DNA Genetic Testing
Cardiovascular Comprehensive Panel
Genes control every aspect of the cardiovascular system from the strength of the blood vessels to the way cells in the heart communicate. A genetic mutation in a single gene can dictate the likelihood of developing heart disease. When a family member is diagnosed with heart disease or a heart disorder, other family members are strongly encouraged to receive screening for risk factors and early stage disease that may not yet produce symptoms.
Cardiac comprehensive testing allows for the evaluation of multiple conditions including: arrhythmia, cardiomyopathies, connective tissues disorders, familial hypercholesterolemia, RASopathies, etc. Sudden cardiac arrest (SCA) is a leading cause of non-traumatic mortality in the United States. At least 25% of SCA events have a genetic component and can be classified as inherited cardiac conditions (ICCs). Understanding and identifying the genetic components are crucial to disease prognosis, therapy choice, and, possibly, outcome.
OnPoint Lab’s Cardiovascular Comprehensive Panel will clearly show a specific genetic change in the case of personal or family history of heart disease. The results will help with diagnosis or management of a condition. For example, steps can be taken to lower risk of developing diseases. Understanding genetic composition allows for a more customized prevention or treatment plan for the patient. Steps may include surgery, medication, frequent screening, or lifestyle changes.
Table 1. Cardiac Conditions Covered by the Panel
| Condition | Number of genes |
|---|---|
| Aortic Valve Disease | 3 |
| Marfan Syndrome | 3 |
| Loeys-Dietz Syndrome | 4 |
| Short QT Syndrome | 4 |
| Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) | 6 |
| Familial Hypercholesterolemia | 7 |
| Restrictive Cardiomyopathy | 9 |
| Non-Compaction Cardiomyopathy | 10 |
| Nooan Syndrome | 12 |
| Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) | 11 |
| Brugada Syndrome | 13 |
| Structural Heart Disease | 15 |
| Long QT Syndrome | 15 |
| Familial Aortic Aneurysm | 16 |
| Familial Atrial Fibrillation | 21 |
| Hypertrophic Cardiomyopathy | 47 |
| Dilated Cardiomyopathy | 59 |
Testing should be considered for patients with a confirmed or suspected diagnosis of an inherited cardiovascular disease. First relatives share genetic variants predisposing them to an inherited cardiovascular disease and are considered to be at higher risk for the same conditions.[1]
Comprehensive Hereditary Cancer Screening
Cancer is a common disease with a lifetime risk of affecting about 1 in 3 individuals in the United States. A majority of these cancer cases are isolated. However, some cancers are hereditary and can cause increased risk of cancer in certain families. Overall, approximately 5-10% of all cancer cases are thought to involve hereditary predisposition. Indications of possible hereditary cancer predisposition include: several members of the same family affected with the same type of cancer or similar types, early onset of cancer in an individual, or personal history of several primary cancers. Identifying those at-risk may help with early intervention through additional screening, increased surveillance, and other intervention processes.
OnPoint Lab’s Comprehensive Hereditary cancer screening is used to test for individuals with a hereditary predisposition for cancer. This panel tests for 29 genes that are associated with hereditary cancers across multiple organ systems and analyzes genes associated with predisposition to the most common hereditary cancer syndromes, such as such as breast and ovarian cancer, colorectal cancer, and Lynch syndrome.[2]
PAD Testing Panel
Alzheimer’s disease is the most common type of dementia. Alzheimer’s typically begins with subtle memory failure that progresses over time until it becomes incapacitating. The disease is characterized by amyloid plaques and neurofibrillary tangles within neurons. Approximately 25% of all Alzheimer’s cases are familial but can be distinguished from non-familial Alzheimer’s by family history and molecular genetic testing. Less than 10% of Alzheimer’s cases are early onset, with patients developing symptoms before the age of 65. This form of Alzheimer’s is more likely to be an inherited disease. Three genes have been linked to early onset Alzheimer’s disease accounting for a majority of cases: APP, PSEN1, PSEN2.
Parkinson’s is the second most common neurodegenerative disease, after Alzheimer’s disease, and has a prevalence of approximately 1% in people over the age of 60. Parkinson’s disease typically consists of motor difficulties, such as tremors and muscle rigidity, but can also include cognitive decline and dementia. Many cases of Parkinson’s are caused by multiple factors, both genetic and environmental. However, 5-10% of patients have a monogenic form caused by mutations in a specific gene.
Dementia is a relatively common disease in people over the age of 60 with a prevalence of 5-7%. Dementia consists of cognitive and behavioral symptoms that interfere with usual activities and represent a decline from previous function. Many forms of dementia are thought to be multifactorial and are genetically complex diseases. However, some have been shown to be due to distinct genetic causes. A clinical evaluation may not be sufficient to distinguish specific types of dementia, therefore a genetic test can be valuable in establishing clinical diagnosis.
OnPoint Lab’s PAD testing panel tests for the presence of genes related to these neurological diseases and identifies patient risk for developing Alzheimer’s, Parkinson’s, or dementia, allowing the patient and physicians to work together to establish a plan of action.[3]
Diabetes and Obesity
Monogenic diabetes is a rare type of diabetes that is caused by a single gene mutation. There are two types of monogenic diabetes:
- Maturity onset diabetes of the young (MODY). There are currently over 10 different types and with new genetic testing, many more are being uncovered. It accounts for about 1-2% of all diabetes cases, though its prevalence may actually be up to 5%. It has characteristics of both Type 1 and Type 2 diabetes and is often misdiagnosed as one of these more common types.
- Neonatal diabetes. This type is usually diagnosed in infants from birth to 6 months, though diagnosis may occur later in some cases. Often these infants are started on insulin but this type of diabetes can be treated with pills known as sulfonylurea agents.
Molecular genetic diagnosis can improve clinical care and provide information on likely disease courses. Who should be tested?
- Those with a diagnosis of diabetes before 6 months of age (neonatal diabetes).
- Those with a family history of MODY.
- Those with a strong family history of diabetes, either Type 1 or Type 2, which is diagnosed at a younger age (teens, 20s or 30s).
- Those with diabetes that does not fit into the Type 1 category (meaning negative antibodies, no DKA) or Type 2 category (meaning not overweight, with central fat or later onset).
Obesity has been associated with Type 2 diabetes, among other health conditions. Overall, obesity is a complex multifactorial condition influenced by multiple genes, lifestyle, and other environmental factors. However, in some cases obesity may be monogenetic due alterations in a single gene. Monogenic obesity may be syndromic or non-syndromic. Most are characterized by early onset and severe phenotype. OnPoint Labs’s diabetes and obesity panel analyzes 56 genes associated with monogenic diabetes and obesity.[4]
Genetic Hearing Loss
Hearing defects are one of the most prevalent chronic conditions in children, with rates of above 1 to 1,000 in newborns and about 3.5 to 1,000 in adolescents. Genetic and environmental factors account for hearing loss, yet genetics are the leading cause, accounting for at least 50-60% of hearing loss in developed countries.
Hearing loss can be syndromic (present with unrelated clinical features) or non-syndromic, with the latter accounting for the majority of cases. Hearing loss can also be categorized as conductive hearing loss, sensorineural hearing loss, or mixed hearing loss. With conductive hearing loss, the outer or middle ear are affected and soundwaves cannot propagate through the ear. With sensorineural hearing loss, the inner ear, auditory nerve, or central auditory pathway are affected. In mixed hearing loss, both conductive and sensorineural hearing loss are present.
Hearing loss is inherited in autosomal recessive, autosomal dominant, and X-linked patterns of inheritance. OnPoint lab’s hearing loss panel screens for defects inherited in all the inheritance patterns mentioned above. Identifying underlying genetic causes of hearing loss might direct therapeutic decision making, assist in prevention, and allow early identification in other family members.
A recent study suggests that genetic testing has become the first test that should be ordered after history, physical examination, and audiometry. Establishing a genetic diagnosis is valuable because it can prevent further invasive and expensive diagnostic testing, identify possible medical comorbidities, and provide families with genetic counseling and valuable prognostic information. As personalized genomic medicine becomes more normalized, genetic testing will be the basis for targeted molecular therapies.
Risk for genetic hearing loss can be analyzed by OnPoint lab’s Genetic Hearling loss tests which searches for mutations in 174 genes associated with hearing loss.[5]
Sources
[1]
The Comprehensive Cardiovascular Panel analyze genes associated with inherited cardiovascular conditions: ABCC9, ABCG5, ABCG8, ACTA1, ACTA2, ACTC1, ACTN2, AKAP9, ALMS1, ANK2, ANKRD1, APOA4, APOA5, APOB, APOC2, APOE, BAG3, BRAF, CACNA1C, CACNA2D1, CACNB2, CALM1, CALR3, CASQ2, CAV3, CBL, CBS, CETP, COL3A1, COL5A1, COL5A2, COX15, CREB3L3, CRELD1, CRYAB, CSRP3, CTF1, DES, DMD, DNAJC19, DOLK, DPP6, DSC2, DSG2, DSP, DTNA, EFEMP2, ELN, EMD, EYA4, FBN1, FBN2, FHL1, FHL2, FKRP, FKTN, FXN, GAA, GATAD1, GCKR, GJA5, GLA, GPD1L, GPIHBP1, HADHA, HCN4, HFE, HRAS, HSPB8, ILK, JAG1, JPH2, JUP, KCNA5, KCND3, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, KLF10, KRAS, LAMA2, LAMA4, LAMP2, LDB3, LDLR, LDLRAP1, LMF1, LMNA, LPL, LTBP2, MAP2K1, MAP2K2, MIB1, MURC, MYBPC3, MYH11, MYH6, MYH7, MYL2, MYL3, MYLK, MYLK2, MYO6, MYOZ2, MYPN, NEXN, NKX2-5, NODAL, NOTCH1, NPPA, NRAS, PCSK9, PDLIM3, PKP2, PLN, PRDM16, PRKAG2, PRKAR1A, PTPN11, RAF1, RANGRF, RBM20, RIT1, RYR1, RYR2, SALL4, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCO2, SDHA, SEPN1, SGCB, SGCD, SGCG, SHOC2, SLC25A4, SLC2A10, SMAD3, SMAD4, SNTA1, SOS1, SREBF2, TAZ, TBX20, TBX3, TBX5, TCAP, TGFB2, TGFB3, TGFBR1, TGFBR2, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TRIM63, TRPM4, TTN, TTR, TXNRD2, VCL, ZBTB17, ZHX3, ZIC3 (175 genes).
“Inherited Cardiovascular Disease.” RWJBarnabas Health,
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A Prospective Study of Sudden Cardiac Death among Children and Young Adults. Richard D. Bagnall, Robert G. Weintraub, Jodie Ingles, Johan Duflou, Laura Yeates, Lien Lam, Andrew M. Davis, Tina Thompson,. 2441-2452, s.l. : N Engl J Med, 2016, Vol. 374.
Epidemiology of inherited arrhythmias. Joost A. Offerhaus, Connie R. Bezzina & Arthur A. M. Wilde. s.l. : Nat Rev Cardiol, 2019.
Genetic testing for inherited cardiac disease. Arthur A. M. Wilde, Elijah R. Behr. 571–583, s.l. : Nat Rev Cardiol , 2013, Vol. 10.
Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. Chiang T, Liu X, Wu TJ, Hu J, Sedlazeck FJ, White S, et al. 2135-2144, s.l. : Genet Med., 2019, Vol. 21(9).
Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement from the American Heart Association. Musunuru, Kiran, et al. Circulation: Genomic and Precision Medicine, vol. 13, no. 4, 2020,
[2]
GAPC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CEBPA, CHEK2, ELAC2, EPCAM, FANCC, FH, HRAS, KIT, MAX, MEN1, MET, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, NF1, NF2, NTRK1, PALB2, PALLD, PDGFRA, PHOX2B, PMS2, PTCH1, PTEN, RAD50, RAD51, RAD51C, RAD51D, RASSF7, RET, RUNX1, SDHA, SDHB, SDHC, SDHD, SMAD4, STK11, TMEM127, TP53, TSC1, TSC2, VHL, WT1
SEER Cancer Statistics Review, 1975-2016. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). National Cancer Institute. Bethesda, MD. [Online] https://seer.cancer.gov/csr/1975_2. 2. Hereditary Cancer Predisposition Syndromes. Offit, Judy E. Garber and Kenneth. 23(2), 2005 Jan, J Clin Oncol, Vol. 10, pp. 276-92. 3. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL and Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Com. 1, 2015, Genet Med., Vol. Jan17, pp. 70-87. 4. Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. Chiang T, Liu X, Wu TJ, Hu J, Sedlazeck FJ, White S, et al. Genet Med. 2019 Sep;21(9):2135-2144.
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[4]
ABCC8, ADRB2, ADRB3, AGRP, ALMS1, ARL6, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BDNF, CARTPT, CEL, CEP290, EIF2AK3, ENPP1, FOXP3, GCK, GHRL, GLIS3, GNAS, HNF1A, HNF1B, HNF4A, INS, KCNJ11, LEP, LEPR, MAGEL2, MC4R, MKKS, MKS1, NEUROD1, NEUROG3, NTRK2, PCSK1, PDX1, POMC, PPARG, PPARGC1B, PTF1A, PYY, RFX6, SDC3, SDCCAG8, SIM1, TRIM32, TTC8, UCP1, UCP3, WDPCP, WFS1.
“What Is Monogenic Diabetes?” Beyond Type 1, 29 Jan. 2020, https://beyondtype1.org/what-is-monogenic-diabetes/.
ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents. Hattersley AT1, Greeley SAW2, Polak M3, Rubio-Cabezas O4, Njølstad PR5,6, Mlynarski W7, Castano L8, Carlsson A9, Raile K10, Chi DV11,12, Ellard S1, Craig ME. 47-63, s.l. : Pediatr Diabetes, 2018, Vol. 19 Suppl 27. doi: 10.1111/pedi.12772
2. Maturity-onset diabetes of the young (MODY): current perspectives on diagnosis and treatment. KM, Jang. 1047-1056, s.l. : Diabetes Metab Syndr Obes., 2019, Vol. Jul 8;12. doi: 10.2147/DMSO.S179793.
3. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Association, American Diabetes. S14-S31, s.l. : Diabetes Care, 2020, Vol. Jan;43(Suppl 1). doi: 10.2337/dc20-S002
4. Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective. Albuquerque D, Stice E, Rodríguez-López R, Manco L, Nóbrega C. 1191-221, s.l. : Mol Genet Genomics, 2015, Vol. Aug;290(4). doi: 10.1007/s00438-015-1015-9.
5. Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. Chiang T, Liu X, Wu TJ, Hu J, Sedlazeck FJ, White S, et al. 2135-2144, s.l. : Genet Med., 2019, Vol. 21(9).
[5]
ADGRV1, AIFM1, ALMS1, AMMECR1, ANKH, ASAH1, ATP6V1B1, BCS1L, BDP1, BSND, BTD, CABP2, CACNA1D, CATSPER2, CCDC50, CDC42, CDH23, CEACAM16, CHD7, CHSY1, CIB2, CISD2, CLDN14, CLIC5, CLPP, CLRN1, COCH, COL11A1, COL11A2, COL2A1, COL4A3, COL4A4, COL4A5, COL4A6, COL9A1, COL9A2, COL9A3, CRYL1, CRYM, DCDC2, DIABLO, DIAPH1, DIAPH3, DSPP, EDN3, EDNRB, ELMOD3, EPS8, ERCC2, ERCC3, ESPN, ESRRB, EYA1, EYA4, FGF3, FGFR1, FGFR2, FOXI1, GATA3, GIPC3, GJA1, GJB2, GJB3, GJB6, GPSM2, GRHL2, GRXCR1, GRXCR2, GSDME, HARS1, HARS2, HGF, HOMER2, HOXB1, HSD17B4, ILDR1, KARS1, KCNE1, KCNJ10, KCNQ1, KCNQ4, KITLG, LARS2, LHFPL5, LHX3, LOXHD1, LRP2, LRTOMT, MANBA, MARVELD2, MET, MIR96, MITF, MSRB3, MYH14, MYH9, MYO15A, MYO1C, MYO3A, MYO6, MYO7A, NARS2, NDP, NF2, NLRP3, OPA1, OSBPL2, OTOA, OTOF, OTOG, OTOGL, P2RX2, PAX3, PCDH15, PDZD7, PEX1, PEX6, PJVK, PMP22, PNPT1, POLR1C, POLR1D, POU3F4, POU4F3, PRPS1, PTPRQ, RDX, RIPOR2, SEMA3E, SERPINB6, SIX1, SIX5, SLC17A8, SLC19A2, SLC26A4, SLC26A5, SLC4A11, SLC52A2, SLC52A3, SLITRK6, SMAD4, SMPX, SNAI2, SOX10, STRC, SYNE4, TBC1D24, TBL1X, TBX1, TCOF1, TECTA, TFAP2A, TIMM8A, TJP2, TMC1, TMEM132E, TMIE, TMPRSS3, TMPRSS5, TNC, TPRN, TRIOBP, TSPEAR, TWNK, TYR, USH1C, USH1G, USH2A, WFS1, WHRN
Genetics: advances in genetic testing for deafness. Shearer, A. E., & Smith, R. J(2012). Current opinion in pediatrics, 24(6), 679–686. https://doi.org/10.1097/MOP.0b013e3283588f5e
Newborn Hearing Screening – A Silent Revolution. Cynthia C. Morton, and Walter E. Nance. 2151-64, s.l. : N Engl J Med, 2006, Vol. 354
Congenital hearing loss. Anna M. H. Korver, Richard J. H. Smith, Guy Van Camp, Mark R. Schleiss, Maria A. K. Bitner-Glindzicz, Lawrence R. Lustig, Shin-ichi Usami & An N. Boudewyns. 16094, s.l. : Nature Reviews Disease Primers, 2017, Vol. 3
Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. Chiang T, Liu X, Wu TJ, Hu J, Sedlazeck FJ, White S, et al. 2135-2144, s.l. : Genet Med., 2019, Vol. 21(9)