PFIC3 or cholesterol gallstone disease (7,26). Different biallelic mutations in PFIC genes may give a benign phenotype, BRIC, or a severe phenotype, PFIC (1,2,24). Intermediate phenotypes between BRIC and PFIC have also been identified, and a patient may display several phenotypes in the course of his or her life (27,28). It is also known that heterozygous mutations for ABCB11 or ABCB4 genes may constitute a genetic predisposition to intrahepatic cholestasis of pregnancy and probably also to drug-induced cholestasis and transient neonatal cholestasis (8,29–32). In our families 1, 2 and 3 the ATP8B1, ABCB11, and ABCB4 mutations identified were likely to be those causing the disease, although the G446R ATP8B1 missense mutation in family 1, whose harmful effect cannot be certified, is not known to constitute a polymorphism and has already been identified in a compound heterozygous PFIC1 patient (2–4,23). In family 1 the foetus was heterozygous and the child was healthy, as expected. In family 2 the foetus was heterozygous and the child was also healthy after birth. In family 3 foetus 1 was heterozygous, but the postnatal evolution was characterized by cholestasis. We postulated that this premature female child experienced transient neonatal cholestasis, favoured by her heterozygous ABCB4 status, as previously reported for children harbouring heterozygous ABCB4 or ABCB11 mutations (8,31,32). In addition, the presence of the R652G polymorphism on the foetus's second allele may have favoured the expression of transient neonatal cholestasis because it has been shown that when this polymorphism is homozygous, it may be associated with a trend towards a low MDR3 protein level in normal human liver (7,8,33). The diagnosis of transient neonatal cholestasis was likely in this child because cholestasis did not recur after UDCA treatment was stopped, and clinical status remained normal (32). In the future this girl may be at risk for developing intrahepatic cholestasis of pregnancy, as already reported in her family (29). In foetus 2 of family 3 the evolution after birth was normal, as expected from the foetus's ABCB4 genotype. Nevertheless, after birth it may be advisable to monitor neonates with a prenatally diagnosed ABCB4 or ABCB11 heterozygous mutation to detect possible transient cholestasis, which is favoured by this genetic status.
In Alagille syndrome the highly variable phenotype expression is of particular concern, and it makes it hard to predict the outcome of mutated individuals and the severity of cardiac and/or hepatic manifestations, even in the same family (17–19,21,22). In the subjects we studied all JAG1 mutations except R184H led to protein truncation and were expected to be harmful. R184H mutation has been reported in Alagille syndrome and was not found in normal controls (14–16). It is therefore believed to be the causative mutation and not a polymorphism. In addition, all of the propositi had a severe clinical phenotype, except in family 12, in which the mother had the isolated particular facies and high-pitched voice characteristic of the syndrome, and biological cholestasis had been discovered during routine investigations performed during her first pregnancy. The discrepancy in phenotypic expression for a given mutation is illustrated in families 9 and 13, in which 1 of the parents was apparently an asymptomatic carrier of the JAG1 mutation, and the severely affected propositus required liver transplantation. In families 10 and 11 the affected mother had chronic neonatal cholestasis, whereas her affected children had chronic neonatal cholestasis and severe complex cardiopathy. So far, no clear genotype-phenotype correlation has been found in Alagille syndrome (12–17). Of the 7 diagnoses performed to detect a de novo JAG1 mutation, none of the foetuses concerned harboured this mutation, suggesting that despite the theoretical possibility of parental mosaicism, prenatal genetic testing may be unnecessary in sporadic cases. Among the 10 diagnoses performed in familial cases, 4 of the foetuses concerned harboured a mutation, constituting a 40% transmission rate for a disease-causing mutation, which is close to the theoretical rate of 50%. For 1 of these 4 mutated foetuses the foetus histological data showed that it was probably affected (25), and after the birth of the female child of family 10, clinical testing showed that she was indeed affected. Among the 12 continued pregnancies with a nonmutated foetus, clinical examination at birth and/or follow-up after birth showed that at least 10 children were healthy. It may be reasonably assumed that the 2 other children were healthy both at birth and thereafter because the foetuses were not mutated. On the basis of these data we cannot make any recommendations concerning the usefulness of prenatal molecular diagnosis in familial cases of Alagille syndrome because 3 of 4 pregnancies with a JAG1-mutated foetus were terminated. Nevertheless, 2 of these 4 cases did have Alagille syndrome. In view of the variable expression of this syndrome, future studies are needed to verify phenotype expression in subjects with a prenatally diagnosed JAG1 mutation.
Despite the small number of families studied, the results of the present study show that it is possible to perform reliable molecular antenatal diagnosis for PFIC1, PFIC2, PFIC3, and Alagille syndrome because clinical outcome after birth was in accordance with the outcome expected on the basis of the molecular data in the foetus. The information acquired here should therefore be helpful for genetic counselling of families with children affected by genetic cholestases or for affected children who reach adulthood with or without liver transplantation (7,11,22–24,26,27,29,30). It is the physician's responsibility to provide adequate medical information and advice to help parents make decisions.
We thank Drs M. Misrahi, N. de Roux, O. Bernard, D. Habes, J. Sarles, B. Roquelaure, S. Sigaudy, F. Gottrand, S. Manouvrier, A. Moerman, J.P. Chouraqui, C. Buffet, M. Gonzales, Z. Gelman-Kohan, and G. Viot for their helpful participation. We are also grateful to I. Boucly and D. Cresteil for excellent technical assistance and to M. Dreyfus for English-language editing.
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