DELETIONS IN XQ26.3-Q27.3 INCLUDING FMR1 RESULT IN A SEVERE PHENOTYPEIN A MALE AND VARIABLE PHENOTYPES IN FEMALES DEPENDING UPON THE X-INACTIVATION PATTERN

High resolution cytogenetics. microsatellite marker analyses, and fluo rescence in situ hybridization were used to define Xq deletions encomp assing the fragile X gene, FMR1. detected in individuals from two unre lated families. In Family 1, a 19-year-old male had facial features co nsistent with fragile X syndrome; however, his profound mental and gro wth retardation, small testes, and lover limb skeletal defects and con tractures demonstrated a more severe phenotype, suggestive of a contig uous gene syndrome. A cytogenetic deletion including Xq26.3-q27.3 was observed in the proband, his phenotypically normal mother, and his lea rning-disabled non-dysmorphic sister. Methylation analyses at the FMR1 and androgen receptor loci indicated that the deleted X was inactive in > 95% of his mother's white blood cells and 80-85% of the sister's leukocytes. The proximal breakpoint for the deletion was approximately 10 Mb centromeric to FMR1, and the distal breakpoint mapped 1 Mb dist al to FMR1. This deletion, encompassing similar to 13 Mb of DMA, is th e largest deletion including FMR1 reported to date. In the second fami ly, a slightly smaller deletion was detected. A female with moderate t o severe mental retardation, seizures, and hypothyroidism, had a de no vo cytogenetic deletion extending from Xq26.3 to q27.3, which removed similar to 12 Mb of DNA around the FMR1 gene. Cytogenetic and molecula r data revealed that similar to 50% of her white blood cells contained an active deleted X. These findings indicate that males with deletion s including Xq26.3-q27.3 may exhibit a more severe phenotype than typi cal fragile X males, and females with similar deletions ma: have an ab normal phenotype if the deleted X remains active in a significant prop ortion of the cells. Thus, important genes for intellectual and neurol ogical development, in addition to FMR1 may reside in Xq26.3-q27.3. On e candidate gene in this region, SOX3, is thought to be involved in ne uronal development and its loss may partly explain the more severe phe notypes of our patients.