Introduction Neonatal cholestasis is the presenting clinical feature of serious and potentially life limiting liver diseases such as progressive familial intrahepatic cholestasis (PFIC), arthrogryposis-renal-cholestasis (ARC) syndrome and Niemann Pick C (NPC) disease. A single rapid molecular test to confirm the diagnosis would reduce the delay from molecular genetic investigation at multiple diagnostic centres thus facilitating optimal clinical management and counselling. We have designed a resequencing microarray (BRUM1) capable of simultaneously sequencing multiple genes associated with neonatal cholestasis.
Aim To assess the utility of BRUM1 as a first-line molecular investigation for patients with neonatal cholestasis in whom an inherited causes is suspected.
Method DNA from 95 infants with neonatal cholestasis in whom an inherited cause was suspected was amplified by PCR and hybridised to BRUM1 (validated against reference sequencing with 98.9% agreement (CI 0.97 to >0.99)) for simultaneous sequencing of the main causes of inherited disease in this group which included ATP8B1, ABCB11, ABCB4, VPS33B, VIPAR, NPC1 and NPC2. Children with known α-1 antitrypsin deficiency or Alagille syndrome were not included.
Results 30 infants had pathogenic mutations, which cause neonatal cholestasis. 23 of the mutations were novel.
|Gene||Total number of mutations||Novel mutations|
In this cohort of patients, 30.5% of infants with neonatal cholestasis had a genetic diagnosis confirmed by BRUM1. The average time to diagnosis was 5–25 days.
Conclusion A specific and rapid genetic diagnosis in infants with a phenotype of neonatal cholestasis can be made using a single resequencing microarray, to optimise clinical management and facilitate appropriate counselling of families.
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