Refinement of the genetic cause of ATR-16

Alpha thalassemia retardation associated with chromosome16 (ATR-16 syndrome) is defined as a contiguous gene syndrome resulting from haploinsufficiency of the alpha-globin gene cluster and genes involved in mental retardation (MR). To date, only few cases have been described which result from pure monosomy for a deletion of 16p. In most of these cases the deletion was identified by densitometric analysis of Southern blot results or by Fluorescent In Situ Hybridization analysis, and these alterations have not been mapped in detail. In this study, we have fine mapped deletions causing alpha-thalassemia within 2 Mb from the telomere of 16p by multiplex ligation-dependent probe amplification (MLPA). We have developed a rapid and simple test for high resolution mapping of rearrangements involving the tip of the short arm of chromosome 16 by incorporating 62 MLPA probes spaced approximately 10-200 kb over a region of 2 Mb from the telomere. One deletion of approximately 900 kb without MR was identified in addition to three de novo deletions varying between 1.5 and 2 Mb causing ATR-16 in three patients having mild MR and alpha-thalassemia. Two were found by chance to be ATR-16 because they were included in a study to search for telomeric loss in MR and not by hematological analysis. This would plead for more alertness when a persistent microcytic hypochromic anemia at normal ferritin levels is observed as suggestive for the ATR-16 syndrome. The region on chromosome 16p for which haploinsufficiency leads to the dysmorphic features and MR typical for ATR-16, has been narrowed down to a 800 kb region localized between 0.9 and 1.7 Mb from the telomere.