6374 Genotype: phenotype relationships in Myhre syndrome

Objectives Myhre Syndrome is a complex multi-system disorder that frequently presents in childhood with developmental delay and failure to thrive.¹ It is caused by specific heterozygous missense variants in SMAD4, a gene that is integral to mediating signal transduction for serine threonine kinase receptors including those in the TGF-β, activin and bone morphogenic protein signalling pathways. We explored the genotype: phenotype relationships in Myhre Syndrome caused by variants at the two established causative sites: p.Ile500 and p.Arg496. Methods A literature review identified 100 Myhre Syndrome patients with an identified causative variant. The phenotypes associated with variation at the p.Ile500 (n=84) and p.Arg496 (n=16) residues were compared using Fishers Exact Test. Results Mutations at the two known causative sites have different growth patterns: p.Ile500 patients are more frequently of short stature than p.Arg496 patients (88% vs 31%, p<0.001) and p.Arg496 patients are more commonly obese compared to p.Ile500 patients (50% vs 14%, p=0.003). p.Ile500 patients have a higher likelihood than p.Arg496 patients of having muscular hypertrophy with a resultant stocky build (50% vs 6%, p<0.001), cardiovascular involvement (62% vs 31%, p=0.029) and developmental delay (74% vs 38%, p=0.007). Development of neoplasia was more likely in p.Arg496 patients than p.Ile500 patients (25% vs 4%, p=0.012). There was no difference in the frequency of dysmorphic features (p=0.18), hearing loss (p=0.25), joint involvement (p=0.58) or stenosis of the gastrointestinal tract (p=0.18) between p.Ile500 and p.Arg496 patients. The summary of genotype-specific phenotypes is shown in figure 1. Conclusion There are clear genotype: phenotype relationships in patients with Myhre Syndrome caused by variants at the two established residues: p.Ile500 and p.Arg496. p.Ile500 patients appear to have a more severe phenotypethan p.Arg496 patients, with a higher prevalence of cardiovascular involvement, developmental delay and characteristic short stocky stature, although p.Arg496 patients have increased neoplasia incidence and obesity. Myhre Syndrome is a complex condition and knowledge of the increased risks associated with the patient's individual genotype can highlight potential complications and may improve patient care. Reference Lin AE, Brunetti-Pierri N, Lindsay ME, Schimmenti LA, Starr LJ, Gene Reviews: Myhre Syndrome, 1993.