Table 2.
Phenotype of mutation‐positive AOS patients
| Fam ID | Gene | ACC (HP:0007385) | TTLD | Cardiac features (HPO id) | Vascular features (HPO id) | Other (HPO id) | Reference of familya |
|---|---|---|---|---|---|---|---|
| Pedigrees suggestive of autosomal recessive inheritance: | |||||||
| 4 | DOCK6 | + | + | ? | ? | ? | Sukalo et al., 2015 (Family 8) |
| 6 | DOCK6 | + | + | ? | CMTC (HP:0000965) | IUGR (HP:0001511), brain abnormalities (HP:0000707), microcephaly (HP:0000252), ocular anomalies (HP:0000478), cognitive impairment (HP:0100543), epilepsy (HP:0001250), cerebral palsy (HP:0100021), abdominal skin defect | Sukalo et al., 2015 (Family 3) |
| 8 | DOCK6 | + | + | ? | ? | Microcephaly (HP:0000252), ventricular dilatation/brain atrophy (HP:0002119; HP:0012444), corpus callosum hypoplasia/atrophy (HP:0007370), periventricular lesions (HP:0002518) | Sukalo et al., 2015 (Family 10) |
| 9 | DOCK6 | + | + | − | ? | Microcephaly (HP:0000252), ocular anomalies (HP:0000478), developmental delay (HP:0001263), epilepsy (HP:0001250), high palate (HP:0000218) | Sukalo et al., 2015 (Family 1) |
| 10 | DOCK6 | + | + | − | ? | IUGR (HP:0001511), microcephaly (HP:0000252), brain abnormalities (HP:0000707), ocular anomalies (HP:0000478), cognitive impairment (HP:0100543), epilepsy (HP:0001250), cryptorchidism (HP:0000028) | Sukalo et al., 2015 (Family 5); Prothero et al., 2007 |
| 11 | DOCK6 | + | + | PDA (HP:0001643) | ? | Brain abnormalities (HP:0000707), microcephaly (HP:0000252), ocular anomalies (HP:0000478), knee dislocation (HP:0004976) | Sukalo et al., 2015 (Family 4) |
| 13 | DOCK6 | + | + | ? | ? | Periventricular lesions (HP:0002518) | Sukalo et al., 2015 (Family 9) |
| 5 | DOCK6 | + | + | VSD (HP:0001629) | ? | IUGR (HP:0001511), microcephaly (HP:0000252), brain abnormalities (HP:0000707), ocular anomalies (HP:0000478), cognitive impairment (HP:0100543), epilepsy (HP:0001250), cerebral palsy (HP:0100021), abdominal skin defects, patella defects (HP:0003045) | Sukalo et al., 2015 (Family 6); Orstavik et al., 1995 |
| 7 | DOCK6 | + | + | TAPVD (HP:0005160) | ? | IUGR (HP:0001511), microcephaly (HP:0000252), brain abnormalities (HP:0000707), ocular anomalies (HP:0000478), cognitive impairment (HP:0100543), epilepsy (HP:0001250), abdominal skin defect, hypothyroidism (HP:0000821) | Sukalo et al., 2015 (Family 7) |
| 1 | EOGT | + | + | ? | CMTC (HP:0000965) | No other features; normal intelligence | − |
| 2 | EOGT | + | − | ? | ? | ? | − |
| 3 | EOGT | + | + | − | CMTC (HP:0000965) | − | Temtamy et al., 2007 (Family 2) |
| 59 | EOGT | + | + | ? | ? | Cryptorchidism (HP:0000028) and small penis (HP:0000054), severe developmental delay (HP:0001263) | Verdyck et al., 2003 (Family 4) |
| Pedigrees suggestive of autosomal dominant inheritance: | |||||||
| 40 | ARHGAP31 | + | + | ‐ | ? | − | Southgate et al., 2011 (Family AOS‐12); Bonafede & Beighton, 1979 |
| 41 | ARHGAP31 | ? | ? | ? | ? | ? | − |
| 42 | ARGHAP31 | ‐ | + | − | − | − | Isrie et al., 2014 |
| 43 | ARHGAP31 | + | + | − | ? | − | Southgate et al., 2011 (Family AOS‐5); Verdyck et al., 2006 |
| 55 | DLL4 | + | − | − | ? | ? | Meester et al., 2015 (Family 6) |
| 56 | DLL4 | + | + | ? | CMTC (HP:0000965), portal hypertension (HP:0001409), esophageal varices (HP:0002040) | Epilepsy (HP:0001250), learning difficulties, mild periventricular leukomalacia (HP:0006970), splenomegaly (HP:0001744), congenital liver fibrosis (HP:0002612) | Meester et al., 2015 (Family 5) |
| 57 | DLL4 | + | − | ? | ? | ? | Meester et al., 2015 (Family 3) |
| 58 | DLL4 | + | + | VSD (HP:0001629), tricuspid valve insufficiency (HP:0005180) | ? | ? | Meester et al., 2015 (Family 1) |
| 181 | DLL4 | + | + | ? | CMTC (HP:0000965) | ? | − |
| 14 | NOTCH1 | + | + | Aortic stenosis (HP:0001650) | ? | ? | − |
| 46 | NOTCH1 | + | − | ? | ? | ? | − |
| 47 | NOTCH1 | + | + | Aortic and pulmonary valve abnormalities (HP:0001646; HP:0001641) | CMTC (HP:0000965) | − | Southgate et al., 2015 (Family 1), Verdyck et al., 2003 (Family 2) |
| 48 | NOTCH1 | + | + | Pulmonic stenosis (HP:0001642) | ? | IUGR (HP:0001511), hypoplastic mandible (HP:0000347), cerebral cortical dysplasia (brain abnormalities) (HP:0000707) | Savarirayan et al., 1999 |
| 50 | NOTCH1 | + | + | ? | CMTC (HP:0000965) | − | Southgate et al., 2015 (Family 3) |
| 52 | NOTCH1 | + | + | Aortic stenosis (HP:0001650), CoA (HP:0001680), Parachute mitral valve (HP:0011571), VSD (HP:0001629) | ? | Long palpebral fissures (HP:0000637) | Southgate et al., 2015 (Family 4) |
| 54 | NOTCH1 | + | − | CoA (HP:0001680), BAV (HP:0001647), parachute mitral valve (nonstenotic with mild regurgitation) (HP:0011571) | ? | − | Southgate et al., 2015 (Family 2); Dallapiccola et al. 1992 (Patient 2) |
| 44 | RBPJ | + | + | TOF (HP:0001636) | CMTC (HP:0000965), pulmonary branch stenosis | Brain abnormalities (HP:0000707) | − |
| 175 | RBPJ | − | + | Severe and complex malformative cardiopathy (HP:0001627) | ? | Digestive malrotation (HP:0002566) | − |
| 45 | RBPJ | + | + | ? | ? | Microcephaly (HP:0000252), hip dislocation (HP:0002827) | − |
| 178 | RBPJ | + | + | Secundum ASD (HP:0001631) and partial anomalous pulmonary venous drainage (HP:0010773) | − | − | − |
| Sporadic probands: | |||||||
| 17 | ARHGAP31 | ? | ? | ? | ? | ? | − |
| 18 | ARHGAP31 | + | + | ? | ? | − | − |
| 30 | DLL4 | + | + | Truncus arteriosus (HP:0001660), VSD (HP:0001629) | ? | Growth hormone deficiency (HP:0000824) | Meester et al., 2015 (Family 8) |
| 31 | DLL4 | + | + | ? | Died from bleeding left sinus transversus | ? | − |
| 32 | DLL4 | + | − | ? | ? | ? | Meester et al., 2015 (Family 9) |
| 182 | DLL4 | + | + | TOF (HP:0001636), absent pulmonary valve (HP:0005134) | Mild CMTC on thorax (HP:0000965), esophageal varices (HP:0002040), absent portal vein with portal hypertension (HP:0001409) | ? | − |
| 34 | DLL4 | + | − | ? | ? | ? | Meester et al., 2015 (Family 4) |
| 196 | DLL4 | + | + | TOF (HP:0001636) | ? | Preterm birth (HP:0001622), cystic leukomalacia, bilateral hypoplasia of optic nerves (HP:0000609), secondary microcephaly (HP:0005484), died from multiorgan failure after heart surgery | − |
| 35 | DLL4 | + | − | Long QT (HP:0001657) | ? | Club feet (HP:0001762), brain abnormalities (leukomalacia), microcephaly (HP:0000252), cognitive impairment (HP:0100543) | − |
| 36 | DOCK6 | + | + | − | ? | IUGR (HP:0001511), brain abnormalities (HP:0000707), spasticity (HP:0001257), visual deficit (HP:0000505), intracranial calcifications (HP:0005671), global dilatation of ventricular system (HP:0002119) | Romani et al., 1998 |
| 37 | DOCK6 | + | + | ? | CMTC (HP:0000965), single umbilical artery (HP:0001195) | Brain abnormalities (HP:0000707), microcephaly (HP:0000252), ocular anomalies (HP:0000478), cognitive impairment (HP:0100543), epilepsy (HP:0001250), cerebral palsy (HP:0100021), cryptorchidism (HP:0000028) | Sukalo et al., 2015 (Family 2) |
| 38 | EOGT | + | − | ? | ? | ? | ‐ |
| 39 | EOGT | + | − | ? | ? | ? | ‐ |
| 22 | NOTCH1 | + | − | VSD (HP:0001629), pulmonary atresia (HP:0004935), right MBTS, Rastelli correction | Portal vein thrombosis, portal hypertension (HP:0001409) | Cognitive impairment (HP:0100543), T‐cell lymphopenia (HP:0001888), complex learning disability, autism (HP:0000717) | Southgate et al., 2015 (Family 5) |
| 23 | NOTCH1 | + | + | ? | Large hepatofugal coronary vein, tiny hepatoportal cavernoma, portal hypertension (HP:0001409) | Obliterative portal venopathy, hepatosplenomegaly (HP:0001433) | Southgate et al., 2015 (Family 11); Girard et al., 2005 (Patient 2) |
| 24 | NOTCH1 | + | + | PTA (HP:0001660), VSD (HP:0001629) | ? | − | Southgate et al., 2015 (Family 6) |
| 25 | NOTCH1 | + | + | ASD (HP:0001631) | CMTC (HP:0000965), hepatopetal and hepatofugal collateral veins, portal hypertension (HP:0001409) | Obliterative portal venopathy, hepatosplenomegaly (HP:0001433) | Southgate et al., 2015 (Family 10); Girard et al., 2005 (Patient 1) |
| 21 | NOTCH1 | + | + | ? | CMTC (HP:0000965), missing portal vein | − | − |
| 26 | NOTCH1 | + | + | VSD (HP:0001629) | CMTC (HP:0000965) | − | − |
| 27 | NOTCH1 | + | + | ? | Sinus sagittalis thrombosis | ? | − |
| 15 | NOTCH1 | ? | ? | ? | ? | ? | − |
| 49 | NOTCH1 | + | + | − | CMTC (HP:0000965) | − | − |
| 198 | NOTCH1 | + | − | − | CMTC (HP:0000965) | Normal brain | − |
| 183 | NOTCH1 | + | + | − | ? | Full body CT normal, brain scan normal. Mildly delayed motor skills (HP:0002194)—walked at 15 months, slow speech—otherwise normal development | Verdyck et al., 2003 (Family 8) |
| 28 | NOTCH1 | + | + | − | CMTC (HP:0000965) | Epilepsy (HP:0001250), dyslexia (HP:0010522) | Southgate et al., 2015 (Family 8) |
ACC, aplasia cutis congenita; AS, aortic stenosis; ASD, atrial septal defect; AV, aortic valve; CHD, congenital heart defect; CMTC, cutis marmorata telangiectatica congenita; CoA, coarctation of the aorta; CT, Computed Tomography; IUGR, intrauterine growth restriction; MBTS, modified Blalock‐Taussig shunt; MV, mitral valve; PH, portal hypertension; PDA, patent ductus arteriosus; PTA, persistent truncus arteriosus; PV, pulmonary valve; TAPVD, total anomalous pulmonary venous drainage; TOF, Tetralogy of Fallot; TTLD, terminal transverse limb defects; TVI, tricuspid valve insufficiency; VSD, ventricular septal defect; ?, unknown; −, absent; +, present
a
This column refers to medical case reports in which clinical features observed in specific families are described.