Einleitung
Notwendigkeit von Evidenzklassen und Gruppierungen
Vererbung | Gene Evidenzklasse Tier 1 | Gene Evidenzklasse Tier 2 |
---|---|---|
Monoallellisch |
ARID1A, NOTCH2, NSD1, ACTB, ADNP, ASXL1, CHD7, COL1A1, COL3A1, EFTUD2, EHMT1, ELN, FBN2, FGFR2, FOXC1, FOXC2, FOXF1, GLI3, HDAC4, HRAS, JAG1, KANSL1, KDM6A, KMT2A, KMT2D, MAP2K1, MAP2K2, MED13L, NOTCH1, NF1, NIPBL, PTPN11, RAI1, SALL1, SALL4, SHOC2, SKI, SMAD3, SMAD4, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SMC1A, SOS1, SOX2, SOX9, TBX1, TBX20, TBX3, TBX5, TFAP2B, TGFBR1, TGFBR2, ZEB2, NRAS, BRAF, CBL, KRAS, BRAF1, RIT1, ABCC9, FLNB, CDK13, CHD4, PRKD1
|
COL2A1, CREBBP, CTCF, DDX59, EP300, KAT6B, NFIX, PKD1, PKD2, RNF135, RPS19, RRAS, SETBP1, SF3B4, SHANK3, SNRPB, SRCAP, TLL1, TWIST1, WNT5A, ZFPM2, CHRNA1, LRP5, NRXN1, RARB, ROR2
|
Biallelisch |
CCBE1, CD96, CHST14, CHST3, EVC, EVC2, IRX5, LTBP3, MEGF8, MGP, MKKS, NEK1, PEX1, PEX10, PEX12, PEX2, PEX26, PEX5, RAB23, RBM8A, SH3PXD2B, SLC2A10, STRA6, UBR1, DHCR7, FLNB
|
ATIC, B3GALT6, CEP290, CEP57, CHUK, DDX11, DIS3L2, EOGT, ESCO2, FBLN5, FIG4, FKBP14, FKTN, GPC6, IGFBP7, KIF7, LRP2, MGAT2, MKS1, MPLKIP, NPHP3, PHGDH, PTF1A, RNU4ATAC, STAMBP, TBC1D24, TTC37, WDR60, ZMPSTE24, FTO, CHRNA1, LRP5, NRXN1, RARB, ROR2
|
X-linked |
FLNA, AMER1, BCOR, GPC3, MED12, MID1, ZIC3, HCCS
|
COX7B, NSDHL
|
Hemizygot | – |
RBM10
|
Vererbung | Gene Evidenzklasse Tier 1 | Gene Evidenzklasse Tier 2 |
---|---|---|
Monoallellisch |
GATA4, GATA6, ACTA2, ACVR2B, CFC1, CITED2, CRELD1, LEFTY2, MYH11, MYH7, NKX2-5, NODAL, NR2F2, NOTCH1, GJA1, ACTC1, MYH6, NOTCH2, ABCC9, FBN2, ELN, SOS1, SALL4, FGFR2, COL1A1
|
NAA15, NFATC1, SMAD2, TAB2, GDF1
|
Biallelisch |
CCDC103, CCDC114, CCDC151, CCDC39, CCDC40, DNAAF3, DYX1C1, GJA1
|
GDF1, NKX2-6, PLXND1
|
X-linked |
FLNA
| – |
Hemizygot | – |
PQBP1
|
Region/Syndrom | Chr | Start | Ende | Typ | Kardialer Phänotyp | Prozent von AHF | Quelle |
---|---|---|---|---|---|---|---|
1p36 microdeletion | chr1 | 834083 | 5408761 | del | CM, PDA, TOF | 71 | DecipherISCA/OMIM Literature review |
1q21.1_susceptibility_for_Thrombocytopenia-Absent_Radius | chr1 | 145401253 | 145928123 | dup | TOF, ASD, VSD, CoA | 74 | DecipherISCA/OMIM Literature review |
1q21.1_microdeletion | chr1 | 146577486 | 147394506 | del | CoA, IAA, PDA, CTD, VSD, ASD, BAV, dilAoAsc, AI, TGA | 29 | DecipherISCA/OMIM Literature review |
1q21.1_microduplication | chr1 | 146577486 | 147394506 | dup | TOF | 20 | DecipherISCA/OMIM Literature review |
2p15p16.1_microdeletion | chr2 | 55000000 | 64100000 | del | VD | NA | DecipherISCA/OMIM Literature review |
2q13_microdeletion | chr2 | 111442130 | 113065779 | del | VSD, PDA, CoA | NA | DecipherISCA/OMIM Literature review |
Mowat-Wilson_[ZEB2_(ZFHX1B)] | chr2 | 145145586 | 145277916 | del | AHF | NA | DecipherISCA/OMIM Literature review |
2q31.1 microdeletion syndrome | chr2 | 173200000 | 178000000 | del | ASD, VSD | 70 | DecipherISCA/OMIM Literature review |
2q37_monosomy | chr2 | 239954693 | 242930600 | del | AHF | 20 | DecipherISCA/OMIM Literature review |
Wolf-Hirschhorn | chr4 | 72448 | 2327204 | del | ASD, VSD | 50 | DecipherISCA/OMIM Literature review |
Cri_du_Chat | chr5 | 37693 | 11347262 | del | VSD, ASD, TOF, PDA | NA | DecipherISCA/OMIM Literature review |
Sotos_microdeletion_(NSD1) | chr5 | 175728978 | 177013961 | del | ASD, VSD, PDA | 21 | DecipherISCA/OMIM Literature review |
6q16_microdeletion | chr6 | 9984014 | 9997014 | del | AHF | NA | DecipherISCA/OMIM Literature review |
6q26q27_microdeletion | chr6 | 164178309 | 164178309 | del | AHF | NA | DecipherISCA/OMIM Literature review |
7q11.23_duplication | chr7 | 72744454 | 74142513 | dup | AHF | NA | DecipherISCA/OMIM Literature review |
Williams-Beuren | chr7 | 72744454 | 74142513 | del | AHF | 53–85 | DecipherISCA/OMIM Literature review |
8p23.1_deletion | chr8 | 8119295 | 11765719 | del | TOF, AVSD, VSD, BSVC | 94 | DecipherISCA/OMIM Literature review |
9q_subtelomeric_deletion_(EHMT1) | chr9 | 140403363 | 141153431 | del | VSD, ASD, TOF | NA | DecipherISCA/OMIM Literature review |
10p15.3_microdeletion | chr10 | 1 | 899000 | del | BAV, PFO | 22 | DecipherISCA/OMIM Literature review |
10q22.3q23.2_microdeletion | chr10 | 81610020 | 89110020 | del | AVSD, PDA, TI | 33 | DecipherISCA/OMIM Literature review |
11q23_microdeletion (Jacobsen syndrome) | chr11 | 118021543 | 119538160 | del | VSD, ASD, HLHS | 56 | DecipherISCA/OMIM Literature review |
12q14_microdeletion | chr12 | 65071919 | 68645525 | del | AHF | 70 | DecipherISCA/OMIM Literature review |
15q11.2 | chr15 | 20303106 | 20635885 | del | VSD, ASD, CoA, LVOTO, TOF, TAPVD | NA | DecipherISCA/OMIM Literature review |
15q24_microdeletion | chr15 | 74377174 | 76162277 | del | AHF | 20 | DecipherISCA/OMIM Literature review |
16p13.3 microduplication | chr16 | 1 | 7900000 | del | PFO, ASD | 40 | DecipherISCA/OMIM Literature review |
16p11.2_microdeletion | chr16 | 3015999 | 3070999 | del | AHF | NA | DecipherISCA/OMIM Literature review |
Rubinstein-Taybi_(CREBBP) | chr16 | 3775056 | 3930121 | del | ASD, VSD, PDA | NA | DecipherISCA/OMIM Literature review |
16p13.11_microdeletion_(ID/MCA_susceptibility_locus) | chr16 | 15504454 | 16292268 | del | AHF | 20 | DecipherISCA/OMIM Literature review |
16p12.2–p11.2 microdeletion syndrome | chr16 | 21474000 | 29652000 | del | PFO, ASD | 60 | DecipherISCA/OMIM Literature review |
16p12.1_microdeletion | chr16 | 29649996 | 30199855 | del | HLHS | 30 | DecipherISCA/OMIM Literature review |
Miller-Dieker | chr17 | 1182956 | 2588909 | del | AHF | 22 | DecipherISCA/OMIM Literature review |
17p13.1 | chr17 | 6500000 | 10700000 | del | ASD, VSD, PDA | NA | DecipherISCA/OMIM Literature review |
Potocki-Lupski | chr17 | 16757111 | 20219651 | dup | ASD, PFO | 50 | DecipherISCA/OMIM Literature review |
Smith-Magenis | chr17 | 16757111 | 20219651 | del | ASD | 40–45 | DecipherISCA/OMIM Literature review |
17p13.2 | chr17 | 25800000 | 31800000 | del | ASD, VSD, PDA | NA | DecipherISCA/OMIM Literature review |
17q12_duplications | chr17 | 34856056 | 36248918 | dup | ASD | NA | DecipherISCA/OMIM Literature review |
17q21.3_microdeletion | chr17 | 43705165 | 44188442 | del | ASD, VSD, PS, BAV | 27 | DecipherISCA/OMIM Literature review |
17q23 microdeletion syndrome | chr17 | 57600001 | 58300000 | del | ASD, VSD, VD | 27–36 | DecipherISCA/OMIM Literature review |
Cat-eye_(Type_1) | chr22 | 17392953 | 18591860 | del | AHF | NA | DecipherISCA/OMIM Literature review |
Common_Smaller_22q11_deletion | chr22 | 18661725 | 20311904 | del | TOF, CTD, IAA, VSD | 26 | DecipherISCA/OMIM Literature review |
Common_Smaller_22q11_duplication | chr22 | 18661725 | 20311904 | dup | variable AHF | NA | DecipherISCA/OMIM Literature review |
Common_Larger_22q11_deletion | chr22 | 18661725 | 21561514 | del | TOF, CTD, IAA, VSD | 26 | DecipherISCA/OMIM Literature review |
Common_Larger_22q11_duplication | chr22 | 18661725 | 21561514 | dup | variable AHF | NA | DecipherISCA/OMIM Literature review |
22q11.2_distal_deletion | chr22 | 22115848 | 23696229 | del | TOF, CTD, IAA, VSD | 26 | DecipherISCA/OMIM Literature review |
Vererbung | Gene Evidenzklasse Tier 1 | Gene Evidenzklasse Tier 2 |
---|---|---|
Monoallellisch |
LDB3, PRDM16, MIB1, DTNA, MYH7, ACTC1, TNNT2, TNNI3, TMP1, LMNA, SCN5A, HCN4
|
PLN, CASQ2, RYR2
|
Biallelisch |
MYBPC3
|
DSP
|
X-linked |
TAZ, DMD
| – |
Hemizygot | – | – |
Syndromale strukturelle Herzfehler
Nicht-syndromale strukturelle Herzfehler
Linksventrikuläre Non-Compaction Kardiomyopathie
Zusammenfassung/Statement/Ausblick
Fazit für die Praxis
-
Aktuell lassen sich ca. 30 % der syndromalen und 10 % der nicht-syndromalen Herzfehler auf genetischer Ebene klären.
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Syndromale AHF werden vorzugsweise durch Neumutationen verursacht, wohingegen bei nicht-syndromalen komplexere Mechanismen, wie bspw. vererbte LOF-Mutationen eine Rolle spielen.
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Auch wenn eine Paneldiagnostik nur einen kleinen Teil der kausalen Gene identifizieren kann, so sollte sie doch Teil eines sequenziellen diagnostischen Vorgehens bei familiären und syndromalen Fällen von AHF werden.
-
Valide Datenbanken, die sowohl der Forschung als auch der Diagnostik, anhand von klar definierten Evidenzkriterien zur Verfügung gestellt werden, sind unumgänglich, um eine bessere Genotyp-Phänotyp-Korrelation zu etablieren und zukünftig potenziell therapeutische Ansätze zu ermöglichen.