In search of the minimal critical region associated with the distinctive Monosomy 1p36 phenotype.
Monosomy 1p36 is the most common cytogenetic deletion of the autosomal subtelomeric regions. We detected 14 cases during routine diagnostic investigations between 1999 and 2004. FISH investigations using the three probes spanning the distal 2.4 Mb of 1p were used to characterise the deletions in thirteen cases. Eight cases were further characterised using CGH array.
The deletions were found to range from ~1 Mb to ~8 Mb in size, with no common breakpoint. Eight cases (56%) were determined to comprise apparently terminal deletions. The remainder included one interstitial deletion (7%), and four (28%) exchanges with other chromosomes. One case (found by FISH) was not visible on G-banding. Assessment of the overall data revealed a common deletion region measuring ~1 Mb, located proximal to the subtelomeric probe CEB108, and distal to the midisatellite D1Z2. The p58 locus located at 1.8 Mb from 1pter was deleted in all cases. The genotype/phenotype correlation suggests that a minimal critical region for the distinctive phenotype is associated with deletion of this intermediate region and involves loss of the p58 locus. The patients with larger deletions, extending to include the D1Z2 locus, presented with more severe phenotype including seizures.
Evidence provided in this report shows that approximately 7% of deletion 1p36 cases are interstitial, and retain the distal 1p specific probe, CEB 108, commonly used in subtelomere FISH arrays. On this basis, our findings warn that FISH subtelomere screens can produce false negative results, in respect of 1pter, leading to under-ascertainment of monosomy 1p36. To avoid this, a combination of at least three FISH probes, encompassing the distal 2.5 Mb, or array-CGH should be considered.