The Genetics of Orphan Diseases

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Recent developments in sequencing technology have had allowed solving the genetic causes of many human genetic diseases. In this presentation I will highlight progress we have made in the University Medical Center in Utrecht in the recent years, on solving X-linked, recessive and dominant de novo disorders. We identified the genetic cause of Cantu syndrome, which is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening.