AbstractThe pure 3.5 Mb subtelomeric deletion syndrome is very rare but causes a recognizable phenotype characterized by prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia in infancy, borderline intelligence, postnatal short stature with delayed bone age due to growth hormone deficiency, and multiple minor anomalies including mildly bell‐shaped chest, minor congenital heart defects, and a distinct facial gestalt. Terminal deletions including the adjacent ∼2 Mb NSD1‐locus show a compound phenotype with overlap to Sotos syndrome. Larger terminal deletions including also chromosomal bands 5q35.1 and 5q35.2 cause a more severe phenotype with normal body length, significant congenital heart defect, microcephaly, profound developmental retardation or early death due to respiratory failure. Heart defects in the latter are explained by haploinsufficiency of the NKX2.5 gene at 5q35.1. The deletion breakpoint of the 3.5 Mb subtelomeric microdeletion maps to a low copy repeat which is identical to the distal copy of two highly similar regions flanking the recurrent interstitial NSD1 microdeletion. As meiotic mispairing between these low copy repeats seem to be much more likely than a terminal aberration, these neighborhood may prevent occurrence of the subtelomeric deletion syndrome, which could explain the rareness of the latter. © 2007 Wiley‐Liss, Inc.