NSD1 intragenic deletion in a patient with Sotos/5q subtelomeric deletion syndrome combined phenotype without 5q35.3 deletion

Pure constitutional deletions of the very distal band 5q35.3, have only been reported in few cases. The pure 3.5 Mb subtelomeric deletion syndrome is characterized by muscular hypotonia in infancy, borderline intelligence, postnatal short stature, multiple minor anomalies and typical facial gestalt. On the contrary terminal deletions including the adiacent ~ 2 Mb NSD1-locus show a compound phenotype with overlap to Sotos syndrome, which is characterized by overgrowth, macrocephaly, developmental delay and distinctive facial features. Sotos syndrome results from mutations and deletions of the NSD1 gene, located at chromosome 5q35.3. A little percentage of NSD1 rearrangements (5-6%) is represented by exonic deletions/duplications; to date only 14 partial NSD1 deletions and 1 partial duplication have been reported in patients with typical facial gestalt in association of one out of three major criteria, namely overgrowth, macrocephaly, and developmental delay. All these rearrangements are de novo events and of unique size. We report on a 4 and half years old patient showing, at clinical evaluation, facial dysmorphism (frontal bossing, mild hypertelorism, deep set eyes, large nasal bridge, anteverted nostrils, malar hypoplasia, small ears with thick helix, thick phyltrum, macrostomia) normal growth, psychomotor delay. A high resolution CGH array analysis on patient and his parents was carried out identifying a hemizygous de novo intragenic NSD1 deletion of 38 kb including part of intron 2 and exon 3. This novel exonic deletion affects part of NSD1 PWWP domain which is thought to be involved in protein-protein interactions. The clinical features of our patient, not typical of Sotos syndrome, remembers those of larger 5q35.3 deletion syndrome (including NSD1 deletion), therefore they can be only partially explained by NSD1 intragenic deletion. We hypothesise that other mutations in 5q35.3 (point mutations and/or cryptic balanced microriarrangements) may dilute the Sotos features resulting in a combined phenotype.