Adobe Systems Case report 2 Alagille syndrome Dagmar Procházková Clinical genetics – practise (aVLKGC7X1) Adobe Systems Clinical genetics – practise (aVLKGC7X1) Learning outcomes ̶the student is presented with a case report of children with microdeletion syndrome Adobe Systems Clinical genetics – practise (aVLKGC7X1) ̶Alagille syndrome is a highly variable, autosomal dominant multisystem disease ̶ ̶Alagille syndrome 1, ALGS1 (MIM # 118450), which is caused by a mutation in the JAG1 gene on chromosome 20p12, with an incidence of 1:30,000 live births, 98% of patients with ALGS ̶ ̶Alagille syndrome 2, ALGS2 (MIM # 610205), which is associated with a mutation in the NOTCH2 gene on chromosome 1p12 and represents a rarer form of disability (1: 70,000 live births), 1-2% of patients with ALGS ̶ Adobe Systems Název předmětu (kód předmětu) (např. První pomoc - cvičení (VLPO011c)) ̶ ̶ ̶ ̶we estimated that less than 7% of patients with Alagille syndrome have deletions of 20p12 ̶ ̶ Adobe Systems Clinical genetics – practise (aVLKGC7X1) ̶The basic symptom of the syndrome is a reduction of intrahepatic bile ducts in combination with 5 diagnostic features: ̶Cholestasis (jaundice with conjugated hyperbilirubinemia, ↑ GGT, ↑ Chol, ↑ TGL, 10-20% of patients with rapid progression of liver disease) ̶Congenital heart disease (most often peripheral pulmonary stenosis, Fallot's tetralogy, pulmonary atresia, atrial or ventricular septal defect) ̶Skeletal abnormalities (most often butterfly vertebrae, vertebral fusion, spina bifida occulta, hemivertebra, 12th rib anomalies) ̶Eye disorders (most often posterior embryotoxon - prominence of the Schwalbe´s ring at the interface of the iris and cornea) ̶Characteristic appearance of a triangular face with a wide forehead, deep set eyes, hypertelorism, lower set ears and a longer onion-shaped nose Adobe Systems Clinical genetics – practise (aVLKGC7X1) 3 of these 5 major characters must be present to confirm the diagnosis Adobe Systems Clinical genetics – practise (aVLKGC7X1) Patient with ALGS, typical face D:\Dokumenty\ala3.JPG D:\Dokumenty\ala2.JPG Adobe Systems Název předmětu (kód předmětu) (např. První pomoc - cvičení (VLPO011c)) ̶posterior embryotoxon ̶bile duct paucity ̶ ̶butterfly vertebrae Adobe Systems Clinical genetics – practise (aVLKGC7X1) ̶About 39% of patients suffer from kidney problems, most often renal dysplasia ̶Growth retardation ̶Pancreatic insufficiency (40%) ̶Hypothyroidism ̶Recurrent infections ̶Mental retardation and learning disabilities usually in patients with deletion 20p12 ̶Alagille syndrome is a genetically heterogeneous disorder ̶ ̶ Adobe Systems Clinical genetics – practise (aVLKGC7X1) ̶We present phenotype of 4 probands with ALGS1, whose involvement was confirmed by molecular genetic examination ̶Method: next generation sequencing technique (MiSeq, Illumina) followed by direct sequencing of PCR products on a genetic analyzer. At the genomic DNA level, the coding region of the JAG1 gene, including exon / intron boundaries, was sequenced. The obtained sequences were compared with the reference sequences of the JAG1 gene NG_007496.1 and NM_000214.2. The analysis of the found variants was performed on the basis of the reference database (http://www.ncbi.nlm.nih.gov/projects/SNP). ̶ Adobe Systems Clinical genetics – practise (aVLKGC7X1) Phenotype of patients with ALGS1 Table 1 Clinical features present in carriers of JAG1 mutations Pacient Diagnosis Peculiar face Cholestasis Liver biopsy Heart disease Ocular Skeletal Renal Others Age anomalies anomalies anomalies 1 16 month yes yes intrahepatic bile duct peripheral pulmonary no butterfly no learning disability paucity artery stenosis vertebrae 2 6 years yes yes intrahepatic bile duct peripheral pulmonary no no no paucity artery stenosis 3 7month yes yes intrahepatic bile duct peripheral pulmonary no no ren behavioral disorders paucity artery stenosis arcuatus 4 3 month yes yes intrahepatic bile duct peripheral pulmonary embryotoxon rib cystic hypothyroidism paucity artery stenosis posterior anomalies disease growth retardation Adobe Systems Clinical genetics – practise (aVLKGC7X1) Results of molecular genetic testing of the JAG1 gene Table 2 Mutations in JAG1 found in patients with Alagille syndrome Pacient identified sequence variants Mutation Exon cDNA Protein Mutation origin type 1 gene JAG1 (NM_000214.2):c.3189dupG in heterozygous state not 25 c.3189dupG p.Asn1064Glufs*45 frameshift novel mutation, duplication investigated 2 gene JAG1(NM_000214.2): c.2039delG in heterozygous state mother 16 c.2039delG p.Gly680Alafs*63 frameshift novel mutation, deletion 3 gene JAG1 (NM_000214.2):c.1913delG in heterozygous state father 15 c.1913delG p.Cys638Leufs*105 frameshift novel mutation, deletion 4 gene JAG1 (NM_000214.2):c.2230C>T p.(Arg744Ter) in heterozygous state de novo 18 c.2230C>T p.Arg744Ter nonsense substitution the c. nomenclature is based on the cDNA sequence NM_000214.2 Adobe Systems Clinical genetics – practise (aVLKGC7X1) Family screening ̶The mother of proband No. 2 was monitored at the Department of Gastroenterology for unexplained hepatitis ̶ ̶Molecular - genetic examination also confirmed ALGS1 ̶ ̶Cardiac examination revealed aortic valve insufficiency ̶ ̶Another sibling - molecular-genetically ALGS1 excluded ̶ ̶Importance: diagnosis and genetic counseling in the family ̶ Adobe Systems Clinical genetics – practise (aVLKGC7X1) ̶The care of these patients is multidisciplinary ̶ ̶It includes a pediatrician, hepatologist, cardiologist, ophthalmologist, nephrologist, endocrinologist, nutritional therapist, radiologist, geneticist and, in some cases, a transplant team. ̶ ̶Molecular-genetic examination x classical scoring system ̶ ̶Genetic testing in unclear cases ̶ Adobe Systems Take home message ̶syndromological analyzes and syndromological diagnostics benefit from working together to share clinical and related laboratory findings ̶ Clinical genetics – practise (aVLKGC7X1) Lékařská fakulta Masarykovy univerzity 2021 Adobe Systems