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    • "Recurrence risk (RR), after the conception of an affected child has always been considered very low and less than 30 cases of recurrences among sibs have been reported so far [Bowen, 1974; Fryns et al., 1983; Reiser et al., 1984; Dodinval and Le Marec, 1987; Philip et al., 1988; Sobetzko et al., 2000]. In one instance it was possible to have the formal demonstration of somatic and germline maternal mosaicism [Henderson et al., 2000]. Thus it is still debatable whether instances of achondroplasia in sibs born to unaffected parents are caused by somatic or germinal mosaicism that appears to be less frequent in achondroplasia than in other autosomal dominant conditions. "
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    ABSTRACT: We describe a sib recurrence for achondroplasia with parents of average stature. The three sibs shared the paternal allele and all carried the same causal mutation in the fibroblast growth factor receptor 3 gene (FGFR3): G > A nt1138 (Gly380Arg). We were able to identify this mutation on sperm DNA confirming paternal germinal mosaicism. Our family shows that a more precise definition of the recurrence risk is feasible using this approach, based on a single DNA test, which could be offered in selected cases.
    American Journal of Medical Genetics Part A 03/2008; 146A(6):784-6. DOI:10.1002/ajmg.a.32228 · 2.16 Impact Factor
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    ABSTRACT: The lifelong spermatogonial stem cell divisions unique to male germ cell production are thought to contribute to a higher mutation frequency in males. The fact that certain de novo human genetic conditions (e.g., achondroplasia) increase in incidence with the age of the father is consistent with this idea. Although it is assumed that the paternal age effect is the result of an increasing frequency of mutant sperm as a man grows older, no direct molecular measurement of the germ-line mutation frequency has been made to confirm this hypothesis. Using sperm DNA from donors of different ages, we determined the frequency of the nucleotide substitution in the fibroblast growth factor receptor 3 (FGFR3) gene that causes achondroplasia. Surprisingly, the magnitude of the increase in mutation frequency with age appears insufficient to explain why older fathers have a greater chance of having a child with this condition. A number of alternatives may explain this discrepancy, including selection for sperm that carry the mutation or an age-dependent increase in premutagenic lesions that remain unrepaired in sperm and are inefficiently detected by the PCR assay.
    Proceedings of the National Academy of Sciences 12/2002; 99(23):14952-7. DOI:10.1073/pnas.232568699 · 9.67 Impact Factor
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    ABSTRACT: In this communication, we report the identification of a mosaic R248C missense mutation in the IgII-III linker region of the gene encoding the fibroblast growth factor receptor-3 (FGFR3), in an individual who manifests a skeletal dysplasia and epidermal hyperplasia. By means of Denaturing High Performance Liquid Chromatography (DHPLC), we determined that 25% of her lymphocytes are heterozygous for this particular missense mutation in FGFR3, and that 12.5% of her lymphocyte-derived genomic DNA encodes a cysteine residue at this position. The proposita has disproportionate short stature, radial head dislocation, coxa vara, and bowing of some of the long bones, associated with an S-shaped deformity of the humerus, accompanied by widespread acanthosis nigricans in the integument. These features do not match any previously described skeletal dysplasia. Further, the proposita's only pregnancy ended in the delivery of a fetus manifesting a lethal short-limbed dwarfism with pulmonary hypoplasia, strongly suggestive of an undiagnosed thanatophoric dysplasia. These findings confirm the proposita to be a somatic and germline mosaic for this particular missense mutation in FGFR3. Thus far, all reported FGFR3 R248C mutations have resulted in thanatophoric dysplasia type I (TDI).
    American Journal of Medical Genetics Part A 07/2003; 120A(2):157-68. DOI:10.1002/ajmg.a.20012 · 2.16 Impact Factor
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