Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes.

T erminal deletions of the long arm of chromosome 2 (2q37) have been recorded in the literature for more than a decade and an associated syndrome first became apparent when nine patients were reported with an Albright hereditary osteodystrophy (AHO)-like metacarpal/ metatarsal shortening (brachymetaphalangism). 2 This is also known as brachydactyly-mental retardation syndrome (BDMR, MIM 600430). To date, some 60 or so cases of 2q37 deletion or monosomy resulting from unbalanced translocations have been reported. Significant variability in clinical presentation is apparent, but almost all patients have some degree of mental retardation and facial dysmorphism. Brachymetaphalangism has been reported in approximately 50% of cases. Congenital heart anomalies are present in around 20% of patients with 2q37 monosomy, compared to 1% of the general population. These are predominantly atrial or ventricular septal defects, but more complex problems have been reported. 22 Additionally, there are two reports of tetralogy of Fallot with monosomy 2q37 resulting from unbalanced translocations, 24 but both cases were also trisomic for 17q25 and it is not clear which imbalance was causative. Other phenotypes repeatedly associated with 2q37 deletions include Wilms tumor and urogenital anomalies, 17 19 epilepsy, 2 7–9 14 16 20 25–27 eczema, 5–7 16 28 29 and autism or repetitive, hyperkinetic behaviour. 2 5 7 10 11 15 16 19 25 26 28–32 Situs abnormalities have been reported in two cases and holoprosencephaly in one infant. Most 2q37 rearrangements reported to date have been only minimally characterised by conventional cytogenetics or subtelomeric fluorescent in situ hybridisation (FISH). A small number have been subjected to more detailed analysis using multiple FISH clones or microsatellite markers, 10 15 26 but the ability to assign breakpoints and make genotype– phenotype correlations has been limited. We therefore sought to conduct detailed molecular analyses of a panel of 2q37 deletion patients, focusing on the critical interval distal to D2S338 and including assessment of individual gene dosage by multiplex amplifiable probe hybridisation (MAPH). We define minimal deletion intervals for all of the major phenotypes associated with 2q37 monosomy.