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Human Mutation Dec 2019Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1...
Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1 (JAG1), but also by variants in NOTCH2. The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants. Conversely, the majority of NOTCH2 variants are missense, though fewer of these variants have been described. In addition, there is a small group of patients with a clear clinical phenotype in the absence of a pathogenic variant. Here, we catalog our single-center study, which includes 401 probands and 111 affected family members amassed over a 27-year period, to provide updated mutation frequencies in JAG1 and NOTCH2 as well as functional validation of nine missense variants. Combining our cohort of 86 novel JAG1 and three novel NOTCH2 variants with previously published data (totaling 713 variants), we present the most comprehensive pathogenic variant overview for Alagille syndrome. Using this data set, we developed new guidance to help with the classification of JAG1 missense variants. Finally, we report clinically consistent cases for which a molecular etiology has not been identified and discuss the potential for next generation sequencing methodologies in novel variant discovery.
Topics: Alagille Syndrome; Female; Genetic Predisposition to Disease; Humans; Jagged-1 Protein; Loss of Function Mutation; Male; Mutation Rate; Mutation, Missense; Pedigree; Receptor, Notch2
PubMed: 31343788
DOI: 10.1002/humu.23879 -
Ultrasound in Obstetrics & Gynecology :... Jan 2022To assess the performance of a non-invasive prenatal screening test (NIPT) for a panel of dominant single-gene disorders (SGD) with a combined population incidence of 1...
OBJECTIVE
To assess the performance of a non-invasive prenatal screening test (NIPT) for a panel of dominant single-gene disorders (SGD) with a combined population incidence of 1 in 600.
METHODS
Cell-free fetal DNA isolated from maternal plasma samples accessioned from 14 April 2017 to 27 November 2019 was analyzed by next-generation sequencing, targeting 30 genes, to look for pathogenic or likely pathogenic variants implicated in 25 dominant conditions. The conditions included Noonan spectrum disorders, skeletal disorders, craniosynostosis syndromes, Cornelia de Lange syndrome, Alagille syndrome, tuberous sclerosis, epileptic encephalopathy, SYNGAP1-related intellectual disability, CHARGE syndrome, Sotos syndrome and Rett syndrome. NIPT-SGD was made available as a clinical service to women with a singleton pregnancy at ≥ 9 weeks' gestation, with testing on maternal and paternal genomic DNA to assist in interpretation. A minimum of 4.5% fetal fraction was required for test interpretation. Variants identified in the mother were deemed inconclusive with respect to fetal carrier status. Confirmatory prenatal or postnatal diagnostic testing was recommended for all screen-positive patients and follow-up information was requested. The screen-positive rates with respect to the clinical indication for testing were evaluated.
RESULTS
A NIPT-SGD result was available for 2208 women, of which 125 (5.7%) were positive. Elevated test-positive rates were observed for referrals with a family history of a disorder on the panel (20/132 (15.2%)) or a primary indication of fetal long-bone abnormality (60/178 (33.7%)), fetal craniofacial abnormality (6/21 (28.6%)), fetal lymphatic abnormality (20/150 (13.3%)) or major fetal cardiac defect (4/31 (12.9%)). For paternal age ≥ 40 years as a sole risk factor, the test-positive rate was 2/912 (0.2%). Of the 125 positive cases, follow-up information was available for 67 (53.6%), with none classified as false-positive. No false-negative cases were identified.
CONCLUSIONS
NIPT can assist in the early detection of a set of SGD, particularly when either abnormal ultrasound findings or a family history is present. Additional clinical studies are needed to evaluate the optimal design of the gene panel, define target populations and assess patient acceptability. NIPT-SGD offers a safe and early prenatal screening option. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Adult; Cell-Free Nucleic Acids; Female; Fetus; Genetic Diseases, Inborn; Gestational Age; High-Throughput Nucleotide Sequencing; Humans; Noninvasive Prenatal Testing; Pregnancy
PubMed: 34358384
DOI: 10.1002/uog.23756 -
Digestive and Liver Disease : Official... Jan 2022Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment....
Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.
Topics: Cholestasis; Evidence-Based Medicine; Female; Gastroenterology; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Practice Guidelines as Topic
PubMed: 34688573
DOI: 10.1016/j.dld.2021.09.011 -
Hepatology International Oct 2023Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is... (Review)
Review
Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is inherited in an autosomal dominant manner in 40% of patients, it carries many implications for genetic counselling of patients and screening of family members. In addition, the considerable variable expression and absence of a clear genotype-phenotype correlation, results in a diverse range of clinical manifestations, even in affected individuals within the same family. With recent therapeutic advancements in cholestasis treatment and the improved survival rates with liver transplantation (LT), many patients with ALGS survive into adulthood. Although LT is curative for liver disease secondary to ALGS, complications secondary to extrahepatic involvement remain problematic lifelong. This review is aimed at providing a comprehensive review of ALGS to adult clinicians who will take over the medical care of these patients following transition, with particular focus on certain aspects of the condition that require lifelong surveillance. We also provide a diagnostic framework for adult patients with suspected ALGS and highlight key aspects to consider when determining eligibility for LT in patients with this syndrome.
Topics: Adult; Humans; Alagille Syndrome; Liver Transplantation
PubMed: 37584849
DOI: 10.1007/s12072-023-10578-x -
Drugs Oct 2021Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic... (Review)
Review
Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic diseases, including progressive familial intrahepatic cholestasis (PFIC). In July 2021, odevixibat received its first approval in the EU for the treatment of PFIC in patients aged ≥ 6 months, followed shortly by its approval in the USA for the treatment of pruritus in patients aged ≥ 3 months with PFIC. Odevixibat is also in clinical development for the treatment of other cholestatic diseases, including Alagille syndrome and biliary atresia, in various countries. This article summarizes the milestones in the development of odevixibat leading to this first approval for PFIC.
Topics: Benzodiazepines; Butyrates; Carrier Proteins; Cholestasis; Drug Approval; Drug Development; Humans; Membrane Glycoproteins; Pruritus
PubMed: 34499340
DOI: 10.1007/s40265-021-01594-y -
The British Journal of Radiology Jan 2022Alagille syndrome (ALGS) is a multisystemic disease caused by mutations in genes of pathway, which regulates embryonic cell differentiation and angiogenesis.... (Review)
Review
Alagille syndrome (ALGS) is a multisystemic disease caused by mutations in genes of pathway, which regulates embryonic cell differentiation and angiogenesis. Clinically, ALGS is characterized by cholestasis, cardiac defects, characteristic facial features, skeletal and ophthalmologic abnormalities. The aim of this review is to illustrate neuroradiological findings in ALGS, which are less well-known and prevalent, including cerebrovascular anomalies (such as aneurysms, dolichoectasia, Moyamoya syndrome and venous peculiarities), Chiari 1 malformation, craniosynostosis, intracranial hypertension, and vertebral anomalies (namely butterfly vertebra, hemivertebra, and craniocervical junction anomalies). Rarer cerebral midline malformations and temporal bone anomalies have also been described.
Topics: Alagille Syndrome; Brain; Cerebral Angiography; Cerebral Arteries; Cerebral Veins; Face; Humans; Magnetic Resonance Imaging; Neuroradiography; Skull; Spine
PubMed: 34609904
DOI: 10.1259/bjr.20201241 -
Radiology Case Reports Nov 2023A man in his 40s presented to our Hospital with abdominal pain, jaundice, and pruritus. He had a history of Alagille Syndrome treated with cholecystojejunostomy in the...
A man in his 40s presented to our Hospital with abdominal pain, jaundice, and pruritus. He had a history of Alagille Syndrome treated with cholecystojejunostomy in the neonatal period because of initial misdiagnosis of biliary atresia. Laboratory investigations showed hyperbilirubinemia (total bilirubin 1.76 mg/dL [<1.2 mg/dL]; conjugated 1.06 mg/dL [<0.3 mg/dL]) and cholestasis (GGT 78 U/L [<50 U/L]; ALP 200 U/L [<50 U/L]). Transabdominal ultrasound was limited by aerobilia due to the cholecystojejuno-anastomosis. Subsequent basal CT scan revealed an impacted stone within the patient's native common bile duct (CBD). Aerobilia in intrahepatic bile ducts and gallbladder was reported. Magnetic Resonance cholangiopancreatography confirmed the gallstone in the CBD compressing cystic duct and common hepatic duct, with dilation of the upstream bile ducts. Furthermore, the native CBD was obstructed by other gallstones. In Mirizzi syndrome, gallstones impacted in gallbladder's Hartmann's pouch or cystic duct extrinsically compress CBD. We suggest naming the present condition "Reverse Mirizzi Syndrome" (Renzulli Matteo Syndrome, RMS) because it is the exact opposite of Mirizzi syndrome.
PubMed: 37745768
DOI: 10.1016/j.radcr.2023.08.077 -
Journal of Multidisciplinary Healthcare 2022Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of various organ systems. It predominantly affects the liver, skeleton, heart,... (Review)
Review
Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by involvement of various organ systems. It predominantly affects the liver, skeleton, heart, kidneys, eyes and major blood vessels. With myriads of presentations across different age groups, ALGS is usually suspected in infants presenting with high gamma glutamyl transpeptidase cholestasis and/or congenital heart disease. In children it may present with decompensated cirrhosis, intellectual disability or short stature, and in adults vascular events like stroke or ruptured berry aneurysm are more commonly noted. Liver transplantation (LT) is indicated in children with cholestasis progressing to cirrhosis with decompensation. Other indications for LT include intractable pruritus, recurrent fractures, hepatocellular carcinoma and disfiguring xanthomas. Due to an increased risk of renal impairment noted in ALGS, these patients would require optimized renal sparing immunosuppression in the post-transplant period. As the systemic manifestations of ALGS are protean and a wider spectrum is being increasingly elucidated, a multidisciplinary team needs to be involved in managing these patients. Moreover, many basic-science and clinical questions especially with regard to its presentation and management remain unanswered. The aim of this review is to provide updated insights into the management of the multi-system involvement of ALGS.
PubMed: 35237041
DOI: 10.2147/JMDH.S295441 -
Obstetric Medicine Mar 2021Alagille syndrome is an autosomal dominant multisystem disorder with an estimated frequency of 1 in 30 000. Only a small number of pregnancy outcomes have been described...
Alagille syndrome is an autosomal dominant multisystem disorder with an estimated frequency of 1 in 30 000. Only a small number of pregnancy outcomes have been described in women with this condition. The report details the pregnancy outcomes of two women with Alagille syndrome. We also review the literature pertaining to this syndrome in pregnancy and demonstrate a significant risk of adverse pregnancy outcomes.
PubMed: 33995572
DOI: 10.1177/1753495X19849738 -
Frontiers in Pharmacology 2021Advancements in treatment for the rare genetic disorder known as Alagille Syndrome (ALGS) have been regrettably slow. The large variety of mutations to the JAG1 and... (Review)
Review
Advancements in treatment for the rare genetic disorder known as Alagille Syndrome (ALGS) have been regrettably slow. The large variety of mutations to the JAG1 and NOTCH2 genes which lead to ALGS pose a unique challenge for developing targeted treatments. Due to the central role of the Notch signaling pathway in several cancers, traditional treatment modalities which compensate for the loss in activity caused by mutation are rightly excluded. Unfortunately, current treatment plans for ALGS focus on relieving symptoms of the disorder and do not address the underlying causes of disease. Here we review several of the current and potential key technologies and strategies which may yield a significant leap in developing targeted therapies for this disorder.
PubMed: 34497511
DOI: 10.3389/fphar.2021.704586