Table 1.
Summary of the genetic features of patients with a pathogenic or likely pathogenic variant detected by variant‐calling analysis of 21 H‐TAD genes
| Patient | Gene | Nucleotide change | Protein change | Effect | Domain | Conservation | SIFT/MutationTaster/Polyphen‐2/Grantham distance | MAF ExAC | Segregation analysisa | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | ACTA2 | c.115C > T | p.(Arg39Cys) | Missense | Actin | Baker's yeast b | + / + / − / 180 | Absent | yes | ( Hoffjan et al., 2011 ) |
| 2 | ACTA2 | c.116G > A | p.(Arg39His) | Missense | Actin | Baker's yeast b | + / + / − / 29 | Absent | yes | ( Guo et al., 2009 ) |
| 3 | ACTA2 | c.179C > A | p.(Ala60Glu) | Missense | Actin | Baker's yeastb | + / + / + / 107 | Absent | n.a. | Novel |
| 4 | ACTA2 | c.419C > T | p.(Ala140Val) | Missense | Actin | Baker's yeastb | + / + / ±/ 64 | Absent | yes | (Lerner‐Ellis et al., 2014) |
| 5c | ACTA2 | c.445C > T | p.(Arg149Cys) | Missense | Actin | Baker's yeast b | + / + / + / 180 | Absent | yes | ( Guo et al., 2007 ) |
| 6 | ACTA2 | c.835A > G | p.(Thr279Ala) | Missense | Actin | Baker's yeastb | + / + / − / 58 | Absent | n.a. | Novel |
| 7 | ACTA2 | c.854T > C | p.(Met285Thr) | Missense | Actin | Baker's yeastb | + / + / ± / 81 | Absent | n.a. | Novel |
| 8 | ACTA2 | c.1120C > T | p.(Arg374Cys) | Missense | Actin | C. elegans (FCUT Baker's yeast) | + / + / − / 180 | 1 / 121346 | n.a. | Novel |
| 9d | COL3A1 | c.318_325del | p.(Pro107Argfs*13) | Frameshift (NMD expected) | NA | NA | NA | Absent | n.a. | Novel |
| 10 | COL3A1 | c.555del | p.(Gly186Valfs*36) | Frameshift (NMD expected) | NA | NA | NA | Absent | yes, incomplete penetrance | ( Pepin et al., 2014 ; Schwarze et al., 2001 ) |
| 11 | COL3A1 | c.971G > A | p.(Gly324Asp) | Missense | Triple helix | Chicken b | + / + / ± / 94 | Absent | de novo e | Novel |
| 12 | COL3A1 | c.2050G > A | p.(Gly684Arg) | Missense | Triple helix | Chicken b | + / + / + / 125 | Absent | yes | Novel |
| 13 | COL3A1 | c.3219_3222dup | p.(Ala1075Trpfs*20) | Frameshift (NMD expected) | NA | NA | NA | Absent | Maternally inherited | Novel |
| 14 | COL3A1 | c.3446G > A | p.(Gly1149Asp) | Missense | Triple helix | Chicken b | + / + / + / 94 | Absent | n.a. | ( Frank et al., 2015 ) |
| 15 | FBN1 | c.32T > G | p.(Leu11Arg) | Missense | Signal peptide | Dogb | + / + / + / 102 | Absent | n.a. | (Baetens et al., 2011) |
| 16 | FBN1 | c.439C > T | p.(Gln147*) | Nonsense (NMD expected) | NA | NA | NA | Absent | n.a. | Novel |
| 17 | FBN1 | c.986dup | p.(Asp330Argfs*18) | Frameshift (NMD expected) | NA | NA | NA | Absent | n.a. | Novel |
| 18 | FBN1 | c.2177A > G | p.(Glu726Gly) | Missense | EGF‐like 11 | Tetraodon b | + / + / + / 98 | Absent | n.a. | ( Stheneur et al., 2009 ) |
| 19 | FBN1 | c.2645C > T | p.(Ala882Val) | Missense | TB 4 | Tetraodonb | + / + / + / 64 | Absent | n.a. | (Aragon‐Martin et al., 2010; Comeglio et al., 2007; Howarth, Yearwood, & Harvey, 2007; Hung et al., 2009; B. Loeys et al., 2004; Robinson et al., 2012) |
| 20 | FBN1 | c.2660G > A | p.(Cys887Tyr) | Missense | TB 4 | Tetraodon b | + / + / + / 194 | Absent | n.a. | Novel |
| 21 | FBN1 | c.2668T > C | p.(Cys890Arg) | Missense | TB 4 | Tetraodon b | + / + / + / 180 | Absent | n.a. | ( Collod‐Beroud et al., 2003 ; Kielty, Rantamaki, Child, Shuttleworth, & Peltonen, 1995 ) |
| 22 | FBN1 | c.2953G > A | p.(Gly985Arg) | Missense | TB 5 | Tetraodon b | + / + / + / 125 | Absent | n.a. | ( Faivre et al., 2009 ; Howarth et al., 2007 ; B. Loeys, Nuytinck, Delvaux, De Bie, & De Paepe, 2001 ; Rommel et al., 2005 ; Turner et al., 2009 ; Yoo et al., 2010 ) |
| 23 | FBN1 | c.3152T > G | p.(Phe1051Cys) | Missense | EGF‐like 15 | Tetraodon b | + / + / + / 205 | Absent | n.a. | Novel |
| 24 | FBN1 | c.3373C > T | p.(Arg1125*) | Nonsense (NMD expected) | NA | NA | NA | Absent | yes | ( Attanasio et al., 2008 ; Comeglio et al., 2007 ; Hung et al., 2009 ; Magyar et al., 2009 ; Rommel et al., 2005 ; Sheikhzadeh et al., 2012 ; Stheneur et al., 2009 ) |
| 25 | FBN1 | c.4987T > C | p.(Cys1663Arg) | Missense | EGF‐like 28 | Zebrafish b | + / + / + / 180 | Absent | n.a. | ( Dietz, Saraiva, Pyeritz, Cutting, & Francomano, 1992 ; Stheneur et al., 2009 ; Yoo et al., 2010 ) |
| 26 | FBN1 | c.5015del | p.(Cys1672Leufs*10) | Frameshift (NMD expected) | NA | NA | NA | Absent | n.a. | Novel |
| 27 | FBN1 | c.5699G > C | p.(Cys1900Ser) | Missense | EGF‐like 32 | Zebrafish b | + / + / + / 112 | Absent | n.a. | ( Stheneur et al., 2009 ) |
| 28 | FBN1 | c.6031T > C | p.(Cys2011Arg) | Missense | EGF‐like 34 | Zebrafish b | + / + / + / 180 | Absent | de novo e | Novel |
| 29 | FBN1 | c.6942C > G | p.(Tyr2314*) | Nonsense (NMD expected) | NA | NA | NA | Absent | de novo e | Novel |
| 30 | FBN1 | c.7708G > A | p.(Glu2570Lys) | Missense | EGF‐like 45 | Tetraodonb | + / + / + / 56 | Absent | n.a. | (Arbustini et al., 2005; Attanasio et al., 2008; Soylen et al., 2009) |
| 31 | FBN1 | c.8188C > T | p.(Arg2730Trp) | Missense | C‐terminal domain | Tetraodonb | + / + / + / 101 | Absent | n.a. | Novel |
| 32 | FBN1 | c.8578_8579dup | p.(Asp2860Glufs*4) | Frameshift (NMD not expected) | Asprosin chain | NA | NA | Absent | n.a. | Novel |
| 33 | FBN2 | c.3812G > C | p.(Gly1271Ala) | Missense | EGF‐like 19 | Chickenb | + / + / + / 60 | Absent | n.a. | (Buchan et al., 2014) |
| 34 | FBN2 | c.3889G > A | p.(Gly1297Ser) | Missense | EGF‐like 20 | Chickenb | + / + / + / 56 | 2 / 121372 | Paternally inherited | Novel |
| 35 | FBN2 | c.7526_7527del | p.0 | Frameshift (NMD confirmed) | NA | NA | NA | Absent | n.a. | Novel |
| 36 | MYH11 | c.3315‐5G > A | p.? | Splice (NMD not expected) | Coiled coil region | NA | NA | Absent | n.a. | Novel |
| 37 | MYH11 | c.5293C > T | p.(Arg1765Trp) | Missense | Coiled coil region | Zebrafishb | + / + / + / 101 | 1 / 115948 | n.a. | Novel |
| 38 | NOTCH1 |
|
p.(Tyr708Cys) | Missense | EGF‐like 18 | Tetraodon (FCUT Fruitfly) | + / + / + / 194 | Absent | de novo (inferred) | Novel |
| 39 | PRKG1 | c.530G > A | p.(Arg177Gln) | Missense | cGMP‐binding, high affinity | C. elegans b | − / + / + / 43 | Absent | n.a. | ( Guo et al., 2013 ) |
| 40 | SLC2A10 | c.510G > A f | p.(Trp170*) | Nonsense (NMD expected) | NA | NA | NA | Absent | n.a. (consaguineous parents) | ( Coucke et al., 2006 ; Moceri et al., 2013 ) |
| 41 | SLC2A10 | c.1276G > T f | p.(Gly426Trp) | Missense | Transmembrane helical region 10 | Tetraodon b | + / + / + / 184 | 3 / 116638 | confirmed parental carriership | ( Callewaert et al., 2008 ) |
| 42 | SMAD3 | c.1A > T | p.(Met1?) | Loss of initiation codon | Initiator methionine | C. elegans b | NA | Absent | n.a. | Novel |
| 43 | SMAD3 | c.391_394dup | p.(Thr132Argfs*35) | Frameshift (NMD expected) | NA | NA | NA | Absent | n.a. | Novel |
| 44 | SMAD3 | c.492dup | p.(Asn165*) | Frameshift (NMD expected) | NA | NA | NA | Absent | Yes | Novel |
| 45 | SMAD3 | c.802C > T | p.(Arg268Cys) | Missense | MH2 | C. elegans b | + / + / + / 180 | Absent | Yes | Novel |
| 46 | SMAD3 | c.893A > G | p.(Tyr298Cys) | Missense | MH2 | Fruitfly | − / + / + / 194 | Absent | Yes | Novel |
| 47 | SMAD3 | c.1010‐2A > G | p.? |
|
MH2 | NA | NA | Absent | n.a. | Novel |
| 48 | SMAD3 | c.1179dup | p.(Cys394Leufs*4) | Frameshift (NMD not expected) | MH2 | NA | NA | Absent | Yes | ( Aubart et al., 2014 ) |
| 49 | TGFB2 | c.709G > T | p.(Glu237*) | Nonsense (NMD expected) | NA | NA | NA | Absent | n.a. | Novel |
| 50 | TGFB2 | c.979C > T | p.(Arg327Trp) | Missense | Transforming growth factor beta‐2 chain | Frog | + / + / + / 101 | Absent | n.a. | (Lindsay et al., 2012; Schubert, Landis, Shikany, Hinton, & Ware, 2016) |
| 51 | TGFB2 | c.989G > A | p.(Arg330His) | Missense | Transforming growth factor beta‐2 chain | Tetraodon | + / + / + / 29 | Absent | Incomplete penetrance? | Novel |
| 52 d | TGFB2 | c.1017‐1G > T | p.? | Splice (NMD possible) | Transforming growth factor beta‐2 chain | NA | NA | Absent | de novo | Novel |
| 53 | TGFB3 | c.899G > A | p.(Arg300Gln) | Missense | Latency‐associated peptide chain | Fruitfly b | + / + / + / 43 | Absent | Yes | (Matyas, Naef, Tollens, & Oexle, 2014 ) |
| 54 | TGFB3 | c.1075A > C | p.(Ser359Arg) | Missense | Transforming growth factor beta‐3 chain | Fruitflyb | + / + / + / 110 | Absent | n.a. | Novel |
| 55 | TGFBR1 | c.790G > A | p.(Ala264Thr) | Missense | Protein kinase | Fruitflyb | + / + / + / 58 | Absent | yes (incomplete penetrance) | Novel |
| 56 | TGFBR1 | c.1255+2T > C | p.[Tyr378Asnfs*3, 0] | Splice (exon 7 skipping partially stable at RNA level) | Protein kinase | NA | NA | Absent | yes | Novel |
| 57 | TGFBR1 | c.1460G > A | p.(Arg487Gln) | Missense | Protein kinase | Fruitfly b | + / + / + / 43 | Absent | de novo e | (Akutsu et al., 2007 ; Jondeau et al., 2016 ; B. L. Loeys et al., 2006 ; Matyas et al., 2006 ; Melenovsky et al., 2008 ; Yang et al., 2012 ) |
| 58 | TGFBR2 | c.1565G > A | p.(Arg522Gln) | Missense | Protein kinase | Zebrafishb | + / + / + / 43 | 1 / 121046 | Paternally inherited | Novel |
| 59 | TGFBR2 | c.1630G > T | p.(Glu544*) | Nonsense (NMD not expected) | Protein kinase | NA | NA | Absent | n.a. | Novel |
| 60 | TGFBR2 | c.1669C > T | p.(Gln557*) | Nonsense (NMD not expected) | Not in functional domain/region | NA | NA | Absent | n.a. | Novel |
Used RefSeq transcripts (based on Genome build: GRCh37/hg19): ACTA2: NC_000010.10(NM_001141945.2), COL3A1: NC_000002.11(NM_000090.3), FBN1: NC_000015.9(NM_000138.4), FBN2: NC_000005.9(NM_001999.3), MYH11: NC_000016.9(NM_001040113.1), NOTCH1: NC_000009.11(NM_017617.3), PRKG1: NC_000010.10(NM_001098512.2), SLC2A10: NC_000020.10(NM_030777.3), SMAD3: NC_000015.9(NM_005902.3), TGFB2: NC_000001.10(NM_001135599.2), TGFB3: NC_000014.8(NM_003239.4), TGFBR1: NC_000009.11(NM_004612.2), TGFBR2: NC_000003.11(NM_001024847.2).
Pathogenic variants (class 5) are depicted in bold.
FCUT, functionally conserved up to; n.a., not available; NA, not applicable; NMD, nonsense mediated mRNA decay
a
Yes, segregation analysis performed in (at least) one family member, variant segregated accordingly.
b
No further alignment available.
c
This family is recently described in literature(Overwater & Houweling, 2017).
d
A variant of unknown significance was identified in these patients as well (Supporting Information Table S1).
e
Paternity and maternity not confirmed.
f
Homozygous variant.
‐ Tolerated (SIFT), polymorphism (MutationTaster), and benign (Polyphen‐2) predictions.
±Possibly damaging (Polyphen‐2) prediction.
+Deleterious (SIFT), Disease‐causing (MutationTaster), probably damaging (Polyphen‐2) predictions.
Alignment, SIFT, MutationTaster, Polyphen‐2, Grantham distance: Alamut GRCh37 accessed July 2017.