Somatic mosaicism is rare in unaffected parents of patients with sporadic tuberous sclerosis

Roberts, Penelope; Dabora, Sandra L.; Thiele, EA; Franz, David Neal; Jóźwiak, Sergiusz; Kwiatkowski, David J.

doi:10.1136/jmg.2003.014126

Cited by 27 publications

(14 citation statements)

References 21 publications

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“…Mosaicism among parents of patients with de novo TSC is suggested to be rare when lymphoblast DNAs were examined. 18 Similar results have been observed for germline mosaic cases. 19 However, an effective method to detect mosaic mutations in de novo patients is not yet available, making it difficult to estimate the frequency of mosaicism in de novo TSC cases.…”

Section: Discussionsupporting

confidence: 78%

Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States

Au¹,

Williams²,

Roach

et al. 2007

Genetics in Medicine

385

296

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Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that It has alternative splice sites at two exons (25 and 31) to create isoforms. 4,5 Tuberin has a calculated molecular weight of approximately 200 kD coding from a transcript of approximately 5.5 kb. The TSC1 gene was discovered a decade after the initial report of linkage (Online Mendelian Inheritance in Man 191100). 6 In contrast with the TSC2 gene, the TSC1 gene has 23 exons extending over approximately 55 kb of genomic DNA on chromosome 9q34.3. The TSC1 gene product is coded from exons 3 to 23. Noncoding sequences include exons 1 and 2, and a 4.5-kb 3= untranslated region. The protein product of the TSC1 gene (hamartin) has an estimated molecular weight of 130 kD coding from an 8.6-kb mRNA transcript. To date, more than 680 disease-causing mutations have been identified in either the TSC1 or TSC2 genes. 7 Approximately 70% to 80% of individuals who meet definite diagnostic criteria have a small identifiable TSC1 or TSC2 gene mutation. The remaining individuals probably have large gene deletions, somatic mosaic mutations, and mutations in unanalyzed gene noncoding regions, rather than an additional TSC gene locus.Of interest is whether the phenotypic presentation of TSC differs by whether the disease results from mutations in TSC1 or TSC2. Early studies reporting genotype/phenotype correlations did not find evidence for phenotypic differences between patients with TSC1 mutations and patients with no mutation identified

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Section: Discussionsupporting

confidence: 78%

Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States

Au¹,

Williams²,

Roach

et al. 2007

Genetics in Medicine

385

296

View full text Add to dashboard Cite

show abstract

“…In tuberous sclerosis, confined gonadal mosaicism seems to be consistent with an estimated recurrence risk of 2% for parents of a child with tuberous sclerosis [Roberts et al, 2004]. A previous study of retinoblastoma [Sippel et al, 1998] identified 3 of 156 (2%) or 3 of 405 (0.7%), of unaffected parents to be obligate germinal carriers of the proband's mutation without evidence of somatic mosaicism.…”

Section: Discussionmentioning

confidence: 74%

“…parents, presumably because such mosaicism causes clinical symptoms [Cohn et al, 1990;Henderson et al, 2000;Roberts et al, 2004;Zlotogora, 1998]. …”

Section: Discussionmentioning

confidence: 99%

Detection of mosaicRB1mutations in families with retinoblastoma

et al. 2009

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The RB1 gene mutation detection rate in 1,020 retinoblastoma families was increased by the use of highly sensitive allele specific-PCR (AS-PCR) to detect low-level mosaicism for 11 recurrent RB1 CGA>TGA nonsense mutations. For bilaterally affected probands, AS-PCR increased the RB1 mutation detection sensitivity from 92.6% to 94.8%. Both RB1 oncogenic changes were detected in 92.7% of sporadic unilateral tumors (357/385); 14.6% (52/357) of unilateral probands with both tumor mutations identified carried one of the tumor mutations in blood. Mosaicism was evident in 5.5% of bilateral probands (23 of 421), in 3.8% of unilateral probands (22 of 572), and in one unaffected mother of a unilateral proband. Half of the mosaic mutations were only detectable by AS-PCR for the 11 recurrent CGA>TGA mutations, and not by standard sequencing. This suggests that significant numbers of low-level mosaics with other classes of RB1 mutations remain unidentified by current technology. We show that the use of linkage analysis in a two-generation retinoblastoma family resulted in the erroneous conclusion that a child carried the parental mutation, because the founder parent was mosaic for the RB1 mutation. Of 142 unaffected parental pairs tested, only one unaffected parent of a proband (0.7%) showed somatic mosaicism for the proband's mutation, in contrast to an overall 4.5% somatic mosaicism rate for retinoblastoma probands, suggesting that mosaicism for an RB1 mutation is highly likely to manifest as retinoblastoma.

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“…Mosaicism is fairly common in TS 2 7. Cases often manifest more than just one characteristic feature of TS8 but may not meet the “diagnostic” criteria.…”

Section: Commentmentioning

confidence: 99%