Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.
We report on further cases of high functioning fragile X males showing decreased expression of FMR1 protein, absence of detectable methylation at the EagI site in the FMR1 gene promoter, and highly unusual patterns of fragile X mutations defined as smears of expansions extending from premutation to full mutation range. Very diffuse and therefore not easily detectable patterns of full mutations were also observed on prenatal testing using DNA from chorionic villi sampled at a time of development when full mutations were still unmethylated in this particular tissue. In the search for possible determinants of such unusual patterns, repeat expansions in the premutation and in the lower full mutation range were identified on genomic PstI blots previously prepared for fragile X DNA testing. Cases with 130 or more triplets, and a number of shorter repeats, were reinvestigated on EcoRI plus EagI digests. Among the 119 expansions, there were 22 in our sample showing either blurred bands or smears on PstI blots. This particular characteristic was strongly associated with the coincidence of a repeat size of more than 130 triplets and absence ofEagI site methylation. Our data set also includes cases ofmosaic patterns consisting of smears of unmethylated expansions to more than 130 CGGs and of clear bands of methylated expansions. We therefore suggest that in fragile X syndrome unusual smeared patterns of mutations result from somatic instability of larger repeats under circumstantial absence of repeat methylation. (JMed Genet 1998;35:103-1 11) Keywords: fragile X syndrome; repeat instability; DNA methylation Fragile X syndrome is a frequent diagnosis in mental retardation. Inherited in an X linked fashion, fragile X syndrome affects both males and females. Affected males usually show intellectual deficits, specific behavioural characteristics such as hyperactivity and autistic-like behaviour, and physical features such as large, protruding ears, long and narrow face, and macro-orchidism. Nearly all cases of fragile X syndrome result from large expansions of the CGG trinucleotide repeat The full mutation may occur at germ cell proliferation or in an early transitional stage of embryogenesis.'7-'9 The substrate is a maternally inherited premutation and the product is usually a mosaic pattern of full mutations detectable in early fetal life.20 21 The patterns of methylated full mutations have been shown to be mitotically stable,'8 22 as different somatic tissues of fetuses with full mutation show identical patterns of mutations and the length of expanded repeats is clonally maintained. This high mitotic stability has been assumed to result from hypermethylation.22 23 As this hypothesis predicts that unmethylated repeat expansions will be unstable, cases of unmethylated full fragile X mutations are of particular interest.Recently, transmitting males have been found with normal or borderline IQs, without or with a few characteristics of fragile X syndrome, and with molecular genetic evidence of full mutations.'0 15 24...
A large kindred with the X-linked dominant form of peroneal muscular atrophy (Charcot-Marie-Tooth disease) was analyzed for individual variation in the length of DNA fragments after restriction endonuclease digestion. A systematic search was performed for linkage with a series of cloned single-copy DNA sequences of known regional assignment to the human X chromosome. Close linkage was found with the pDP34 probe (DXYS1 locus, Xq13-q21), suggesting that the gene responsible for the disease is located on the proximal long arm of the X chromosome.
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