Mutation screening and genotype : phenotype correlation in familial hypercholesterolaemia

The aim of this study was to develop a mutation screening protocol for fami lial hypercholesterolaemia (FH) patients and to assess genotype/phenotype e ffects in terms of pre-treatment lipid profiles and presentation of tendon xanthomata (TX). A total of 158 families with clinical definitions of possi ble (120) or definite (38) FH were studied using a tiered screening protoco l. Mutations were identified in 52 families, 44 families showing 23 differe nt LDLR gene defects and eight families showing the common Apo B100 gene de fect R3500Q. LDLR defects were detected in various regions of the gene with 56% in the LDL binding domain (exons 2-6) and 37% in the EGF precursor hom ology domain (exons 7-14). The most common mutations were D461N(7), C210X(5 ), 932delA(5), and C163Y(4). Frameshift mutations accounted for 20% with no nsense 13%, mis-sense 35%, splice 3%, Apo B 13% and 2% large deletion, 13% of clinically definite FH remained undefined. In conclusion, DNA based diag nosis is possible in 79% (30/38) of clinically definite FH families and of the 120 possible FH families at the start of the screening program, 18% (22 /120) now have defined mutations. Overall 60 families from the original 158 meet the clinical and/or genetic criteria for definite FH. Tendon xanthoma ta were present in only 58% (30/52) of genetically defined FH families, thu s limiting its use as a strict diagnostic criteria. Families with low densi ty lipoprotein receptor (LDLR) defects present with higher total and LDL ch olesterol levels and a higher incidence of TX than do those with the common Apo B variant, and frameshift mutations appear to have the most severe pre sentation. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.