IllnessCholestasis, congenital + adult; differential diagnosis

NGS +

[Sanger]

Cholestasis is defined as a decrease in bile flow due to impaired secretion by hepatocytes or obstruction of bile flow by intra- or extrahepatic bile ducts. The clinical definition of cholestasis is any condition in which substances normally secreted into the bile are retained. The mechanisms of cholestasis can be broadly divided into hepatocellular, in which impairment of bile formation occurs, and obstructive, in which obstruction of bile flow occurs after its formation. Accumulation of bile acids leads to pruritus, hepatocyte toxicity, and cirrhosis. Neonatal cholestasis includes a variety of different disorders, several of which are caused monogenically. Progressive familial intrahepatic cholestasis accounts for more than 15% of neonatal cholestasis syndromes and approximately 15% of liver transplants in childhood. Using a large targeted gene panel for infants with cholestasis after exclusion of biliary atresia, more than 80% of infants received a diagnosis of monogenic etiology. Although affected individuals typically develop liver failure before adulthood, cases with later onset can be differentiated by comprehensive DNA studies. Most monogenic cholestatic disorders are inherited in an autosomal recessive manner. DNA diagnostic yield, by its very nature, depends critically on prior clinical case workup. But a negative molecular genetic result does not constitute exclusion of the clinical diagnosis.

Reference: https://doi.org/10.1002/cld.872

• Allelic: Bardet-Biedl syndrome 14, modifier of (TMEM67)
• Allelic: Bjornstad syndrome (BCS1L)
• Allelic: Bronchiectasis with or without elevated sweat chloride 1, modifier of (CFTR)
• Allelic: Bronchiectasis with/-out elevated sweat chloride 1, modifier of (CFTR)
• Allelic: Charcot-Marie-Tooth disease, DI C (YARS1)
• Allelic: Congenital bilateral absence of vas deferens (CFTR)
• Allelic: Deafness, AR 66 (DCDC2)
• Allelic: Deafness, congenital heart defects + posterior embryotoxon (JAG1)
• Allelic: Emphysema due to AAT deficiency (SERPINA1)
• Allelic: Hajdu-Cheney syndrome (NOTCH2)
• Allelic: Heimler syndrome 1 (PEX1)
• Allelic: Heimler syndrome 2 (PEX6)
• Allelic: Hyper-IgD syndrome (MVK)
• Allelic: Hypertrypsinemia, neonatal (CFTR)
• Allelic: Joubert syndrome 28 (MKS1)
• Allelic: Joubert syndrome 6 (TMEM67)
• Allelic: Joubert syndrome 7 (RPGRIP1L)
• Allelic: Joubert syndrome 9 (CC2D2A)
• Allelic: Lewy body dementia, susceptibility to (GBA1)
• Allelic: Meckel syndrome 1 (MKS1)
• Allelic: Meckel syndrome 3 (TMEM67)
• Allelic: Meckel syndrome 5 (RPGRIP1L)
• Allelic: Meckel syndrome 6 (CC2D2A)
• Allelic: Nephronophthisis 11 (TMEM67)
• Allelic: Nephronophthisis 19 (DCDC2)
• Allelic: Pancreatitis, hereditary (CFTR)
• Allelic: Parkinson disease, late-onset, susceptibility to (GBA1)
• Allelic: Perrault syndrome 1 (HSD17B4)
• Allelic: Porokeratosis 3, multiple types (MVK)
• Allelic: Progressive external ophthalmoplegia with mtDNA deletions, AR 4 (DGUOK)
• Allelic: RHYNS syndrome (TMEM67)
• Allelic: Renal cell carcinoma (HNF1B)
• Allelic: Short stature, optic nerve atrophy + Pelger-Huet anomaly (NBAS)
• Allelic: Spastic paraplegia 5A, AR (CYP7B1)
• Allelic: Sweat chloride elevation without CF (CFTR)
• Allelic: Tetralogy of Fallot (JAG1)
• Allelic: Type 2 diabetes mellitus (HNF1B)
• Renal cysts + diabetes syndrome (HNF1B)
• Acute liver failure, included
• Alagille syndrome 1 (JAG1)
• Alagille syndrome 2 (NOTCH2)
• Alpha-1 Antitrypsin Deficiency, included
• Alpha-methylacyl-CoA racemase deficiency (AMACR)
• Arthrogryposis, renal dysfunction + cholestasis 1 (VPS33B)
• Arthrogryposis, renal dysfunction + cholestasis 2 (VIPAS39)
• Bardet-Biedl syndrome 13 (MKS1)
• Bile acid synthesis defect, congenital, 1 (HSD3B7)
• Bile acid synthesis defect, congenital, 2 (AKR1D1)
• Bile acid synthesis defect, congenital, 3 (CYP7A1, CYP7B1)
• Bile acid synthesis defect, congenital, 4 (AMACR)
• Bile salt synthesis defect, included
• Bilirubin, serum level of, QTL1 (UGT1A1)
• COACH syndrome 1 (TMEM67)
• COACH syndrome 2 (CC2D2A)
• COACH syndrome 3 (RPGRIP1L)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Cholestasis, benign recurrent intrahepatic (ATP8B1)
• Cholestasis, benign recurrent intrahepatic, 2 (ABCB11)
• Cholestasis, included
• Cholestasis, intrahepatic, of pregnancy, 1 (ATP8B1)
• Cholestasis, intrahepatic, of pregnancy, 3 (ABCB4)
• Cholestasis, progressive familial intrahepatic, 1 (ATP8B1)
• Cholestasis, progressive familial intrahepatic, 2 (ABCB11)
• Cholestasis, progressive familial intrahepatic, 3 (ABCB4)
• Cholestasis, progressive familial intrahepatic, 4 (TJP2)
• Cholestasis, progressive familial intrahepatic, 5 (NR1H4)
• Cholestasis, progressive familial intrahepatic, 7, with/-out hearing loss (USP53)
• Cholestasis, progressive familial intrahepatic, 8 (KIF12)
• Cholestasis, progressive familial intrahepatic, 9 (ZFYVE19)
• Cholesteryl ester storage disease (LIPA)
• Citrullinemia, adult-onset type II (SLC25A13)
• Citrullinemia, type II, neonatal-onset (SLC25A13)
• Congenital disorder of glycosylation, type IIe (COG7)
• Congenital disorder of glycosylation, type Ib (MPI)
• Congenital hepatic fibrosis, included
• Crigler-Najjar syndrome, type I (UGT1A1)
• Crigler-Najjar syndrome, type II (UGT1A1)
• Cystic fibrosis (CFTR)
• D-bifunctional protein deficiency (HSD17B4)
• Dubin-Johnson syndrome (ABCC2)
• Emphysema-cirrhosis, due to AAT deficiency (SERPINA1)
• Familial intrahepatic cholestasis, included
• Fanconi renotubular syndrome 3 (EHHAADH)
• Fat soluble vitamin deficiency, included
• Fatty liver, acute, of pregnancy (HADHA)
• Fructose intolerance, hereditary (ALDOB)
• GRACILE syndrome (BCS1L)
• Galactokinase deficiency with cataracts (GALK)
• Galactose epimerase deficiency (GALE)
• Galactosemia (GALT)
• Galactosemia IV (GALM)
• Gallbladder disease 1 (ABCB4)
• Gallbladder disease 4 (ABCG8)
• Gaucher disease, perinatal lethal (GBA1)
• Gaucher disease, type I, II, III, IIIC (GBA1)
• Gilbert syndrome (UGT1A1)
• Glycogen storage disease IV (GBE1)
• HELLP syndrome, maternal, of pregnancy (HADHA)
• Hemorrhagic diathesis due to antithrombin Pittsburgh (SERPINA1)
• Hyperbilirubinemia, familial transient neonatal (UGT1A1)
• Hypercholanemia, familial (BAAT, TJP2)
• Hypermethioninemia due to adenosine kinase deficiency (ADK)
• Ichthyosis, leukocyte vacuoles, alopecia and sclerosing cholangitis (CLDN1)
• Ichthyosis-hypotrichosis-sclerosing cholangitis, included
• Infantile liver failure syndrome 2 (NBAS)
• Infantile liver failure syndrome 3 (RINT1)
• Infantile-onset multisystem neurologic, endocrine + pancreatic disease 2 (YARS1)
• LCHAD deficiency (HADHA)
• MYO5B associated diseas, included
• Mevalonic aciduria (MVK)
• Microvillus inclusion disease (MYO5B)
• Mitochondrial DNA depletion syndrome 3 [hepatocerebral type] (DGUOK)
• Mitochondrial complex III deficiency, nuclear type 1 (BCS1L)
• Mitochondrial trifunctional protein deficiency (HADHA)
• Neonatal and adult cholestasis (GPBAR1)
• Neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome, included
• Neonatal sclerosis cholangitis, included
• Nephronophthisis 2, infantile (INVS)
• Nephronophthisis, included
• Niemann-Pick disease, type C1 (NPC1)
• Niemann-Pick disease, type C2 (NPC2)
• Niemann-Pick disease, type D (NPC1)
• Ornithine transcarbamylase deficiency (OTC)
• Osteootohepatoenteric syndrome (UNC45A)
• Peroxisome biogenesis disorder 10A, Zellweger (PEX3)
• Peroxisome biogenesis disorder 10B (PEX3)
• Peroxisome biogenesis disorder 11A, Zellweger (PEX13)
• Peroxisome biogenesis disorder 11B (PEX13)
• Peroxisome biogenesis disorder 12A, Zellweger (PEX19)
• Peroxisome biogenesis disorder 13A, Zellweger (PEX14)
• Peroxisome biogenesis disorder 1A, Zellweger (PEX1)
• Peroxisome biogenesis disorder 1B, NALD/IRD (PEX1)
• Peroxisome biogenesis disorder 3A, Zellweger (PEX12)
• Peroxisome biogenesis disorder 3B (PEX12)
• Peroxisome biogenesis disorder 4A, Zellweger (PEX6)
• Peroxisome biogenesis disorder 4B (PEX6)
• Peroxisome biogenesis disorder 5A, Zellweger (PEX2)
• Peroxisome biogenesis disorder 5B (PEX2)
• Peroxisome biogenesis disorder 6A, Zellweger (PEX10)
• Peroxisome biogenesis disorder 6B (PEX10)
• Peroxisome biogenesis disorder 7A, Zellweger (PEX26)
• Peroxisome biogenesis disorder 7B (PEX26)
• Peroxisome biogenesis disorder 8A, Zellweger (PEX16)
• Peroxisome biogenesis disorder 8B (PEX16)
• Polyglucosan body disease, adult form (GBE1)
• Portal hypertension, noncirrhotic (DGUOK)
• Sclerosing cholangitis, neonatal (DCDC2)
• Severe neonatal cholestasis, included
• Sitosterolemia 1 (ABCG8)
• Sitosterolemia 2 (ABCG5)
• Smith-Lemli-Opitz syndrome (DHCR7)
• Transaldolase deficiency (TALDO1)
• Tyrosinaemia, type 1 (FAH)
• Unconjugated jaundice, included
• Wilson disease (ATP7B)
• Wolman disease (LIPA)