BACKGROUND: Williams-Beuren syndrome (WBS, OMIM-194050) is a neurodevelopmental disorder with multisystemic manifestations caused by a 1.55-1.83 Mb deletion at 7q11.23 including 26-28 genes. Reported endocrine and metabolic abnormalities include transient hypercalcaemia of infancy, subclinical hypothyroidism in ∼30% of children and impaired glucose tolerance in ∼75% of adult individuals. The purpose of this study was to further study metabolic alterations in patients with WBS, as well as in several mouse models, to establish potential candidate genes. METHODS: We analysed several metabolic parameters in a cohort of 154 individuals with WBS (data available from 69 to 151 cases per arameter), as well as in several mouse models with complete and partial deletions of the orthologous WBS locus, and searched for causative genes and potential modifiers. RESULTS: Triglyceride plasma levels were significantly decreased in individuals with WBS while cholesterol levels were slightly decreased compared with controls. Hyperbilirubinemia, mostly unconjugated, was found in 18.3% of WBS cases and correlated with subclinical hypothyroidism and hypotriglyceridemia, suggesting common pathogenic mechanisms. Haploinsufficiency at MLXIPL and increased penetrance for hypomorphic alleles at the UGT1A1 gene promoter might underlie the lipid and bilirubin alterations. Other disturbances included increased protein and iron levels, as well as the known subclinical hypothyroidism and glucose intolerance. CONCLUSIONS: Our results show that several unreported biochemical alterations, related to haploinsufficiency for specific genes at 7q11.23, are relatively common in WBS. The early diagnosis, follow-up and management of these metabolic disturbances could prevent long-term complications in this disorder.

This work was supported by grants from the Spanish Fondo de Investigación Sanitaria (FISPI1002512 and PI1302841 to LAP-J), the Catalan Government (SGR2009-1274, SGR2014-1468 and ICREA Acadèmia to LAP-J), the Spanish Ministry of Science and Innovation (SAF2012-40036 to VC), an intramural CIBERER grant(to VC), and AGAURpredoctoral fellowships(FI_B2 00137 to MGP-V and FI_B1 00018 to CB)