Table 4.
The association of gene variations with AVSD
| Candidate gene (OMIM ID) | CHD-associated syndromes caused by heterozygous or haploinsufficient variations | Association with AVSD |
|---|---|---|
| NOTCH2 (600275) | Alagille syndrome 2; Hajdu-Cheney syndrome | Chick Notch2 initiates the signaling cascades that delimits the non-chamber AV canal regions, causes the progressive restriction of Bmp2 and Tbx2 expression to within the developing AV canal [31]. |
| COL11A1 (120280) | Stickler syndrome, type II | Murine Col11a1 can express in AV valve and involved in AV valve development and maintenance [32,33]. |
| NIPBL (608667) | Cornelia de Lange syndrome 1 | 30% Cornelia de Lange syndrome patients have CHD, including AVSD, ASD, VSD [34]. Nipbl ± mice can exhibit the phenotypes of Cornelia de Lange syndrome 1, septal defects were especially common [35]. |
| EHMT1 (607001) | Kleefstra syndrome 1 | 41% Kleefstra syndrome patients have CHD, including VSD, ASD; EHMT1 de novo mutation was reported in an AVSD patient [36,37]. |
| NR2F2 (107773) | Congenital heart defects, multiple types, 4 | Nr2f2 is expressed in the endocardium and the epicardium; Nr2f2 mutant mice exhibit a spectrum of cardiac defects (including AVSD) resulting from the disruption of endocardial cushion development in a dosage-sensitive fashion [38]. Rare variants in NR2F2 gene were reported in AVSD patients [39]. |
| COL6A1 (120220) | - | Collagen VI is expressed in the AV cushions in human and mouse heart, plays a role in valve and septal differentiation; overexpression or insufficient expression of COL6A1 could cause AVSD formation [2,40]. |
| COL6A2 (120240) | - | Collagen VI is expressed in the AV cushions in human and murine heart, plays a role in valve and septal differentiation; overexpression or insufficient expression of COL6A2 could cause AVSD formation [2,40]. |
| TBX1 (602054) | Chromosome 22q11.2 deletion syndrome | Tbx1 regulates SHF progenitor cell status during heart tube elongation, its failure results in a spectrum of morphological defects affecting the cardiac poles, including AVSD [41,42]. |
| SHANK3 (606230) | Chromosome 22q13.3 deletion syndrome | Patient 253,900 with 86.55 Kb duplication containing SHANK3 gene at 22q13.33 has AVSD in DECIPHER. |
| SMC1A (300040) | Cornelia de Lange syndrome 2 | 30% Cornelia de Lange syndrome patients have CHD, including AVSD, ASD, VSD [34]. |
| C5ORF42 (614571) | - | C5orf42 -/- mice exhibit multiple CHD, including AVSD, VSD; its mutation disrupts ciliogenesis and cilia transduced Hedgehog signaling, and the Hedgehog signaling is required in the SHF for AV septation [43,44]. |
| GLI3 (165240) | Pallister-Hall syndrome; Greig cephalopolysyndactyly syndrome | GLI3 is a transcription factor that functions in the Hedgehog signaling [44]. |
| LRP2 (600073) | - | LRP2 acts as a receptor of Hedgehog signaling, Lrp2 -/- mice result in abnormal development of the SHF [45]. |
| GATA6 (601656) | Atrioventricular septal defect 5; Atrial septal defect 9; Tetralogy of Fallot | Gata6 is expressed in the endocardial cushions, atrial and ventricular myocardium, atrioventricular valve leaflets, and a heterozygous missense mutation in the gene was identified in an AVSD patient [49]. |
| HSPG2 (142461) | - | HSPG2 is expressed in the basal surface of myocardium and endocardium, plays a role in the earliest stages of formation of the endocardial cushions [50]. |
Abbreviations: AVSD, atrioventricular septal defect; CHD, congenital heart disease; AV, atrioventricular; ASD, atrial septal defect; VSD, ventricular septal defect; SHF, second heart field.