scholarly journals Exome Sequencing in Individuals with Isolated Biliary Atresia

2019 ◽  
Author(s):  
Ramakrishnan Rajagopalan ◽  
Ellen A. Tsai ◽  
Christopher M. Grochowski ◽  
Susan M. Kelly ◽  
Kathleen M. Loomes ◽  
...  
Keyword(s):  
Biliary Atresia ◽  
Exome Sequencing ◽  
Stress Responses ◽  
Rare Variants ◽  
De Novo ◽  
Genetic Model ◽  
Single Gene ◽  
Biliary Tree ◽  
Causal Genes ◽  
Extrahepatic Biliary Tree

AbstractBiliary atresia (BA) is a severe pediatric liver disease resulting in necroinflammatory obliteration of the extrahepatic biliary tree. BA presents within the first few months of life as either an isolated finding or with additional syndromic features. The etiology of isolated BA is unknown, with evidence for infectious, environmental, and genetic risk factors described. However, to date, there are no definitive causal genes identified for isolated BA in humans, and the question of whether single gene defects play a major role remains open. We performed exome-sequencing in 100 North American patients of European descent with isolated BA (including 30 parent-child trios) and considered several experimental designs to identify potentially deleterious protein-altering variants that may be involved in the disease. In a case-only analysis, we did not identify genes with variants shared among more than two probands, and burden tests of rare variants using a case-case control design did not yield significant results. In the trio analysis of 30 simplex families (patient and parent trios), we identified 66 de novo variants in 66 genes including a nonsense variant, p.(Cys30Ter), in the gene STIP1. STIP1 is a co-chaperone for the heat-shock protein, HSP90AA1, and has been shown to have diverse functions in yeast, flies and mammals, including stress-response.ConclusionOur results do not support the hypothesis that a simple genetic model is responsible for the majority of cases of isolated BA. Our finding of a de novo mutation in a candidate gene for BA (STIP1) linked to evolutionarily conserved stress responses suggests further exploration of how genetic susceptibility and environmental exposure interact to cause BA is warranted.

scholarly journals Novel findings from family-based exome sequencing for children with biliary atresia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kien Trung Tran ◽  
Vinh Sy Le ◽  
Lan Thi Mai Dao ◽  
Huyen Khanh Nguyen ◽  
Anh Kieu Mai ◽  
...  
Keyword(s):  
Biliary Atresia ◽  
Exome Sequencing ◽  
Bile Flow ◽  
De Novo ◽  
Biliary Tree ◽  
Mendelian Inheritance ◽  
Genome Project ◽  
Blood Samples ◽  
Whole Exome ◽  
Family Based

AbstractBiliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. This study aimed to explore the elusive aetiology of BA by conducting whole exome sequencing for 41 children with BA and their parents (35 trios, including 1 family with 2 BA-diagnosed children and 5 child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, 6 de novo and 5 homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and had a low minor allele frequency against the employed databases: Kinh Vietnamese (KHV), GnomAD and 1000 Genome Project. Interestingly, AMER1, INVS and OCRL variants were found in unrelated probands and were first reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic variants were unlikely to occur during morphogenesis. Consistent with earlier attempts, this study implicated genetic heterogeneity and non-Mendelian inheritance of BA.

scholarly journals Novel Findings From Family-based Exome Sequencing for Children With Biliary Atresia

2021 ◽  
Author(s):  
Kien Tran ◽  
Vinh Le ◽  
Lan Dao ◽  
Huyen Nguyen ◽  
Anh Mai ◽  
...  
Keyword(s):  
Biliary Atresia ◽  
Exome Sequencing ◽  
Bile Flow ◽  
Somatic Mutations ◽  
De Novo ◽  
Biliary Tree ◽  
Mendelian Inheritance ◽  
Genome Project ◽  
Whole Exome ◽  
Family Based

Abstract Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree, characterized by the obstruction of bile flow led to liver failure, scarring and cirrhosis. This study aimed to explore the elusive etiology of BA by conducting whole exome sequencing (WES) for 41 children with BA and their parents (35 trios, including one family with two BA diagnosed children and five child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, six de novo and five homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and having a low minor allele frequency against three employed databases: Kinh Vietnamese (KHV), gnomad and 1000 Genome project. Interestingly, AMER1, INVS and OCRL variants were repeatedly found in unrelated probands, and were firstly reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic mutations were unlikely to occur during the morphogenesis. In agreement with earlier attempts, this study implicated a genetical heterogeneity and non-Mendelian inheritance of BA.

Biliary Atresia Revisited

2004 ◽  
Vol 7 (2) ◽  
pp. 109-124 ◽  
Author(s):  
Ellen Kahn
Keyword(s):  
Biliary Atresia ◽  
Congenital Anomalies ◽  
Cell Transformation ◽  
Biliary Tree ◽  
Bile Acid Metabolism ◽  
Biliary Cirrhosis ◽  
Intrahepatic Bile Ducts ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Extrahepatic Biliary Tree

Extrahepatic biliary atresia (EHBA) is an inflammatory fibrosing process affecting the extrahepatic and intrahepatic biliary tree resulting in fibrous obliteration of the extrahepatic biliary tract, ductopenia of intrahepatic bile ducts, and biliary cirrhosis. EHBA is divided into a correctable and a noncorrectable type with focal patency of the otherwise atretic biliary tree in the former and no patency of the biliary tree in the noncorrectable type. EHBA is divided in a fetal, prenatal or embryonic, and a more common, perinatal, acquired form. The symptoms of the former start shortly after birth and there is frequently an association with a variety of congenital anomalies. Children with the perinatal form become jaundiced several weeks after birth; no associated congenital anomalies are present. Morphologically, an inflammatory and fibrosing process of the extrahepatic biliary tree leads to complete lumenal obliteration. The liver is characterized by a nonspecific giant cell transformation, and portal expansion by fibrous connective tissue with marked ductular proliferation. With time, ductopenia and biliary cirrhosis develop. The diffential diagnosis with other conditions with similar microscopic patterns such as alpha-1 antitrypsin deficiency, total parental nutrition, obstruction by a choledochal cyst, arteriohepatic dysplasia, familial progressive intra-hepatic cholestasis, and alteration of the bile acid metabolism is discussed. In the fetal group, abnormalities in different genes seem to play a role; ductal plate malformation is another possibility. Different etiologies have been postulated in the perinatal form of EHBA: genetic susceptilibility, vascular factors, toxins, and infections mainly by rotavirus and reovirus. The pathogenesis is complex. EHBA is a heterogenous disease, resulting from a combination of genetic factors, insults, and activation of different genetic and immunologic pathways. The treatment of EHBA is surgical, with anastomosis between the biliary tree and the intestine in the correctable type and a hepatic portoenterostomy (HPE) for the noncorrectable group. HPE is a temporizing treatment allowing the infant to develop and grow, followed in the majority of the patients by liver transplantation.

scholarly journals Association of De Novo RNF213 Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy

Neurology ◽  
2021 ◽  
Vol 96 (13) ◽  
pp. e1783-e1791
Author(s):  
Amélie Pinard ◽  
Maximillian D.J. Fiander ◽  
Alana C. Cecchi ◽  
Andrea L. Rideout ◽  
Mohamed Azouz ◽  
...  
Keyword(s):  
Amino Acids ◽  
Exome Sequencing ◽  
Moyamoya Disease ◽  
Abdominal Aorta ◽  
Rare Variants ◽  
De Novo ◽  
Ring Domain ◽  
Vascular Lesions ◽  
De Novo Mutations ◽  
Limited Region

ObjectiveTo test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.MethodsExome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.ResultsWe identified 3 novel rare de novo RNF213 variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114–4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.ConclusionsThese results indicate a novel syndrome associated with RNF213 rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

scholarly journals Recent advances in understanding biliary atresia

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 218 ◽  
Author(s):  
Andrew Wehrman ◽  
Orith Waisbourd-Zinman ◽  
Rebecca G Wells
Keyword(s):  
Biliary Atresia ◽  
Extrahepatic Bile Duct ◽  
Biliary Tree ◽  
Liver Parenchyma ◽  
Early Diagnostics ◽  
The Past ◽  
Recent Advances ◽  
Neonatal Liver ◽  
Extrahepatic Biliary Tree ◽  
Extrahepatic Bile Duct Obstruction

Biliary atresia (BA) is a neonatal liver disease characterized by progressive obstruction and fibrosis of the extrahepatic biliary tree as well as fibrosis and inflammation of the liver parenchyma. Recent studies found that infants who will go on to develop BA have elevated direct bilirubin levels in the first few days of life, suggesting that the disease starts in utero. The etiology and pathogenesis of BA, however, remain unknown. Here, we discuss recent studies examining potential pathogenetic mechanisms of BA, including genetic susceptibility, involvement of the immune system, and environmental insults such as viruses and toxins, although it is possible that there is not a single etiological agent but rather a large group of injurious insults that result in a final common pathway of extrahepatic bile duct obstruction and liver fibrosis. The management and diagnosis of BA have not advanced significantly in the past decade, but given recent advances in understanding the timing and potential pathogenesis of BA, we are hopeful that the next decade will bring early diagnostics and novel therapeutics.

scholarly journals Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients

2017 ◽  
Vol 103 (2) ◽  
pp. 415-428 ◽  
Author(s):  
Nitash Zwaveling-Soonawala ◽  
Marielle Alders ◽  
Aldo Jongejan ◽  
Lidija Kovačič ◽  
Floor A Duijkers ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Variants ◽  
De Novo ◽  
Hypogonadotropic Hypogonadism ◽  
Reference Population ◽  
Pituitary Stalk ◽  
Polygenic Inheritance ◽  
Pathogenic Variants ◽  
Brain Anomalies ◽  
Posterior Pituitary Lobe

Abstract Context Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. Objective To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Methods Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. Results We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Conclusion Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

scholarly journals BILIARY ATRESIA: evaluation on two distinct periods at a reference pediatric service

2014 ◽  
Vol 51 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Thais Costa Nascentes QUEIROZ ◽  
Alexandre Rodrigues FERREIRA ◽  
Eleonora Druve Tavares FAGUNDES ◽  
Mariza Leitão Valadares ROQUETE ◽  
Francisco José PENNA
Keyword(s):  
Biliary Atresia ◽  
Waiting Time ◽  
Neonatal Period ◽  
Biliary Tree ◽  
Probability Of Survival ◽  
Age At Surgery ◽  
Pediatric Service ◽  
Extrahepatic Biliary Tree ◽  
Observation Period

Context Biliary atresia is a progressive, idiopathic, fibro-obliterative disease of the extrahepatic biliary tree that presents with biliary obstruction exclusively in the neonatal period. Objectives To assess the differences regarding age at referral, age at surgery, duration of propaedeutics and waiting time for surgery between two groups of infants in different periods. Methods Retrospective study of infants diagnosed with biliary atresia on two periods: 1983-1993 and 1998-2011. Results Biliary atresia was diagnosed in 129 infants, being 48 in casuistic I and 81 in casuistic II. The median age at admission was 94 and 60 days, respectively (P = 0.0001). On evaluating patients who had undergone portoenterostomy before 120 days of age, no difference was observed regarding the duration of propaedeutics or waiting time for surgery (P = 0.15), but difference was found when comparing the age at surgery (P = 0.002). Among those infants with no biliary flow and without liver transplantation or death after 18 post-operative months, the estimated probability of survival was 44.6% and 38.7% in casuistics I and II, respectively. In casuistic I, all infants who showed biliary flow were alive during the observation period and, in casuistic II, 80.3% were alive after 7 years of follow-up. Conclusions Even though patients were admitted and treated earlier, it is clear that surgery could be done sooner. Delay in referral and timely propaedeutics were the main contributors.

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