Table 7.
Clinical phenotypic abnormalities and molecular findings in children with Marfan syndrome
| Clinical manifeastations | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Protein change Nucleotidchangers |
Age | Height SDS | n |
Exon Intron |
Domain | Variant type | Family history | CVS | Eye | Skeletal | Facial | ClinVar | Variant classificaiton based on ACMG | |||||||
| AD | MVP | MR | TR | EL | LL | TWS | HD | LF | MH | MRG |
Class 5, pathogenic (n = 26) |
|||||||||
|
p.Cys2040fs c.6119_6120del (rs1057517851) |
5 | 2.16 | 1 | 49 | Cterminal EGF-like |
Frameshift (nullvariant) |
+ | - | + | + | + | - | + | + | + | + | + | - | Pathogenic | PVS1, PM2, PS3, PP3 |
|
p.Cys790Tyr c.2369G > A (rs193922188) |
10 | 2.56 | 1 | 20 | Cterminal -EGF-like | Missense | - | - | + | + | - | + | + | + | - | + | - | - |
Pathogenic Likely pathogenic |
PS1, PM1, PM2, PM5, PM6, PS3, PP3 |
|
p.Gly1013Arg c.3037G > A rs140593 |
15 | 1.73 | 1 | 25 | TGFβ (TB) | Missense | - | + | + | + | - | + | + | + | - | - | - | - |
Pathogenic Likely pathogenic VUS |
PS1, PM2, PM5, PM6, PP3, PP4, PS3 |
|
p.Cys220VfsTer109 c.657_660delGGGG rs757505269 |
14 | 3.04 | 1 | 6 | TGFβ |
Frameshift (nullvariant) |
- | + | + | + | - | - | + | + | - | + | - | - | Pathogenic | PVS1, PM2, PM6 |
|
p.Arg215Ter c.643C > T (rs111687884) |
17 | 3.75 | 1 | 7 | TGFβ | Missense | - | + | - | + | + | - | + | + | - | + | + | + | Pathogenic | PS1, PM2, PM4, PM6, PP3 |
|
p.Cys2295Arg c.6883 T > C (rs1555394644) |
2 | 2.53 | 1 | 57 | EGF-like | Missense | + | + | - | + | - | - | + | - | - | - | - | - | Pathogenic | PM1, PM2, PM5, PP2, PP3, PS3 |
|
p.Gly880Ser c.2638G > A (rs794728194) |
11 | 2.18 | 1 | 22 | TGFβ | Missense | - | - | + | - | - | + | + | + | - | + | - | + |
Pathogenic Likely pathogenic |
PM2, PM5, PM6, PP2, PP3, PS3 |
|
p.Cys596Arg c.1786 T > C |
7 8 18 18 |
1.05 0.58 1.98 1.58 |
4 | 14 | EGF-like2 | Missense | - |
- + + + |
+ + - + |
- + - - |
- - - - |
+ + + - |
- - + - |
- - + - |
- - - - |
- - + - |
- - - - |
- - - - |
Pathogenic | PS1, PM1, PM2, PM5, PM6,P P3 |
|
p.Arg165Ter c.493 C > T rs113905529 |
11 | 1.94 | 1 | 5 | EGF-like |
Nonsense Nullvariant |
- | - | + | - | + | + | + | - | - | - | - |
Pathogenic Likely pathogenic |
PVS1, PM2, PM4, PP3, PS3 | |
|
p.Gly1127Val c.3380G > T rs1064794882 |
16 | 3.31 | 1 | 28 | EGF-like | Missense | - | + | + | + | - | + | + | + | - | - | - | - | Likely pathogenic | PM1, PM2, PM5, PM6, PP2, PP3, PS3 |
|
p.Asn1484Asp c.4450 A > G rs76551543 |
11 4 |
133 3.79 |
2 | 36 | EGF-like | Missense | - |
- + |
- + |
- - |
- - |
- + |
- + |
+ - |
- - |
+ - |
- - |
- - |
VUS | PS1, PM1, PM2, PM5, PM6, PP2, PP3, PS3_Supportive |
|
p.Pro2175Leu c.6524 C > T |
8 | 3.97 | 1 | 54 | cbEGF-like | Missense | - | - | + | + | - | - | + | + | + | + | + | + | VUS | PS1, PM1, PM2, PM5, PM6, PP2, PP3, PS3_Moderate |
|
p.Ala2655Val c.7964C > T rs202240409 |
13 7 8 18 |
3.24 1.77 1.58 0.98 |
4 | 64 | cbEGF-like | Missense | - |
+ + - - |
+ - + + |
+ - + - |
- - - - |
+ - - + |
+ + + - |
+ + + - |
- - + - |
+ - + - |
+ + - - |
+ + + - |
Likely benign Benign VUS |
PVS1, PS1, PM1, PM2, PM5, PP2, BS3 |
|
p.Pro1148Ala** c.3442 C > G 56 rs140598 |
13 9 13 |
0.34 2.43 2.86 |
3 | 28 | EGF-like | Missense | - |
+ - + |
+ + + |
+ + + |
+ - - |
- - + |
- + + |
- + + |
- + - |
- - + |
- - - |
- - + |
Benign | PVS1, PS1, PM1, PM2, PP2, BS3 |
|
p.Thr1020Ala* c.3058 A > G rs111801777 |
18 3 17 |
2.52 1.77 1.74 |
3 | 25 | TGFβ | Missense | + |
- - - |
- - - |
- - + |
- - - |
- - - |
+ + + |
+ - + |
- - + |
+ - - |
- - - |
- - - |
Likely benign VUS |
PVS1, PS1, BP1, PP2, PM6, BP4 |
| Total (n) | 3 | 13 | 18 | 15 | 3 | 12 | 20 | 18 | 5 | 12 | 5 | 7 | ||||||||
| Class 4 (n = 1) | ||||||||||||||||||||
|
p.Pro731Arg c.2192C > G rs961565152 |
10 | 2.79 | 1 | 15 | EGF-like | Missense | - | - | - | - | - | - | + | + | - | - | - | - | Likely pathogenic | PVS1, PM1, PM2, PM5, PM6, PP2,PP3,PS3 |
| Total (n) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | ||||||||
| Class 3 (n = 1) | ||||||||||||||||||||
|
p.Glu810Val c.2429A > T |
10 | 1.84 | 1 | 23 | cbEGF-like | Missense | - | - | - | - | - | - | + | - | - | - | - | - | VUS | PS1, PM1, PM2, PM5, PM6, PP2, PP3 |
| Total (n) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | ||||||||
| Intronic variants | Intron | N = 4 | ||||||||||||||||||
|
- c.2168-2A > G |
5 | 3.87 | 1 | 18 | TGFβ | Missense | + | - | + | + | + | + | + | + | - | + | + | + | Pathogenic | PS1, PM2, PP2 |
|
- c.5789-1G > A |
1 18 |
1.47 1.98 |
2 | 47 | cbEGF-like | Missense | - |
+ + |
- - |
- + |
+ + |
- - |
+ + |
+ + |
+ |
- + |
- + |
- - |
Pathogenic Likely pathogenic |
PS1, PM2, PM6, PP2 |
|
- c.5788 + 5 G > A (rs193922219) |
14 | 2.54 | 1 | 47 | cbEGF-like | Missense | - | + | + | + | + | + | + | + | + | + | + | + |
Pathogenic Likely pathogenic |
PS1, PM2, PM6, PP2, PP3, PS3 |
| Total (n) | 4 | 1 | 3 | 2 | 3 | 4 | 2 | 4 | 4 | 2 | 3 | 3 | 2 | |||||||
| Total FBN1 positive group | 32 | 4 | 16 | 20 | 18 | 7 | 14 | 26 | 23 | 7 | 15 | 8 | 9 | |||||||
CVS cardiovascular signs, AD aortic dilatation, MVP mitral valve prolapse, MR mitral valve regurtation, TR tricuspid valve regurtation, EL ectopia lentis, TWS thumb/wrist sign, HD heel deformity, LF long face, MHmolar hypoplasia, MRG microganti/retrognaita, EGF epideraml growth factor, cbEGFcalcium binding epidermal grawth factor, TGFβ transforming growth factor
aThere are also cases reported as variant of uncertain significance (VUS) in the Clinvar database
bReported as benign (Class 1) in all databases