Identification of a subtle t(16;19)(p13.3;p13.3) in an infant with multiple congenital abnormalities using a...

There is increasing evidence that cytogenetically invisible chromosome rearrangements are an important cause of genetic disease. Clues to the chromosomal location of these rearrangements may be provided by a specific clinical diagnosis, which can then be investigated by targeted FISH or molecular studies. However, the phenotypic features of some microdeletion syndromes are difficult to recognise, particularly in infants. In addition, the presence of other chromosome aneuploidy may mask the typical clinical features. In the present study, the presence of tubers on cranial magnetic resonance imaging (MRI) of a 5-week-old infant prompted an investigation, by FISH, with probes from the tuberous sclerosis gene, TSC2. This and further FISH deletion mapping studies revealed a submicroscopic deletion encompassing the entire TSC2 gene and the adjacent PKD1 gene on one chromosome 16, confirming a del(16)(p13.3). Because of the large number of abnormal phenotypic features in this infant, we performed a 12-colour FISH assay (M-TEL) to screen for subtelomeric rearrangements involving the del(16p). The M-TEL assay revealed a cryptic der(16)t(16;19)(p13.3;p13.3). Further FISH with 19p and 19q subtelomeric probes demonstrated that this was derived from a balanced maternal t(16;19)(p13.3;p13.3). Importantly, 24-colour painting by multiplex FISH (M-FISH) failed to detect the translocation in either the infant or his mother. Based on our FISH mapping studies, we estimate the size of the trisomic region from 19p13.3 to be approximately 2 Mb, and the region of monosomy for 16p13.3 as 2.25 Mb. This case adds to the growing literature which indicates that many apparent chromosomal deletions are unbalanced translocations. The M-TEL assay provides a sensitive alternative to M-FISH for the detection of these subtle telomeric rearrangements.