SMAD2 – SMAD2-related Loeys-Dietz Syndrome

Loeys-Dietz syndrome (MONDO:0018954) is a rare autosomal dominant connective tissue disorder marked by aggressive arterial aneurysms, dissections, tortuosity, hypertelorism, and craniofacial features such as cleft palate. Heterozygous pathogenic variants in TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3, and SMAD2 define LDS subtypes LDS1–LDS6. SMAD2 (HGNC:6768) encodes an R-Smad transcriptional effector in the TGF-β pathway and its role in LDS6 has emerged only recently (Gene Symbol).

In a cohort of five families with thoracic aortic aneurysm and dissection, heterozygous SMAD2 variants (n=5 probands) were identified: one nonsense (c.612dup (p.Asn205Ter)) and four missense. One variant, c.953A>G (p.Asn318Ser), segregated with LDS features including aortic root aneurysm and arterial tortuosity in a three-generation pedigree (two additional affected relatives) (PMID:29967133). Additional SMAD2 families exhibited marfanoid and overlapping connective tissue phenotypes, but only a single family fulfilled LDS clinical criteria. No recurrent or founder SMAD2 alleles have been reported.

Clinical Validity Assessment

• Overall association: Limited
  • Rationale: Five SMAD2 probands reported with a single LDS-defined family, segregation in only two additional relatives, no replication in independent LDS cohorts.

Genetic Evidence (ClinGen)

• Tier: Limited
• Rationale: Five heterozygous SMAD2 variants in five probands; one LDS pedigree with modest segregation (n=3) and lack of replication in broader LDS cohorts.

Functional Evidence (ClinGen)

• Tier: Limited
• Rationale: No published SMAD2-specific functional studies modelling LDS; pathogenicity inferred from general loss-of-function in TGF-β signaling.

Key Take-home: Heterozygous SMAD2 variants can underlie a Loeys-Dietz-like phenotype (LDS6), but current evidence is limited to a small number of families and further studies are needed to establish definitive clinical validity.

References

• Journal of medical genetics • 2019 • Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype. PMID:29967133

Evidence Based Scoring (AI generated)