Rothmund-Thomson Syndrome: in Search of a New Gene

Project location: Italy
Project start date: December 2007 - Project end date: December 2008
Project number: 2007-14
Beneficiary: Università degli Studi di Milano

Università degli Studi di Milano

Dipartimento di Biologia e Genetica per le Scienze Mediche

The University of Milan is a public institution whose academic achievements are in the intellectual, political, social and technological areas. This project, cofunded by the Nando Peretti Foundation, aims at giving financial support to two Departments of the Faculty of Medicine: the Department of Biogenetics ( and the Department of Medicine, Surgery and Dentistry (

The Department of Biogenetics  is committed to research on human genome: identification of mechanisms controlling gene expressions, identification of chromosomal, genomic and gene mutations leading to diseases.

Rothmund-Thomson syndrome  is a rare autosomal recessive genodermatosis characterized by growth deficiency, premature aging and susceptibility to malignant tumours, particularly osteosarcomas. Mutations in the RECQL4 gene account for 60% of the RTS cases (RTS type II) and patients carrying a truncating mutation in RECQL4 gene show a high risk of osteosarcoma.

Mutations in other gene(s) are responsible for the remaining 40% patients affected by RTS type I.

One family of South Italy with three affected sibs approached us for genetic counseling to assess the risk of osteosarcoma: RECQL4 sequencing one of the three  index cases  the proband ruled out RECQL4 involvement and the related risk for osteosarcoma, and raised a challenging question:

how can we counsel this family, unless identifying the causative gene, is this pedigree a genetic tool to identify new gene(s) responsible for RTS type I?

A large and very inbred family with three individual affected by Rothmund-Thomson syndrome (RTS OMIM #268400) in the fifth generations addressed us for genetic counselling, to assess the risk of osteosarcoma in the affected members. Direct sequencing of the RECQL4 gene in the patients ruled its involvement in RTS aetiology in this family and the related increased risk of osteosarcoma. 

Further analysis highlighted seven polymorphism's within the gene in the proband.. Analysis of proband DNA also highlighted heterozygosity at seven intragenic polymorphisms, a finding conflicting with the initial  expectation of a RECQL4 mutated allele identical by descent in the highly inbred family.  In this family the gene responsible for RTS is not RECQL4 but another gene still unidentified.

This family is a good candidate for linkage analysis. The family is large (26 members), quite co-operative and with a high level of inbreeding: the generation of grand-

grandparents (generation II) normally represented by 4 couples and 8 individuals, in this family is represented by 3 couples from only three families (generation I) (See pedigree).


Looking at similar pathologies (Werner, Bloom, Baller Gerold, RAPADILINO, Rothmund-Thomson type II, see Dietschy T. et al. 2007 Mar 15 Cell Mol Life Sci.: The molecular role of the Rothmund-Thomson-, RAPADILINO- and Baller-Gerold-gene product, RECQL4: recent progress.) we base our project over the following assumptions:

RECQL4 gene is not involved;

The disease segregating in the family appears Mendelian;

The transmission pattern is consistent with autosomal recessive inheritance.

Genomewide SNPs genotyping using a 500K platform (Affymetrix, Santa Clara, CA)  will indicate the haplotype shared by the three  homozygous  affected brothers, shared as well in heterozygosity by the parents that should be obligatory carriers, following  a "Homozygosity Mapping" approach (Chiang AP et al PNAS 2006 Apr 18;103(16):6287-92).

Genomewide SNPs Genotyping platform will highlight genomic regions harbouring  homozygous haplotypes  shared only by the affected patients.Analysis of polymorphic DNA loci within the homozygous regions will restrict the number of the regions still homozygous only in the affected patients and not in the other family members.Bioinformatic search of plausible candidate genes within the regions will priorititize genes to be scanned in their  coding regions. Direct sequencing of candidate gene(s)  searching  for mutations that should:

Confirm the role of the candidate gene in the syndrome  segregating in the investigated family. Be exploited  to address  genotype/phenotype correlation. Functional analysis of physiological and pathological products of candidate gene(s) should help to highlight the biological mechanisms leading to the syndrome.


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