In the search for genetic causes of mental retardation, we have studied a 
five-generation family that includes 10 individuals in generations IV and V who 
are affected with mild-to-moderate mental retardation and mild, nonspecific 
dysmorphic features. The disease is inherited in a seemingly autosomal dominant 
fashion with reduced penetrance. The pedigree is unusual because of (1) its size 
and (2) the fact that individuals with the disease appear only in the last two 
generations, which is suggestive of anticipation. Standard clinical and 
laboratory screening protocols and extended cytogenetic analysis, including the 
use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal 
the cause of the mental retardation. Therefore, a whole-genome scan was 
performed, by linkage analysis, with microsatellite markers. The phenotype was 
linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter 
was demonstrated in patients, similar to the deletion observed in patients with 
ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a 
duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of 
obligate carriers revealed that a balanced translocation between the terminal 
parts of 16p and 3q segregated in this family. This case reinforces the role of 
cryptic (cytogenetically invisible) subtelomeric translocations in mental 
retardation, which is estimated by others to be implicated in 5%-10% of cases.