Hereditary Breast and Ovarian Cancer
Omicia’s Hereditary Breast/Ovarian Cancer (HBOC) panel includes two genes, BRCA1 and BRCA2, which account for the majority of hereditary breast and ovarian cancer cases in all ethnic and racial groups. Mutations in these genes behave in an autosomal dominant fashion and are associated with a very high likelihood of developing breast and/or ovarian cancer, especially at an early age.
Elevated risk of hereditary breast cancer may also occur in patients with other cancer susceptibility syndromes (see Hereditary Breast Cancer – Extended panel).
Hereditary Breast Cancer– Extended
(ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53)
(Hereditary Breast and Ovarian Cancer, Cowden, Hereditary Diffuse Gastric Cancer, Li Fraumeni Syndrome, Peutz-Jeghers Syndrome)
Omicia’s extended Hereditary Breast Cancer panel includes validated high penetrance and moderate penetrance breast cancer susceptibility genes recognized by the US National Cancer Institute. These are mostly part of inherited cancer syndromes and include the highly penetrant autosomal dominant genes BRCA1 and BRCA2 (Hereditary Breast/Ovarian Cancer Syndrome), PTEN (Cowden Syndrome), CDH1 (Hereditary Diffuse Gastric Cancer), TP53 (Li Fraumeni Syndrome) and STK11 (Peutz-Jeghers Syndrome) and the moderately penetrant autosomal dominant genes ATM (Ataxia telangiectasia), PALB2 (Fanconi anemia) and CHEK2.
(Last updated 10/2/14, accessed 10/9/14)
(MLH1, MSH2, MSH6, PMS2, EPCAM)
Omicia’s Lynch Syndrome panel includes four mismatch repair gene regions recognized by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) group as responsible for Lynch Syndrome. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominantly-inherited genetic condition that greatly increases the risk of colorectal cancer. It is caused by mutations in any one of four mismatch repair genes (MLH1, MSH2, MSH6 and PMS2). MLH1 and MSH2 germline mutations account for approximately 90% of pathogenic variants in families with Lynch syndrome, MSH6 pathogenic variants account for ~7%-10%, and PMS2 pathogenic variants account for fewer than 5%. Germline deletions in EPCAM (while not itself a mismatch repair gene) inactivate MSH2 in about 1% of individuals with Lynch syndrome.
Elevated risk of colon cancer may also occur in patients with other cancer susceptibility syndromes (see Hereditary Colon Cancer – Extended panel).
Hereditary Colon Cancer – Extended
(APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4, STK11, TP53)
(Lynch Syndrome, Familial Adenomatous Polyposis, Cowden Syndrome, Peutz-Jeghers Syndrome, Juvenile polyposis syndrome, Li-Fraumeni Syndrome, MYH-associated polyposis, Oligopolyposis)
Omicia’s extended Hereditary Colon Cancer panel includes high penetrance colon cancer susceptibility genes recognized by the US National Cancer Institute. These include: autosomal dominantly-inherited genes for Lynch Syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM), Familial Adenomatous Polyposis (APC), Cowden Syndrome (PTEN), Peutz-Jeghers Syndrome (STK11), Juvenile polyposis syndrome (BMPR1A, SMAD4), Li-Fraumeni Syndrome (TP53); the autosomal recessive gene for MYH-associated polyposis (MUTYH); and two genes for dominantly-inherited Oligopolyposis (POLD1, POLE).
Genetics of Colorectal Cancer (PDQ®) from the NCI
(Last updated 7/11/14, accessed 10/9/14)
Inherited Cancer Syndromes
(APC, BRCA1, BRCA2, EPCAM, MEN1, MLH1, MSH2, MSH6, PMS2, PTEN, RB1, RET, TP53, VHL)
(Hereditary Breast and Ovarian Cancer, Lynch Syndrome, Familial Adenomatous Polyposis, Cowden Syndrome, Li-Fraumeni Syndrome, Retinoblastoma, Multiple Endocrine Neoplasia Type 1 (Werner Syndrome), Multiple Endocrine Neoplasia Type 2, Von Hippel-Lindau Syndrome)
Omicia’s Inherited Cancer Syndromes panel includes genes for the most common cancer syndromes recognized by the US National Cancer Institute. These include highly penetrant autosomal dominant genes for Hereditary Breast and Ovarian Cancer (BRCA1, BRCA2), Lynch Syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM), Familial Adenomatous Polyposis (APC), Cowden Syndrome (PTEN), Li-Fraumeni Syndrome (TP53), Retinoblastoma (RB1), Multiple Endocrine Neoplasia Type 1 – also know as Werner Syndrome (MEN1), Multiple Endocrine Neoplasia Type 2 (RET) and Von Hippel-Lindau Syndrome (VHL).
Genetic Testing for Hereditary Cancer Syndromes from the NCI
(Last updated 4/11/2013; accessed 10/6/14)
(AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, PKP2, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SLMAP, SNTA1, TGFB3, TMEM43, TRPM4)
(Long QT Syndrome, Brugada Syndrome and Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia)
Omicia’s Arrhythmia panel was developed with leading cardiologist Tom Quertermous, MD from Stanford. It includes genes underlying several syndromes whose symptoms are consistent with cardiac rhythm abnormalities, including Long QT Syndrome, Brugada Syndrome and Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia.
Long QT Syndrome: includes Romano-Ward Syndrome, Jervell-Lange Nielsen Syndrome, Andersen-Tawil Syndrome, Timothy Syndrome – See Long QT Panel description – (AKAP9, ANK2, CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1).
Brugada Syndrome: mutations in 15 genes have been implicated, but these account for only ~25%-30% of Brugada Syndrome. The vast majority (15-30%) are in one gene, SCN5A, while the remaining 14 genes (SCN1B, SCN2B, SCN3B, GPD1L, CACNA1C, CACNB2, CACNA2D1, KCND3, KCNE3, KCNE1L (KCNE5), KCNJ8, HCN4, SLMAP, and TRPM4) each account for <1% of Brugada Syndrome cases.
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D): Mutations in 8 genes account for ~30 to 40 percent of cases of ARVC/D. Mutations in four genes account for the majority of inherited disease (PKP2, DSG2, DSP, DSC2). Mutations in four other genes are rare (TGFB3, RYR2, TMEM43, JUP).
• Brugada Syndrome
(Last updated 4/10/2014; accessed 10/6/14)
• Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
(Last updated 1/9/2014; accessed 10/6/14)
(ACTC1, ACTN2, ANKRD1, BAG3, CSRP3, DES, DMD, DSC2, DSG2, DSP, EYA4, JUP, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYOZ2, NEXN, PKP2, PLN, PSEN1, PSEN2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, VCL)
(Familial Hypertrophic Cardiomyopathy, non-syndromic Familial Dilated Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia)
Omicia’s Cardiomyopathy panel was developed with leading cardiologist Tom Quertermous, MD from Stanford. This panel covers several types of cardiomyopathies, including Familial Hypertrophic Cardiomyopathy (HCM), non-syndromic Familial Dilated Cardiomyopathy (DCM) and Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D).
Familial Hypertrophic Cardiomyopathy: Mutations in two genes (MYH7 and MYBPC3) account for ~80% of HCM. Another ~10% are attributed to mutations in TNNT2 and TNNI3. The remaining 12 genes (TPM1, MYL2, MYL3, ACTC1, CSRP3, ACTN2, MYH6, TCAP, TNNC1, PLN, MYOZ2, NEXN) are rare causes of the disease. All of these mutations confer disease in an autosomal dominant manner.
Familial Dilated Cardiomyopathy: Mutations in more than 30 genes have been found to cause non-syndromic familial DCM, most inherited in an autosomal dominant fashion. Mutations in one gene, TTN, account for ~20% of cases. Mutations in the genes LMNA, MYH7, MYH6, SCN5A, MYBPC3, TNNT2, BAG3, ANKRD1 and RBM20 each account for ~2-6% of familial DCM. The remaining genes each account for 1% or less of familial DCM (TMPO, LDB3, TCAP, VCL, TPM1, TNNI3, TNNC1, ACTC1, ACTN2, CSRP3, DES, NEXN, PSEN1, PSEN2, SGCD, EYA4, PLN, DSG2). There are also rare X-linked forms due to mutations in DMD and TAZ.
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: Mutations in 8 genes account for ~30 to 40 percent of cases of ARVC/D. Mutations in four genes account for the majority of inherited disease (PKP2, DSG2, DSP, DSC2). Mutations in four other genes are rare (TGFB3, RYR2, TMEM43, JUP).
• Familial Hypertrophic Cardiomyopathy
(Last updated 1/16/2014; accessed 10/6/14)
• Familial Dilated Cardiomyopathy
(Last updated 5/9/2013; accessed 10/6/14)
• Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
(Last updated 1/9/2014; accessed 10/6/14)
(APOB, LDLR, PCSK9)
Omicia’s Familial Hypercholesterolemia (FH) panel includes three genes that harbor autosomal dominantly-inherited mutations associated with hypercholesterolemia. The most commonly mutated gene is LDLR, where high penetrance alleles account for 60-80% of FH. Mutations in APOB account for 1-5% of FH, but are incompletely penetrant. Mutations in PCSK9 are an uncommon cause of FH, accounting for 0-3% of the disorder. Penetrance varies depending on the mutation, but the p. Ser127Arg and p. Asp374Tyr variants are known highly penetrant variants of PCSK9.
(last updated 1/2/14; accessed 10/8/14)
Long QT Syndrome
(AKAP9, ANK2, CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1)
(Romano-Ward Syndrome, Jervell-Lange Nielsen Syndrome, Andersen-Tawil Syndrome, Timothy Syndrome)
Omicia’s Long QT Syndrome panel was developed with leading cardiologist Tom Quertermous, MD from Stanford. It includes genes underlying syndromes that include clinical features of syncopal episodes, long QT interval, and sudden death. The autosomal dominant Romano-Ward Syndrome is the most common form of inherited long QT syndrome. Among the genes known to be associated with Romano-Ward Syndrome, KCNQ1, KCNH2 and SCN5A are the most common. Other, less frequently involved genes include KCNE1, KCNE2, CAV3, SCN4B, AKAP9, SNTA1 and KCNJ5. Approximately 25% of families meeting clinical diagnostic criteria for Romano-Ward Syndrome do not have detectable mutations in one of the above genes. ANK2 mutations can cause a variety of heart problems, including the irregular heartbeat often found in Romano-Ward syndrome, although this may be a different type of heart condition.
A form of Long QT Syndrome associated with autosomal recessive inheritance and congenital deafness is called the Jervell-Lange Nielsen Syndrome. Most cases of this syndrome are due to mutations in the KCNQ1 gene; KCNE1 mutations are responsible for the remaining cases. Genes for the rare autosomal dominant Andersen-Tawil Syndrome (KCNJ2) and extremely rare autosomal dominant Timothy Syndrome (CACNA1C) are also included in this panel.
• Romano-Ward Syndrome
(last updated 5/31/12; accessed 10/8/14)
• Jervell-Lange Nielsen Syndrome
(last updated 10/4/12; accessed 10/8/14)
• Andersen-Tawil Syndrome
(last updated 1/3/13; accessed 10/8/14)
• Timothy Syndrome
(last updated 4/21/11; accessed 10/8/14)
Marfan, Aneurysm, and Aortopathies
(ACTA2, COL3A1, FBN1, MYH11, MYLK, SMAD3, TGFB2, TGFBR1, TGFBR2)
(Marfan Syndrome, Ehlers-Danlos Syndrome Type IV, Loeys-Dietz Syndrome, Familial Thoracic Aortic Aneurysm and Dissection)
Omicia’s Marfan, Aneurysm and Aortopathies panel was developed with leading cardiologist Tom Quertermous, MD from Stanford and includes genes related to cardiovascular structural abnormalities. Marfan Syndrome (FBN1) and Ehlers-Danlos Syndrome, Type IV (COL3A1) are each caused my mutations in a single gene. Loeys-Dietz Syndrome is due to mutations in one of four genes (SMAD3, TGFB2, TGFBR1, TGFBR2). Mutations in TGFBR2 account for the majority (~70%) of cases. Familial Thoracic Aortic Aneurysm and Dissection is primarily inherited in an autosomal dominant fashion with decreased penetrance and variable expressivity. Less than 25% of Thoracic Aortic Aneurysm and Dissection (TAAD) is attributed to known genes, the most commonly mutated gene being ACTA2. Five other genes (MYH11, MYLK, SMAD3, TGFBR1, and TGFBR2) each account for ~1-5% of TAAD.
• Marfan Syndrome
(last updated 6/12/14; accessed 10/8/14)
• Ehlers-Danlos Syndrome Type IV
(last updated 5/3/11; accessed 10/8/14)
• Loeys-Dietz Syndrome
(last updated 7/11/13; accessed 10/8/14)
• Familial Thoracic Aortic Aneurysm and Dissection
(last updated 1/12/12; accessed 10/8/14)
(ALDH7A1, ARHGEF9, ARX, CACNA1H, CACNB4, CDKL5, CHRNA2, CHRNA4, CHRNB2, CLCN2, CPA6, CSTB, EFHC1, EPM2A, GABRA1, GABRB3, GABRD, GABRG2, GOSR2, GPR98, GRIN2A, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MAPK10, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SLC25A22, SPTAN1, SRPX2, ST3GAL3, ST3GAL5, STRADA, STXBP1)
Omicia’s non-syndromic epilepsy panel was developed in collaboration with Dr. Oreste Eziquel Salavaggione, author of The Concise Encyclopedia of Genomic Diseases. The panel includes genes underlying epilepsies of neonatal or childhood onset, including episodic and paroxysmal disorders: Autosomal dominant nocturnal frontal lobe epilepsy; Autosomal dominant familial temporal lobe epilepsy; Childhood absence epilepsy or pyknolepsy; Juvenile myoclonic epilepsy or Janz syndrome; Progressive myoclonus epilepsies; Amish infantile epilepsy syndrome; Epilepsy with neurodevelopmental defects; Polyhydramnios, megalencephaly and symptomatic epilepsy; Rolandic epilepsy with speech dyspraxia and mental retardation; Early infantile epileptic encephalopathy or Ohtahara syndrome; Dravet syndrome; Benign familial neonatal epilepsy; Febrile seizure; Generalized epilepsy with febrile seizures plus; West syndrome; Lennox–Gastaut syndrome; Pyridoxamine 5′-phosphate oxidase deficiency or Pyridoxal phosphate-responsive seizures; Pyridoxine dependent seizures.
• Salavaggione OE, 2013. The Concise Encyclopedia of Genomic Diseases: Genomics and Disease Prevention, 1 edition. ed. Oreste Salavaggione.
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