Bleparophimosis ptosis epicanthus inversus syndrome (BPES) is a rare disorder characterized by eyelid malformation and in some cases associated with premature ovarian failure. Although the familial form is autosomal dominant, many cases are also sporadic. The mutations causing this disorder were found in a winged/forkhead transcription factor gene named FOXL2. We have sequenced the mouse homolog for the FOXL2 gene and identified the Fugu rubripes (pufferfish) ortholog from the database. By alignment of the three sequences, we found an almost complete conservation of the forkhead domain in the three species. There is 95% and 61% conservation at the protein level between human-mouse and human-pufferfish, respectively. The polyalanine and polyproline tracts within the gene are absent in Fugu rubripes. An overview identifies four breaks in the conservation of the gene within these species. Using a direct sequencing approach, we performed mutation analysis from DNA of nine affected individuals from familial and sporadic cases. The mutations are distributed throughout the coding region of the FOXL2 gene. We identified five novel mutations: g.292delG (E19fsX149); g.530G>A (W98X); g.548A>G (H104R); g.652G>T (E139X); and g.1178_1185del8 (A314fsX530). In addition we also identified two known mutations g.823C>T (Q196X) and g.1092_1108dup17, the latter in individuals from three unrelated pedigrees.

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Cone rod dystrophy 5 (CORD5) is an autosomal dominant retinal disease that primarily affects cone function. The locus has previously been mapped to human chromosome 17p12-p13 between the markers D17S926/D17S849 and D17S945/D17S804. One of our "unaffected" recombinant individual from family 1175 was subsequently found to cross through this interval. Reexamination revealed that he was in fact mildly affected. This expanded the minimum candidate region. Direct sequencing of the GUCY2D and other candidate genes within this interval was carried out on 2 American families affected with CORD5. There was an R838C missense mutation within the GUCY2D gene in one and a R838H missense mutation in another families. The previously reported mutations for CORD6 are clustered at the same position within the gene. These results indicate that both CORD5 (MIM# 600977) and CORD6 (MIM# 601777) are actually the same disease. We conclude that significant variability in expression and incomplete penetrance exists even within one family.

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