Most Martin-Bell syndrome (FMR1-related disorder) Venezuelan patients did not show CGG expansion but instead display genetic heterogeneity

Martin-Bell syndrome is mainly caused by the expansion of CGG trinucleotide repeats (>200 CGG) in the first exon of the FMR1 gene, leading to hypermethylation of the promoter region and silencing of the FMR1 protein expression. These changes are responsible for a phenotype with varying degrees of mental retardation, a long face with large and protruding ears, macroorchidism and autistic behavior. There may also be, however, patients who exhibit typical features of the syndrome without any expansion in the FMR1 gene; thus, other mechanisms affecting the expression of the FMR1 gene were assessed in 25 out of 29 ascertained patients with the typical phenotype without full mutation. Promoter methylation status of FMR1, mutations in its sequence and copy number variations (CNVs) in genes associated with intellectual disability were investigated. In 25 independent male patients without expansion, the promoter region was unmethylated; one patient with a full mutation showed methylation mosaicism; and a female patient had 81.2% of CpG sites methylated and 18.8% hemimethylated. One heterozygous duplication in exon 6 of the PDCD6 gene (programmed cell death 6) and a heterozygous deletion in exon 5 of the CHL1 gene (cell adhesion molecule L1), respectively, were found in two independent patients.