The sister (II-3) of the proband is a 43-year-old normotensive Caucasian female (height 170 cm, weight 57 Kg) with severe scoliosis and osteoporosis. She presented normal aortic root (31 mm; Z-score 0.23) and ascending aorta (25 mm).
BAV was present only in the proband out of the 5 family members evaluated. In history taking of each member of the family there was no evidence of either occurrence of BAV or aortic surgery or sudden death.
NGS targeted approach identified in the proband (II-1) 5 rare heterozygous variants [minor allele frequency (MAF)<0.01] (Table 1) in 4 different genes: FBN1 (p.Asn542Ser and p.Lys2460Arg), NOTCH1 (p.Val1739Met), LTBP1 (p.Arg1330Gln), and TGFBR3 (p.Arg423Trp) (Figure 1). These variants were confirmed through Sanger technology (Figure 2).
Characteristics of identified variants and results from in silico prediction of the pathogenetic effect were reported in Table 1. Variants detected in the proband were also investigated in his first-degree relatives (Figure 1). NOTCH1 and LTBP1 mutations were present in proband's mother (I-1) and brother (II-2). Concerning FBN1 gene, both p.Asn542Ser and p.Lys2460Arg variants were inherited in cis by the mother (I-1) and not found in any of other family members. Finally, the TGFBR3 variant was transmitted by the father to the offspring (Figure 1).
In the proband, we also identified 139 common genetic variants (39 nonsynonymous) in the coding regions (data available if required).