Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy

Abstract

Progressive dilatation of the thoracic aorta leads to thoracic aortic aneurysm (TAA), which is often asymptomatic but predisposes to lethal aortic dissections and ruptures. TAA is a common complication in patients with bicuspid aortic valve (BAV). Recently, rare loss-of-function SMAD6 variants were shown to contribute significantly to the genetic aetiology of BAV/TAA. Intriguingly, patients with craniosynostosis have also been reported to be explained molecularly by similar lossof-function SMAD6 variants. While significantly reduced penetrance of craniosynostosis has been reported for the SMAD6 variants as such, near-complete penetrance is reached upon co-occurrence with a common BMP2 SNP risk allele. Here, we report on the results of a SMAD6-variant analysis in 473 unrelated non-syndromic TAA patients, of which the SMAD6positive individuals were also studied for the presence of the BMP2 risk allele. Although only 14% of the TAA patients also presented BAV, all novel likely pathogenic SMAD6 variants (N = 7) were identified in BAV/TAA individuals, further establishing the role of SMAD6 variants to the aetiology of BAV/TAA and revealing limited contribution to TAA development in patients with a tricuspid aortic valve. Familial segregation studies confirmed reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity. None of our six BMP2+/SMAD6+ patients presented with craniosynostosis. Hence, the proposed digenic model for craniosynostosis was not supported in the presented BAV/TAA cohort, suggesting that additional factors are at play. Finally, our data provide improved insights into the clinical spectrum of SMAD6-related BAV/TAA and has important implications for molecular diagnostics.

SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

“…An enrichment of SMAD6 variants considered to be pathogenic has been reported in several pathologies distinct from CRS. [10][11][12][13][14][15][16][17] Using our variant categorization (based on AF and DS), we evaluated all SMAD6 variants that were previously reported as pathogenic. Systematic review identified 74 different SMAD6 variants, including 30 missense (Table S4, Fig.…”

“…4 SMAD6, originally identified in mammals by homologybased cloning, 5,6 encodes one of two (with SMAD7) inhibitory members of the SMAD family required for regulated intracellular signal transduction by members of the transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) superfamily. [7][8][9] Intriguingly, enrichment of rare SMAD6 variants has also been reported in association with several other distinct phenotypes, namely congenital heart disease, [10][11][12] bicuspid aortic valve (BAV) and ascending thoracic aortic aneurysm (TAA), [13][14][15] intellectual disability, 16 and radioulnar synostosis. 17 In a follow-up study, Timberlake et al increased the sample size of probands with midline CRS and no other genetic diagnosis to 379 (45 pedigrees included ≥1 additional affected family member).…”

“…Similar observations of nonpenetrance of SMAD6 variants were made for several of the other described disease associations. 13,14,17 To seek an explanation for the unpredictable penetrance, Timberlake et al 4,18 genotyped a single-nucleotide polymorphism (SNP), rs1884302, previously reported in a genome-wide association study (GWAS) of nonsyndromic SS to be the most significant associated SNP, which may differentially regulate the most proximal gene BMP2. 19,20 The risk-conferring C allele (prevalence in non-Finnish Europeans of 32.7%, gnomAD), 21 was found to be present in 15/21 individuals with CRS but only 1/20 unaffected relatives heterozygous for the SMAD6 variant but without CRS, suggesting a two-locus mechanism to account for variable manifestation of CRS.…”

ATR-16 syndrome: mechanisms linking monosomy to phenotype

“…Another example is the SMAD6 R12X nonsense mutation present in all three affected members of family TN. Some patients with loss of function mutations in SMAD6 have neurological abnormalities25 while others have not,26 suggesting variable penetrance. Our analysis shows there are no likely pathogenic variants on the hemizygous region of chromosome 16 in TN, suggesting modifying loci are present elsewhere in the genome.…”

ADAMTS19‐associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype

“…BAV may be asymptomatic and undetected in early life but poses a risk for serious complications and sudden cardiac death later in life 5 . The extreme clinical variability, reduced penetrance, and suspected genetic heterogeneity have complicated the identification of genes involved in non‐syndromic CHD, with only a limited number of genes identified to date 6‐9 …”