Appendix Table 1.Easily internet accessible genetic resources (not necessarily all inclusive)

Name of resource / Role / Website
Online Mendelian Inheritance in Man (OMIM) /
  1. Comprehensive list of known genes and their disorders
  2. Phenotype information available and regularly updated
/
Genetests /
  1. List of laboratories providing particular test, allows comparison between labs
  2. Connects to GeneReviews
/
GeneReviews /
  1. Updated review of particular genetic disorders
  2. Overview of common genetic findings, genotype-phenotype information, and management guidelines for that disorder
/ or via Pubmed (below)
Genetics Home Reference /
  1. Patient oriented information about particular genes or disorders
/
American College of Medical Genetics and Genomics /
  1. Contact information for geneticists in your area
  2. Guidelines on specific testing
/
Specific Genetic testing laboratories (e.g. GeneDx, Baylor, Prevention, etc.) /
  1. The genetic test offered and price/CPT code information
  2. Occasional some disease specific information
  3. If employs genetic counselors, contact information for their genetic counselors
/ Genetic testing laboratory websites
National Society of Genetic Counselors /
  1. Information on expanding role of genetic counselors
  2. Some practice guidelines
  3. Contact information for genetic counselors in your area
/
PubMed / Access to review articles and case reports related to genetic disease / or

Appendix Table 2. Genetic testing types and strengths and weakness

Testing / Target / Strengths / Weakness
Karyotype (chromosomes) /
  1. Missing and extra chromosomes
  2. Large translocations
/
  1. Excellent for trisomies
  2. Excellent for large translocations
  3. Relatively low cost
/
  1. Cells must be growing
  2. Can take several days for results
  3. Limit of detection to 10 Mb.

Chromosomal Microarray (SNP based) /
  1. Subtle aneuploidy (microdeletions or microduplications
  2. Loss of heterozygosity
/
  1. Ease with identification of micro-deletions or microduplications
  2. Can identify loss of heterozygosity
/
  1. Deletions less than 500kb or duplications less than 1 Mb may not be reported
  2. Can identify non-paternity or close family relationships
  3. Familial variants can be identified

Fluorescent In situ hybridization (FISH) /
  1. Look for missing or extra genetic information that not easily visible from chromosomes or faster
/
  1. Fast screen for trisomies or monosomies without need for cell growth
  2. Detects probe-specificmicroduplications or deletions
  3. Confirmation of microdeletions or duplications seen by chromosomal microarray
/
  1. Need to have probe for region of interest

Single gene sequencing
(sequencing) /
  1. Looks for mutations in a single identified gene
/
  1. Mutations can be identified
  2. Coverage for all exons and some exon-intron junctions is usually good
  3. May be better in regions not amendable to next generation sequencing
/
  1. Must know exact gene to test
  2. Sanger sequencing (the most common) is technically difficult
  3. Deep intron mutations may be missed

Gene Panels /
  1. Looks for mutations in several genes with similar phenotypes or presentations
/
  1. Can examine more than one gene at same time
  2. Avoids non-phenotype-relevant genes with changes to be interpreted.
/
  1. Only as strong as the panel designed
  2. Currently most are done using Next-generation sequencing techniques so those weaknesses as well.

Next-Generation Sequencing---Whole Exome Sequencing (WES) / Examines the coding regions of human-disease causing genes /
  1. Many genes’ coding regions examined at one.
  2. Not limited to a single gene or single gene panel
/
  1. Can identify changes which are unrelated to the phenotype and difficulty to interpret.
  2. Does not include some sequence involved with the gene (less coverage of introns and some older technique have difficulty with 1st exome
  3. Coverage of sequencing differs for different genes
  4. Can provide unexpected information about genes that not involved with phenotype
  5. Special Pre and post-consent
  6. Helps if have DNA samples from both parents

Next-Generation Sequencing ---Whole Genome Sequencing(WGS) / Examines the coding and non-coding regions of the genome /
  1. Identified changes in all areas including deep intron
  2. Not limited to clinical-disease associated genes
  3. Not limited by genes known to be associated with CHD
/
  1. Predominately research tool currently
  2. All individuals will have variations throughout their genome, interpretation can be very complicated
  3. Special pre- and post-consent
  4. Helps if have DNA samples from both parents

Appendix Table 3. Genetic changes identified to have CHD and some of these differences

Genetic difference / Common names (if one) / Heart differences seen
Chromosomal number difference
Trisomy 21 / Down syndrome / AV septal defect, VSD, PDA, TOF
Trisomy 13 / Patau syndrome / ASD, VSD, PDA
Trisomy 18 / Edwards syndrome / Septal defects (VSD), PDA, valvular disease
45 X / Turner syndrome / Coarc, bicuspid AV, partial anomalous Pulmonary venous return, coronary art abnl
47, XXY / Kleinfelter / PDA, ASD
Microdeletion syndromes
1p36 deletion / Monosomy 1p36 syndrome / ASD, VSD, Valvular anomalies, PDA, TOF, Coarc, infundibular stenosis of RV, Ebstein anomaly / (1),(2)
1p21.1 recurrent microdeletion / PDA, TA, ASD, VSD, TOF, bicuspid aortic valve, Coarc, interrupted aortic arch, anomalous origin of right CA, Pulmonary valve stenosis, TGV / (3)
2q37 microdeletion / Albright Hereditary Osteodystrophy-like syndrome, Brachydactyly-Mental Retardation Syndrome / PDA, ASD, VSD / (4)
3q29 recurrent deletion syndrome / PDA, VSD, PV stenosis / (5), (6)
4p16.3 deletion / Wolf-Hirshhorn Syndrome / ASD, Pulm A stenosis, VSD, PDA, TOF / (7)
7q11.23micordeletion / Williams Syndrome / Peripheral pulm stenosis, supravalvular Aortic stenosis / (8)
9q22.3 microdeletion / Cardiac fibromas / (9),(10)
15q24 microdeletion / VSD, rhabdomyoma / (11)
16p12.2 microdeletion / Conotruncal, HLHS and variants, bicuspid aortic valve, VSD / (12, 13)
17p11.2 deletion with/or RAI1 / Smith-Magenis Syndrome / VSD, ASD, TV stenosis, mitral stenosis, TV/MV regurg, AS, PS, MVP, TOF, TAPVR / (14)
22q11.2 deletion syndrome / DiGeorge Syndrome
Velocardiofacial Syndrome
(see TBX1) / TOF, IAA, VSD, TA, ASD, Vascular ring / (15)
Microduplication syndromes
7q11.23 duplication syndrome / Dilation of aorta / (16)
17q12 duplication / Potocki-Lupski / VSD, valvular disease, vascular ring, HLHS / (17)
Xq28 duplication (Int22h1/Int11h2 Mediated) / PDA, ASD / (18)
Translocations
Der(22)t(11;22) / Emanuel Syndrome / Coarc, ASD, VSD, PDA, TA, pulmA stenosis, TOF, aberrant subclavian A. / (19), (20), (21), (22)
Single Gene disorders
ADNP / ADNP-related intellectual disability / VSD, MVP / (23)
ARHGAP31
DLL4
DOCK6
EOGT
NOTCH1
RBPJ
Unknown others / Adams-Oliver / Coarc, Aortic Stenosis, bicuspid aortic valve, parachute mV, Shone’s complex, ASD, VSD, PDA / (24)
JAG1
NOTCH2 / Alagille Syndrome / Peripheral pulmonary artery stenosis, TOF, VSD, ASD, AS, Coarc / (25), (26)
ATRX / Alpha-thalassemia X-linked intellectual disability syndrome / Heterotaxy / (27)
HBA1
HBA2 / Alpha-thalassemia / Heart failure and hydrops, PDA, / (28)
ALMS1 / Alström / Dilated/constricted CM / (29)
SLC2A10 / Arterial Tortuosity Syndrome / Tortuosity of aorta and middle-sized arteries, stenosis of any artery, valvular regurgitation or MVP / (30), (31)
MYH6 / Atrial Septal defect 3 / ASD, DCM, HCM / (32)
TBX20 / Atrial Septal defect 4 / ASD, PFO / (33)
ACTC1 / Atrial Septal defect 5 / ASD, DCM, HCM, LV noncompaction / (34),(35)
TLL1 / Atrial Septal defect 6 / ASD / (36)
CITED2 / Atrial Septal defect 8 / ASD / (37)
GATA6 / Atrial Septal defect 9 / ASD, TOF / (38)
STAT3 / Autosomal dominant HyperIg E syndrome / Middle-sized arteral tortuosity and aneurysms / (39), (40), (41)
WNT5A
DVL1 / AD Robinow / PV stenosis/atresia, ASD, VSD, Coarc, TOF, Tricuspid atresia / (42), (43)
ACTB
ACTG1 / Baraitser-Winter Cerebrofrontofacial Syndrome / Bicuspid aortic valve, MV regurg, VSD, ASD, PDA / (44)
BBS1
BBS2
BBS4
BBS7
BBS9
BBS10
BBS12
MKKS
MKS1
TTC8 / Bardet-Beidl / AS, PDA, CM, valvular stenosis, ASD, VSD / (45), (46), (47)
TAZ / Barth / Cardiomyopathy (Dilated, hypertrophic and LV non-compaction) / (48), (49)
TFAP2A / Bronchiooculofacial syndrome / ASD, TOF / (50)
TXNL4A / Burn-McKeown Syndrome / PDA, PFO / (51)
CHD7 / CHARGE / TOF, AV canal, Aortic arch anomalies, ASD, VSD, PDA / (52), (53)
CHST3 / Chondrodysplasai with Congenital joint dislocations, AR Larsen, CHST3-Related skeletal dysplasia / Valvular abnormalities / (54), (55), (56)
ABCC9
KCNJ8 / Cantu / Cardiomegaly, PDA, increased vascular tortuosity, bicuspid aortic valve, / (57), (58)
BRAF
MAP2K1
MAP2K2
KRAS / Cardiofaciocutaneous Syndrome / Pulmonic stenosis, ASD, VSD, HCM, rhythm disturbances, MV dysplasia, TV dysplasia, bicuspid AV / (59)
PRKAR1A / Carney / Cardiac Myxomas / (60)
CPT2 / Carnitinepalmitoyltransferase II / CM, arrhythmias / (61), (62)
TFAP2B / Char syndrome / PDA, VSD, / (63)
EBP / Chondrodysplasia punctate 2 (X-linked)
Conradi-Hunermann Syndrome
Happle syndrome / ASD VSD / (64), (65)
RPS6KA3 / Coffin-Lowry / Dilated aorta, CM, short chordae, dilated pulmonary artery, abnormal MV, AV, TV / (66)
ARID1A
ARID1B
SMARCA4
SMARCB1
SMARCE1
SOX11
PHF6 / Coffin-Siris / VSD, ASD, TOF, PDA / (67), (68)
FBN2 / Congenital ContracturalArachnodactyly / ASD, VSD, interrupted AA, Aortic root dilation / (69), (70)
UROS
GATA1 / Congenital Erthropoietic Porphyria / Fetal hydrops / (71)
NIPBL
RAD21
SMC3
HDAC8
SMC1A / Cornelia de Lange
Brachmann de Lange
De Lange / VSD, ASD, Pulm Stenosis, TET, HLHS, bicuspid aortic valve / (72), (73), (74)
HRAS / Costello / HCM, pulmonary valve stenosis, arrhythmias, mild aortic dilation / (75),
IFT122/CED1
WDR35/CED2
IFT43/CED3
WDR19/CED4 / Cranioectodermal Dysplasia
Sensenbrenner Syndrome / PDA, ASD, VSD, MV and TV thickening, Peripheral Pulm Stenosis / (76), (77), (78), (79)
ZFP57
(also imprinting defect of 6q24) / Diabetes Mellitus, 6q24 related transient neonatal / MV insufficiency, IAA, VSD, hypoplastic annular aorta / (80)
DLD / Dihydrolipoamide Dehydrogenase deficiency / HCM / (81), (82), (83)
MMACHC / Cobalamin C deficiency / DCM, VSD, dysplastic PV, ASD, LV non-compaction, MVP, MV regurg / (84)
LMBRD1 / Cobalamin F deficiency / VSD / (85)
ABCD4 / Cobalamin J deficiency / ASD, Coarc, Pulm Hypertension / (86)
EFEMP2 / EFEMP2-related cutis laxa, AR Cutis Laxa type 1B / Arterial tortuosity, stenosis and aneurysms, Pulm HTN, stenosis and dilation of PA / (87), (88), (89)
FBLN5 / FBLN5-related cutis laxa / Peripheral pulm A stenosis, Supravalvular Aortic stenosis / (90), (91)
FGFR2 / Apert / ASD, VSD, PDA, Pulm Stenosis, Coarc, TOF, HLHS, Dexorotation / (92)
FLNA / FLNA-related periventricular nodular heterotopia / PDA, ASD, VSD, Dilation and rupture of thoracic aorta, Valvular dystrophy / (93), (94), (95)
RAD51
FANCA
FANCB
FANCC
FANCD2
FANCE
FANCF
FANCG
FANCI
BRCA2
BRIP1 / Fanconi Anemia / ASD, PDA, Coarc, TA, situs inversus / (96)
MCYN / Feingold Syndrome / PDA / (97)
SRCAP / Floating Harbor / Coarc, ASD / (98), (99)
PIGN
And others / Fryns / VSD, ASD, HLHS, Tricuspid incompetence
DORV, TOF, TA / (100)
GATA4 / GATA4 / ASD, VSD, Pulm Stenosis, TOF, AV canal / (101)
GDF1 / GDF1 related disorders / DORV, TOF, TA / (102)
GLB1 / GM1 Gangliosidosis / Hydrops, CM / (103)
GBA / Gaucher (IIIC) or Cardiovascular form / Mitral and aortic valve calcifications / (104)
ADAMTSL2
FBN1 / Geleophysic dysplasia / Progressive cardiac valve disease, ASD, Pulm stenosis / (105)
ENPP1
ABCC6 / Generalized Arterial Calcification of Infancy (GACI) / Arterial calcification or narrowing of large or medium-sized vessels / (106)
GBE1 / Glycogen Storage Disease IV, Andersen, Glycogen branching enzyme deficiency / Fetal hydrops, DCM, / (107), (108),(109), (110)
TBX5 / Holt-Oram / ASD (ostium secundum), VSD, cardiac conduction defects, Coarc, AV canal / (111), (112), (113), (114)
KANSL1
(included in 17q21.31 microdel) / KANSL1-related Intellectual disability syndrome / ASD, VSD, Aortic root dilation, Pulm stenosis, Valve disease / (115), (116)
KAT6B / KAT6B-related disorders, Genitopatellar syndrome, Say-Barbar-Biesecker variant of Ohdo syndrome / ASD, VSD, PFO / (117)
KMT2D
KDM6A / Kabuki syndrome / VSD, ASD, Coarc, PDA, TA / (118), (119), (120)
EHMT1
(included in 9q34.3 deletion) / Kleefstra / VSD, ASD, pulm A stenosis, bicuspid aortic V, PFO, PDA / (121)
LTBP4 / LTBP4-related Cutis Laxa, Urban-Rifkin-Davis syndrome / Peripheral Pulmon A stenosis, ASD, atrial septal aneurysms, MV insufficiency, TV insufficiency, AV insufficiency, PV stenosis, AV stenosis / (122), (123)
NOTCH3 / Lateral Meningocele Syndrome, Lehman syndrome / Bicuspid aortic valve, aortic dilation, Coarc, VSD / (124), (125), (126)
SPRED1 / Legius syndrome / Pulmonic stenosis, MVP / (127)
TGFBR1
TGFBR2
SMAD3
TGFB2 / Loeys-Dietz Syndrome / Aortic aneurysms, vascular tortuosity / (128)
FOXC2 / Lymphedema-Distichiasis Syndrome / VSD, ASD, PDA, TOF / (129),(130)
MED12 / MED12-Related disorders (FG syndrome 1, Lujan syndrome, X-linked Ohdo syndrome) / AV canal, ASD, VSD, HLHS, MVP, PA hypertension, PDA / (131), (132), (133), (134)
EFTUD2 / MandibulofacialDysostosis with Microcephaly / ASD, VSD / (135),(136),(137)
FBN1 / Marfan syndrome / Dilation of aorta and aneurysm, MVP, TV prolapse, enlargement of Proximal Pulm A / (138)
MKKS / McKusick-Kaufman Syndrome / Atrioventriulariscommunis with left-sided superior vena cava, ASD, VSD, AV canal, small aorta with HLHS, TOF, PDA / (47)
HCCS
(can be due to Xp22 interstitial microdeletion) / Microphthalmia with Linear Skin Defects / HCM, oncocytic CM, ASD, VSD, SVT, VF / (139)
ZEB2 / Mowat-Wilson Syndrome / Pulm artery sling, PDA, ASD, VSD, TOF, Coarc, bicuspid AV, AV stenosis / (140), (141)
GNPTAB / Mucolipidosis II
Mucolipidosis III alpha/beta / MV thickening and insufficiency, AV thickening and insufficiency, PA hypertension / (142), (143)
FGFR3 / Muenke syndrome / ASD, VSD, / (144)
MMP2 / Multicentric OsteolysisNodulosis and Athropathy (Torg-Winchester syndrome) / TGV, ASD, VSD, bicuspid AV, MVP / (145), (146), (147)
RYR1
SEPN1 / Multiminicore disease / MVP, RV failure, CM / (148)
DMPK (CTG repeat expansion) / Myotonic dystrophy I / Conduction abnl, respiratory compromise / (149)
NF1 (mutations or full deletion) / Neurofibromatosis I / Valvular PulmStensosis, HCM, intracardiac neurofibromas, MV insuff, VSD, AS, AI, HTN / (150)
PTCH1
SUFU / Nevoid Basal Cell Carcinoma (Gorlin) / Cardiac fibromas, rhabdomyomas / (151), (152)
NKX2-5 / NKX2-5 / ASD, HLHS, TOF, VSD / (153), (154),(155)
SMARCA2 / Nicolaides-Baraitser Syndrome / ASD, PA stenosis, Coarc, PDA, double aortic arch / (156)
PTPN11, SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, MAP2K1 / Noonan / Pulm v stenosis, ASD, HCM, cystic hygroma, VSD, TOF, Coarc / (157), (158)
PTPN11, RAF1, BRAF, MAP2K1 / Noonan syndrome with multiple lentigines (formerly LEOPARD) / HCM, pulm v stenosis, MV stenosis / (159)
FLNA / Otopalatodigital Syndrome type II / ASD, VSD, pulm A stenosis. / (160)
PIK3CA / Megalencephaly-Capillary Malformations / Vascular rings, VSD, ASD, right sided Aortic arch, TOF, MVR / (161)
PMM2 / PMM2-CDG (CDG-1a) / HCM, pericardial effusion, / (162)
B3GLCT / Peters Plus syndrome / ASD, VSD, Subvalvular AS, Pulm A stenosis, bicuspid PV / (163), (164)
PKD1
PKD2 / Polycystic Kidney Disease (AD) / Aortic root dilation, MVP / (165)
DNAH5
DNAH11
CCDC39
DNAI1
CCDC40
CCDC103
SPAG1
ZMYND10
AEMC4
CCDC151
DNAI2
RSPH1
CCDC114
RSPH4A
DNAAF1 (LRRC50)
DNAAF2 (KTU)
LRRC6
Other less common / Primary Ciliary Dyskinesias / Heterotaxy, TGA, DORV, TAPVR, interrupted infer. Vena cava, bilateral superior vena cavae / (166)
KIAA0196 / Ritscher-Schnizel Syndrome
Craniocerebellocardiac Dysplasia
3C Syndrome / VSD, ASD, TOF, DORV, HLHS, AS, PS / (167), (168)
ROR2 / ROR2-related Robinow / PV stenosis/atresia, ASD, VSD, Coarc, TOF, Tricuspid atresia / (43)
ESCO2 / Roberts Syndrome / ASD, VSD, PDA / (169)
CREBBP
EP300 / Rubinstein-Taybi / PDA, ASD, VSD, Coarc, Pulm A stenosis, bicuspid AV / (170)
SALL4 / SALL4-related disorders (Duane-radial ray, acro-renal-ocular, SALL4-related Holt Oram) / VSD, ASD, TOF / (171)
TWIST1 / Saethre-Chotzen Syndrome / * / (172)
PIK3R1 / SHORT syndrome / Pulm A stenosis, ASD, PDA / (173), (174)
SKI / Shprintzen-Goldberg Syndrome / MVP, MR/I, Aortic regurg, Aortic root dilation / (175)
GPC3
GPC4 / Simpson-Golabi-Behmel Syndrome Type 1 / VSD, ASD, Pulm A stenosis, Coarc, TGA, PDA, PFO, conduction defects / (176)
DHCR7 / Smith-Lemli-Optiz syndrome / Av canal, ASD, VSD, TAPVR, PDA, Pulm Stenosis, HLHS / (177)
NSD1 / Sotos Syndrome / PDA, ASD, VSD, LV-non-compaction, TGA / (178)
COL2A1
COL9A1
COL9A2
COL9A3
COL11A1
COL11A2 / Stickler Syndrome / MVP (maybe) / (179), (180)
TBC1D24 / TBC1D24-related Disorders
DOORS Syndrome / DORV, ASD, VSD / (181), (182)
TBX1 / TBX1 related disorders
(see 22q11.2 deletion) / TOF, IAA, VSD, TA, ASD, Vascular ring / (183)
WNT3 / Tetra-Amelia Syndrome / VSD, small Rt heart, MV aplasia, hypo/aplasia of pulmvesses. / (184), (185)
TGFBR1
TGFBR2
MYH11
ACTA2
FBN1
MYLK
SMAD3 / Thoracic Aorta Aneurysm Syndromes / Progressive dilation of asc aorta, Bicuspid Aortic valve / (186), (187)
RBM8A (mutation or deletion/duplication) / Thrombocytopenia Absent Radii Syndrome / ASD, VSD, PDA / (188), (189)
SALL1 / Townes-Brocks Syndrome / ASD, VSD, TOF, TA, Pulm V atresia, PDA / (190), (191),(192), (193)
TSC1
TSC2 / Tuberous Sclerosis Complex / Cardiac Rhabdomyomas / (194)
ADAMTS10
FBN1
LTBP2 / Weill-Marchesani Syndrome / PDA, pulm A Stenosis, MV insufficiency, AV stenosis, VSD / (195)
MID1 / X-linked Opitz G/BBB syndrome / VSD, ASD, persistent L superior vena cava, PDA / (196)
ZFPM2 / ZFPM2/FOG2 / TOF, DORV / (197)
Imprinting defects
Abnormal methylation of the 11p15.5 region / Beckwidth-Weidemann / CM / (198), (199)

*”congenital heart defects” (no clarification)

**Not included are genes associated with arrhythmias (like Long QT syndrome)

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