Abstract

Whole exome sequencing performed on a male patient with a complex phenotype including short stature associated with hypopituitarism, sensorineural deafness, hypoparathyroidism, retinal dystrophy, and developmental delay revealed a novel de novo variant in FASN (p.Ala2132Val), encoding fatty acid synthase. The patient failed to respond to growth-promoting treatment, only reaching a height of 128.3 cm (-6.98 SDS) at 24.7 years of age, and was prepubertal with a delayed bone age (13.6 years). Subsequent metabolic investigations demonstrated high triglyceride concentrations throughout an 18 h fast with a failure to increase 3-hydroxybutyrate, suggesting a defect in fatty acid oxidation or ketone body synthesis. Human embryonic brain analysis revealed FASN expression in the diencephalon, hypothalamus and Rathke's pouch. Following the labelling of glucose with carbon-13 (C13) in cultured fibroblasts, mass spectrometry data revealed that more C13-glucose was incorporated into de novo synthesised palmitic acid in controls compared to patient cells, suggesting reduced fatty acid synthesis in the patient. Our data suggest that the FASN p.Ala2132Val variant is associated with a complex phenotype including hypothalamo-pituitary dysfunction, consistent with previous studies showing that rodent neural/progenitor brain stem cells are governed by Fasn-dependent de novo lipogenesis (fatty acid synthesis) for proliferation.