Genetic heterogeneity for a Nijmegen breakage-like syndrome.

Nijmegen breakage syndrome (NBS) is a rare, autosomal-recessive chromosome instability disorder characterized by growth and developmental defects, immunodeficiency, high susceptibility to lymphoid malignancies, hypersensitivity to ionizing radiation and aberrant cell-cycle checkpoint control. The disease is caused by mutations in the NBS1 gene, which encodes nibrin, a component of the hMre11-Rad50-p95 complex involved in cellular response to DNA double-strand breaks. Genetic heterogeneity has been suggested in at least two patients with the NBS phenotype, but no mutation in the NBS1 gene; recently, mutations in the gene encoding the enzyme ligase IV have been identified in patients with signs of NBS. We describe a boy with an NBS clinical phenotype but no mutation in either the NBS1 or the LIG4 genes. The analysis of his cellular phenotype reveals chromosome instability and radiosensitivity, but normal cell-cycle checkpoint control. In addition, a literature review was carried out to summarize and compare data of all NBS-like patients reported to date. This case confirms genetic heterogeneity for NBS. We believe that dissecting the clinical and cellular phenotypes of this and other NBS-like patients will provide useful information for the research of new genes involved in cellular response to DNA damage and the assessment of cancer risk in NBS-like syndrome.

Linkage analysis for prenatal diagnosis in a familial case of Stickler syndrome.

The Stickler syndrome is among the most common heritable disorders of connective tissue. The syndrome fully expressed clinical phenotype includes the degeneration of the vitreous gel and retina, frequently associated with myopia, accompanied by non-ocular features, such as craniofacial dysmorphisms or malformations, hearing impairment, skeletal dysplasia and progressive arthropathy. So far, mutations at three collagen loci, COL2A1, COL11A1 and COL11A2, have been found in Stickler syndrome patients, with about two thirds of investigated familial cases found to be associated to COL2A1 gene mutations. We report on a three generation family in which a diagnosis of Stickler syndrome was made and linkage analysis suggested COL2A1 to be the causing gene. These data permitted us to perform two prenatal diagnosis analysing the 3'VNTR polymorphism of the involved gene on amniocytes' DNA and to provide the family with genetic counselling and paediatric support at the delivery.