Findings that shed new light on the possible pathogenesis of a disease or an adverse effect
De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features
1 Section for Pediatrics, Department of Clinical Medicine, University of Bergen, Bergen, Norway
2 Department of Pediatrics, University of California, San Fransisco, CA, USA
3 Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
4 Section for Pathology, the Gade Institute, University of Bergen, Bergen, Norway
5 Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
6 Department of Neurology, Haukeland University Hospital, Bergen, Norway
7 Department of Pathology, Haukeland University Hospital, Bergen, Norway
Correspondence to:
anders.molven{at}gades.uib.no
Mutations in genes involved in Ras signalling cause Noonan syndrome and other disorders characterised by growth disturbances and variable neuro-cardio-facio-cutaneous features. We describe two sisters, who presented with dysmorphic features, hypotonia, retarded growth and psychomotor retardation. The patients were initially diagnosed with Costello syndrome, an autosomal recessive inheritance was assumed. Remarkably, however, we identified a germline HRAS mutation (G12A) in one sister and a germline KRAS mutation (F156L) in her sibling. Both mutations had arisen de novo. The F156L mutant K-Ras protein accumulated in the active, guanosine triphosphate-bound conformation and affected downstream signalling. The patient harbouring this mutation was followed for three decades, and her cardiac hypertrophy gradually normalised. However, she developed severe epilepsy with hippocampal sclerosis and atrophy. The occurrence of distinct de novo mutations adds to variable expressivity and gonadal mosaicism as possible explanations of how an autosomal dominant disease may manifest as an apparently recessive condition.
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