Fine mapping of Smith-Fineman-Myers syndrome and exclusion of GPC3, GPCR2, MST4 and GLUD2 as candidate genes

Objective: Smith-Fineman-Myers syndrome (SFMS) is an X-linked mental retardation syndrome. The authors had ascertained a large Chinese family with SFMS from Shandong and had mapped the disease locus to an interval of 19.8 Mb on Xq25 flanked by markers DXS8064 and DXS8050. Further investigation suggested that SFMS exhibited locus heterogeneity. In this study for facilitating the identification of the gene responsible for SFMS, the additional markers were analyzed to narrow down the candidate region, and four candidate genes (GPC3, MST4, GPCR2 and GLUD2) were chosen and screened for disease-causing mutation. Methods: PCR and denaturing polyacrylamide gel electrophoresis were used to genotype 13 new polymorphic markers distributed within the candidate region. Mutation detection was accomplished by sequencing the exons and intron-exon junctions of the candidate genes. Results: By analyzing 13 additional polymorphic markers, SFMS candidate region can be reduced to an interval of 10.18 Mb bounded by XSTR3 and XSTR4, and no disease-causing mutation was identified in the coding regions of four candidate genes. Conclusion: GPCR2, GPC3, MST4 and GLUD2 were excluded as pathogenic genes for SFMS. The refined SFMS locus will assist in the identification and characterization of other candidate genes for SFMS.