Submicroscopic terminal deletions and duplications in retarded patients with unclassified malformation syndromes

Unbalanced submicroscopic subtelomeric chromosomal rearrangements represent a significant cause of unexplained moderate to severe mental retardation w ith and without phenotypic abnormalities. We investigated 254 patients (102 from Zurich, 152 from Liege) for unbalanced subtelomeric rearrangements by using fluorescence in situ hybridisation with probes mapping to 41 subtelo meric regions. Mental retardation combined with a pattern of dysmorphic fea tures, with or without major malformations, and growth retardation and a no rmal karyotype by conventional G-banding were the criteria of inclusion. Se lection criteria were more restrictive for the Zurich series in terms of cl inical and cytogenetic pre-investigation. We found 13 unbalanced rearrangem ents and two further aberrations, which, following the investigation of oth er family members, had to be considered as variants without influence on th e phenotype. The significant aberrations included three de novo deletions ( two of 1pter, one of 5pter), three de novo duplications (8pter, 9pter, Xpte r), one de novo deletion 13qter-duplication 4qter, and five familial submic roscopic translocations [(1q;18p), (2q;4p), (2p;7q), (3p;22q), (4q;10q), (1 2p;22q)], most of them with several unbalanced offspring with deletion-dupl ication. Although the incidence of abnormal results was higher (10/152) in the Liege versus the Zurich series (3/102), similar selection criteria in Z urich as in Liege would have resulted in an incidence of 7/106 and thus sim ilar figures. In our series, submicroscopic unbalanced rearrangements expla in the phenotype in 13/ 254 study probands. The most important seletion cri terion seems to be the presence of more than one affected member in a famil y. An examination of subtelomeric segments should be included in the diagno stic work-up of patients with unexplained mental retardation combined with physical abnormalities, when a careful conventional examination of banded c hromosomes has yielded a normal result and a thorough clinical examination does not lead to another classification. The proportion of abnormal finding s depends strongly on selection criteria: more stringent selection can elim inate some examinations but necessitates a high workload for experienced cl inical geneticists. Once the costs and workload of screening are reduced, l ess selective approaches might finally be more cost-effective.