Spinal muscular atrophy (SMA) is a common autosomal-recessive motor neuron disease caused by the homozygous loss of the SMN1 gene. A nearly identical gene, SMN2, has been shown to decrease the severity of SMA in a dose-dependent manner. However SMN2 is not the sole phenotypic modifier, because there are discrepant SMA cases in which the SMN2 copy number does not explain the clinical phenotype. This report describes three unrelated SMA patients who possessed SMN2 copy numbers that did not correlate with the observed mild clinical phenotypes. A single base substitution in SMN2, c.859G>C,, was identified in exon 7 in the patients' DNA. We now show that the change creates a new exonic splicing enhancer element and increases the amount of full-length transcripts, thus resulting in the less severe phenotypes. This demonstrates that the c.859G>C substitution is a positive modifier of the SMA phenotype and that not all SMN2 genes are equivalent. We have shown not only that the SMA phenotype is modified by the number of SMN2 genes but that SMN2 sequence variations can also affect the disease severity.
Mutations in the dystrophin gene result in both Duchenne and Becker muscular dystrophies (DMD and BMD). Approximately two-thirdsDuchenne and Becker muscular dystrophies (DMD and BMD) are X-linked, allelic, neuromuscular diseases characterized by progressive muscular weakness and degeneration of skeletal muscle. DMD is the most common X-linked recessive lethal disease with an incidence of ϳ1 in 3500 newborns, and it has been estimated that approximately one third of the cases result from new mutations.
Fragile X syndrome , which is caused by expansion of a (CGG) n repeat in the FMR1 gene , occurs in approximately 1:3500 males and causes mental retardation/ behavioral problems. Smaller (CGG) n repeat expansions in FMR1, premutations , are associated with premature ovarian failure and fragile X-associated tremor/ataxia syndrome. An FMR1-sizing assay is technically challenging because of high GC content of the (CGG) n repeat , the size limitations of conventional PCR , and a lack of reference materials available for test development/validation and routine quality Fragile X syndrome (FXS) is the most common inherited cause of mental retardation, with an incidence in males of approximately 1 in 3500 (for a recent review, see http:// genetests.org). Clinical features in males include mental retardation, specific physical characteristics (enlarged testes, large ears, and long face), and behavioral abnormalities, sometimes including autism spectrum disorder. Affected females, with an incidence of approximately 1 in 8000, have mild mental retardation. Our knowledge of the spectrum of phenotypes associated with expansion of the FMR1 gene now also includes premature ovarian failure 1 and fragile X (FX)-associated tremor/ataxia syndrome.2-5 Thus, genetic testing for FX mutations is important at all life stages, prenatally to adulthood.
Polyposis associated with mutations in the gene MYH is an autosomal recessive syndrome characterized by the development of colorectal adenomas and cancer. Two common mutations, p.Tyr165Cys (exon 7) and p.Glu382Asp (exon 13), have been shown to account for the majority of the mutations occurring in individuals of Caucasian ancestry. Other mutations have been found throughout the gene and many have been shown to have very low frequencies. Ethnic differences in the mutation spectrum have also been observed. Thus, in order to achieve the highest clinical sensitivity, it is necessary to perform whole-gene sequencing of the MYH gene. The sequencing protocol described allows one to identify mutations throughout the MYH gene.
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