Musolino, Patricia L.

AbstractMyhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016–2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence‐based guidelines in anticipation of disease‐specific therapies.

Introduction: Even though neuroinflammation is increasingly recognized as an essential contributor to ischemic brain injury, the exact underlying mechanisms remain unclear. Higher expression of the vascular cell adhesion molecule 1 (VCAM-1) increases leukocyte-brain endothelium interaction and has been associated with larger infarct size following acute ischemic stroke (AIS). The activation of the TGF-β signaling pathways can down-regulate VCAM-1 expression and ameliorate deleterious tissue outcome during neuroinflammation. Hypothesis: We sought to investigate whether genetic variation in the TGF-beta pathway and adhesion molecule genes is associated with acute stroke lesion size. Methods: We completed genome-wide association (GWA) testing and diffusion-weighted imaging lesion volume (DWIv) analysis in a discovery cohort of 532 AIS patients of European ancestry enrolled within 48 hours of symptom onset. An independent European ancestry cohort of 724 AIS patients with GWA data and automated DWIv served as replication cohort. GWA testing per SNP was performed using linear regression modeling of natural log-transformed DWIv adjusted for age, sex and relevant principal components. We selected 42 inflammatory genes in the TGF-beta pathway for a gene-based analysis using VEGAS (Versatile Gene-based -Association Study) software. A pre-specified discovery phase Bonferroni-corrected threshold was set at p<0.001. In the replication phase, 14 SNPs overlapping were tested at the Bonferroni-corrected p-value threshold of p<0.004. Results: Of all genes in the TGF-beta pathway, VCAM1 (p=0.0006) was significantly associated with DWIv in the discovery AIS cohort (age: 66 ± 14.9 years, sex: 63.4% male, DWIv: 2.2cm 3 (IQR: 0.6-11.7cm 3 )). A single SNP within the VCAM1 gene boundaries (rs3176876 (BETA=0.2341, p=0.003)) was significantly associated with DWIv in the replication AIS cohort (age: 65 ± 14.1 years, sex: 68.6% male, DWIv: 4cm 3 (IQR: 1.3-17.2cm 3 )). Conclusion: The genetic variant rs3176876 in the VCAM1 gene is associated with larger infarct lesion size measured on brain MRI of AIS patients. These findings suggest genetic contribution to the pro-inflammatory mechanisms in acute cerebral ischemia and warrant further investigation.