FGS Update Submitted by Greenwood Genetics Center, September 20, 2006

As many of you are aware, FG syndrome (FGS) was first described by Dr. John Opitz in 1974 based on a family containing affected males with mental retardation (MR), macrocephaly (large head), imperforate anus, broad thumbs and hypotonia (“floppiness”). Many additional findings have been noted in other individuals and families considered to have FG syndrome.

Since 1997 when Dr. Sylvain Briault and his collaborators published a localization for a FGS gene on the long arm of the X chromosome, many laboratories have attempted to identify the FGS gene. Unfortunately, these studies have revealed that FG syndrome is a heterogenous condition caused by mutations in perhaps as many as 5 genes: FGS1 in Xq12-q21.31, FGS2 in Xq28, FGS3 in Xp22.3, FGS4 in Xp11.4-p11.3 and FGS5 in Xq22.31. Thus, it appears that no single gene test will cover all cases of FGS.

Our group at the Greenwood Genetic Center has been actively pursuing the FGS1 gene since 1998 when we described 3 FGS families linked to Xq13-q21. Last year we identified mutations in a gene that caused another syndrome, Allan-Herndon-Dudley. Because this gene, MCT8, functions as a thyroid hormone transporter, we hypothesized that other genes on the X chromosome connected to thyroid function were worthy of investigation in other X-linked MR (XLMR) conditions. One such gene, HOPA, located in Xq13, functions as a thyroid hormone receptor associated protein. We thus undertook an extensive analysis of HOPA in all XLMR families in our collection linked to Xq13. This included our 3 FGS families. We identified the same mutation in 2 of the FGS families while observing no mutation in the other 22 families. This mutation is a single base substitution (a “C” for a “T” at position 2422 in the HOPA gene) which results in an amino acid substitution (tryptophan for arginine). A subsequent study of FGS patients obtained via our collaboration with Dr. Opitz and colleagues at the University of Utah identified another 3 patients (out of 45 individuals) who had this same mutation, referred to as p.R808W. We have been unable to find this change in either 451 normal adult males or 343 male newborns. This leads us to believe that the p.R808W mutation in the HOPA gene is associated with FGS and that HOPA is likely the FGS1 gene. However our work has not been completed. We still need to sequence the entire HOPA gene in all available FG patients because if HOPA is the FGS1 gene, it is likely other mutations exist. Unfortunately the gene is quite large so the study will take some time.

The group at the Greenwood Genetic Center will continue to conduct sequencing analysis of the HOPA gene in patient material available to them. We will also initiate functional studies to determine the role of this gene in the causation of FGS. While the HOPA work is continuing, we will be exploring other candidate genes for FGS.

As more data are generated from these studies, we will begin evaluating the requirements for establishing diagnostic testing for FGS. We hope to have a clearer picture by the end of 2006 by which we can develop guidelines for FGS testing.

For the moment, individuals will be considered for testing if clinical information, photographs and blood samples are available to the GGC.

For additional information, please contact either Dr. Charles Schwartz (phone: (864) 941-8140; email: ceschwartz@ggc.org) or Dr. Roger Stevenson (phone: (864) 941-8146; email: res@ggc.org). To arrange for the shipment of blood samples and clinical information/photos please contact our sample coordinator, Cindy Skinner, RN (phone: (864) 941-8115; email: cindy@ggc.org).