Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients

Wang, Lisa L.; Levy, Moise L.; Lewis, Richard A.; Chintagumpala, Murali; Lev, Dorit; Rogers, Maureen; Plon, Sharon E.

doi:10.1002/1096-8628(20010722)102:1<11::aid-ajmg1413>3.0.co;2-a

Cited by 286 publications

(244 citation statements)

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“…4 To date, no malignancies have developed in the elder sibling, despite the fact that RTS is a syndrome predisposing to cancer, particularly osteosarcoma, that has an estimated prevalence of 30% and a mean age at diagnosis of 11 years. 16 Interestingly, from literature revision we noticed that 10 reported patients (9 RTS and 1 RAPADILINO) carry the c.2269C4T mutation (p.Q757*), 1,2,17,18 mapping 3 nt upstream the here described c.2272C4T mutation. No transcript analysis has been performed for the c.2269C4T, but according to our ESEFinder analysis (data not shown), this mutation is also predicted to be a splicing instead of a truncating mutation.…”

Section: Growth Parametersmentioning

confidence: 64%

Novel physiological RECQL4 alternative transcript disclosed by molecular characterisation of Rothmund–Thomson Syndrome sibs with mild phenotype

et al. 2014

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Rothmund-Thomson syndrome is a rare genodermatosis caused by biallelic mutations of the RECQL4 gene and is characterised by poikiloderma, sparse hair, eyelashes and/or eyebrows, small stature, skeletal and dental abnormalities and cancer predisposition. Mutations predicted to result in the loss of RECQL4 protein have been associated with osteosarcoma risk, but mutation(s)-phenotype correlations are better addressed by combined DNA and RNA analyses. We describe two siblings with a mild phenotype, mainly restricted to the skin, who carry the unreported paternal c.2272C4T alteration in exon 14 and the previously reported maternal exon 15 c.2492_2493delAT, both predicted to result in premature termination codons (p.(Arg758*), p.(His831Argfs*52)). However real-time and transcript analysis showed, in the carrier father and affected daughter, increased levels of a novel RECQL4 physiological alternative transcript with partial in-frame skipping of exon 14, generated by increased usage of a weak cryptic splice site. This alternative transcript is expressed in all controls and tested tissues, its upregulation is specific to the paternal c.2272C4T mutation and depends on the abrogation of the binding motifs for SF2 and SRp55 serine/arginine-rich proteins with bypass of the mutation site located in the skipped exon 14 portion. Moreover, in the proband the increased levels of the alternative transcript, likely encoding a protein isoform with residual activity, may compensate for the dearth of the canonical transcript with the c.2492_2493delAT, accounting for the mild clinical phenotype of the siblings. Our results emphasise the value of RNA analysis to better predict the effects of RECQL4 mutations on the clinical phenotype. Keywords: Rothmund-Thomson; mild phenotype; RECQL4; alternative splicing; exonic splicing enhancer; hypomorphic mutation INTRODUCTION Rothmund-Thomson syndrome (RTS, MIM#268400) is a clinically and genetically heterogeneous autosomal recessive disorder caused by biallelic mutations of the RECQL4 gene (MIM*603780) 1 in up to 66% of patients. 2 To date, more than 60 different RECQL4 mutations, only a few recurrent, have been described in RECQL4-related diseases, 45 of which were in patients with RTS, defined as RTS type II. 3-6 RECQL4-negative patients are classified as RTS type I. 3 The relationship between RECQL4 genotype and syndromic phenotype depends on mutation type and intragenic position and the specific combination of two different mutations, which makes (with a few exceptions) each case incomparable to others previously described. It has been proposed that in RTS patients, 'deleterious' RECQL4 mutations, predicted to lead to truncated proteins, predispose to osteosarcoma 2 and skeletal malformations. 7 Until functional studies, currently available for a restricted number of RECQL4 mutations, 8 unravel possible genotype-phenotype correlations, the analysis of mutant alleles at the transcript level may complement DNA analysis in predicting the effect of mutations on the clinical phenotype, includi...

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Section: Growth Parametersmentioning

confidence: 64%

Novel physiological RECQL4 alternative transcript disclosed by molecular characterisation of Rothmund–Thomson Syndrome sibs with mild phenotype

et al. 2014

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“…Various manifestations reported include: 4,5 • Head, ENT, eye: microcephaly, juvenile cataracts, corneal dystrophy, saddle nose;…”

Section: Discussionmentioning

confidence: 99%

Rothmund–Thomson syndrome: anaesthesia considerations

Kasat

Shah

Chhabria

et al. 2016

Southern African Journal of Anaesthesia and Analgesia

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Rothmund-Thomson syndrome (RTS) or poikiloderma congenitale is a rare autosomal recessive disorder. Approximately 300 cases of this syndrome have been reported in the scientific literature worldwide. This study reports the case of an 11-yearold female child with RTS undergoing diagnostic oesophago-gastro-duodeno (OGD) scopy as a result of dysphagia to solids. Adequate knowledge of the condition is needed when planning anaesthesia in such a case as associated anomalies can interfere with anaesthesia management.

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“…Molecular testing allows for the correct diagnosis, which is necessary for accurate targeting of syndrome-specific oncosurveillance. 12 A study on the response to therapy for osteosarcoma in patients with RTS indicated that these patients do not present the same level of sensitivity to genotoxic agents as patients with other chromosomal instability disorders. Therefore, they should be treated initially with conventional doses.…”

Section: Clinical Specificity (Proportion Of Negative Tests If the DImentioning

confidence: 99%