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Genetic Carrier Screening Technical Bulletin

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Genetic Carrier Screening Technical Bulletin Genetic Carrier Screening Test Indications Carrier screening is a significant testing tool for inherited genetic beta-lipoproteins causes the associated nutritional and neurological conditions of prenatal care. The purpose of carrier screening is to problems in people with abetalipoproteinemia. identify couples at-risk for passing on genetic conditions to their Abetalipoproteinemia has been reported in approximately offspring. The Genetic Carrier Screening Ashkenazi Jewish Panel 100 cases worldwide. provides not only the currently recommended carrier screening tests, but also other important high-risk inherited genetic conditions. Alport syndrome: Also known as Collagen type IV alpha 3 (COL4A3), Identification of a pathogenic variant in one of these genes, or variants gene-related Alport syndrome has either autosomal recessive in genes associated with 43 high-risk diseases, can help health care or dominant inheritance. This condition is featured by kidney providers and genetic counselors who wish to establish or confirm a malfunction, hearing loss, and eye abnormalities. diagnosis, predict the risk of having a child with a genetic disorder, or to guide patients’ management decisions. Pathogenic variants of the COL4A3 gene encoding type IV collagen prevent the kidneys from filtering the blood properly, blocks Considerations for Testing transformation of sound waves into nerve impulses to the brain, and fails to maintain the shape of the lens and the normal color of the A health care provider or genetic counselor may determine if an retina. individual is at-risk to have offspring with a genetic disorder by obtaining a family health history. The Carrier screening test should be offered if: Worldwide, Alport syndrome occurs in approximately 1 in 50,000 newborns, and is estimated to affect approximately 1 in 5,000-10,000 • an individual has a genetic disorder. people in the general population in the United States. • an individual has a child who has a genetic disease. Arthrogryposis, Mental Retardation and Seizures (AMRS) is an • an individual has a family history of a genetic disorder. autosomal recessive inherited disorder where newborns have • an individual belongs to an ethnic group that has a high carrier multiple joint contractures in their arms or legs. Affected infants rate of genetic disorders (e.g., Ashkenazi Jewish heritage). may have limb malformations, hypotonia, and microcephaly. Furthermore, The American College of Obstetricians and Gynecologists Children with AMRS typically develop intellectual disability, autistic (ACOG) recommends that carrier screening for cystic fibrosis should be characteristics, as well as seizures. offered to all women who are considering pregnancy or are currently ARMS is caused by genetic changes in the solute carrier family 35 pregnant (2). member A3 (SLC35A3) gene, which encodes a transporter found in If a patient considering pregnancy is determined to be a carrier, testing the Golgi apparatus membrane. is also recommended for their partner. AMRS is a rare disorder, which is seen more commonly in those of Genetics Ashkenazi Jewish descent, where it has a 1 in 453 carrier frequency. The conditions listed in Table 1 can be caused by inherited genetic Bardet-Biedl Syndrome is an autosomal recessive disorder variants. The variants are inherited in an autosomal recessive pattern characterized by severe pigmentary retinopathy, obesity, in which a gene variant is a recessive gene located on one of the polydactyly, renal malformation and mental retardation. non-sex chromosomes (non-X and non-Y), or autosomes. One needs Pathogenic variants of the Bardet-Biedl syndrome (BBS) genes are to inherit both copies of the pathogenic gene variant to be affected responsible for this disorder. Most cases of Bardet-Biedl syndrome by the associated disorder. Autosomal recessive disorders are usually result from pathogenic variations in BBS1, BBS2, and BBS10. The passed by two carriers, or individuals whose health is rarely affected BBS genes are involved in cell movement and various chemical but have one variant and one normal copy of the recessive gene. Two signaling pathways. They are also necessary for the perception of carriers have a 25% chance of having an affected child. sensory input. Clinical Characteristics Bardet-Biedl syndrome has a prevalence of 1 in 140,000 to 1 in 160,000 in newborns in most of North America and Europe. It is more Abetalipoproteinemia is an autosomal recessive inherited disorder common on the island of Newfoundland, Canada (1 in 17,000 that affects the absorption of dietary fats, cholesterol, and fat-soluble newborns), and the Kuwait Bedouin population, affecting 1 in 13,500 vitamins. Patients with abetalipoproteinemia are unable to produce newborns. certain lipoproteins that help carry fats and fat-like substances in the blood. Symptoms including failure to gain weight and thrive, and Bloom Syndrome is an inherited condition following an autosomal occur in the first few months of life. Malfunctions of the nervous system recessive pattern. Patients with this condition are characterized by and eye disorders may develop later in childhood. short stature, a skin rash that develops after exposure to the sun, and a greatly increased risk of cancer. Others features may appear in Pathogenic variants of the microsomal triglyceride transfer protein patients, including learning disabilities, a high risk of diabetes, chronic (MTTP) gene fail to produce beta-lipoproteins which are necessary for the absorption of fats and fat-like substances from the diet. A lack of Division of Genetics & Oncology 1 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • www.geneveda.com • 877.269.0090 Upd: 5/2018 Table 1. MDL’s Genetic Carrier Screening Ashkenazi Panel Detected Diseases, Target Genes and Frequencies. Carrier Frequency- The chance of an individual with no symptoms having a disease-causing variant. Detection Rate- The percentage of carriers calculated to be detected by the Genetic Carrier Screening test. Residual Risk- The chance of being a carrier even if an individual is found negative for the disease-causing variants tested. Carrier Detection Disease Gene Population Frequency Rate Residual Risk Ashkenazi 1 in 186 75% 1 in 744 Abetalipoproteinemia MTTP General <1 in 500 10% 1 in 556 Ashkenazi 1 in 192 48% 1 in 369 Alport Syndrome, COL4A3-related COL4A3 General 1 in 354 44% 1 in 632 Ashkenazi 1 in 453 95% 1 in 9,060 Arthrogryposis, Mental Retardation, and Seizures (AMRS) SLC35A3 General <1 in 500 95% 1 in 10,000 Bardet-Biedl Syndrome, BBS1-related BBS1 General 1 in 392 70% 1 in 1,307 Ashkenazi 1 in 140 95% 1 in 2,800 Bardet-Biedl Syndrome, BBS2-related BBS2 General <1 in 500 29% 1 in 704 Bardet-Biedl Syndrome, BBS10-related BBS10 General 1 in 423 46% 1 in 783 Ashkenazi 1 in 134 97% 1 in 4,466 ♦ Bloom Syndrome BLM General <1 in 500 10% 1 in 556 Ashkenazi 1 in 55 99% 1 in 5,500 ♦ Canavan Disease ASPA General 1 in 158 53% 1 in 336 Caucasian 1 in 200 70% 1 in 667 Carnitine Palmitoyltransferase II Deficiency CPT2 Ashkenazi 1 in 45 73% 1 in 167 General 1 in 182 65% 1 in 520 Caucasian 1 in 266 82% 1 in 1,478 ♦ Congenital Amegakaryocytic Thrombocytopenia MPL Ashkenazi 1 in 57 95% 1 in 1,140 General 1 in 415 76% 1 in 1,729 Caucassian 1 in 42 77% 1 in 183 Congenital Disorder of Glycosylation Type 1a PMM2 Ashkenazi 1 in 61 89% 1 in 555 General 1 in 124 71% 1 in 428 Caucasian 1 in 25 94% 1 in 417 ♦*Cystic Fibrosis CFTR Asian 1 in 94 65% 1 in 269 Ashkenazi 1 in 24 97% 1 in 800 Ashkenazi 1 in 165 95% 1 in 3,300 Dyskeratosis Congenita, RTEL1-related RTEL1 General <1 in 500 46% 1 in 926 Ashkenazi 1 in 187 96% 1 in 4,675 Ehlers-Danlos Syndrome Type VIIC ADAMTS2 General <1 in 500 80% 1 in 2,500 Ashkenazi 1 in 31 99% 1 in 3,100 ♦ Familial Dysautonomia IKBKAP General <1 in 500 10% 1 in 556 Ashkenazi 1 in 52 97% 1 in 1,733 ♦ Familial Hyperinsulinism: ABCC8-related ABCC8 Finnish 1 in 100 43% 1 in 175 Ashkenazi 1 in 89 99% 1 in 8,900 ♦ Fanconi Anemia Type C FANCC General 1 in 417 30% 1 in 596 Ashkenazi 1 in 58 95% 1 in 1,160 ♦* Fragile X Syndrome FMR1 General 1 in 250 95% 1 in 5,000 Caucasian 1 in 152 80% 1 in 760 ♦ Galactosemia, GALT-related GALT Ashkenazi 1 in 156 80% 1 in 780 General 1 in 112 80% 1 in 560 General 1 in 158 60% 1 in 395 ♦ Gaucher Disease GBA Ashkenazi 1 in 15 95% 1 in 300 Caucasian 1 in 177 69% 1 in 571 ♦ Glycogen Storage Disease 1a G6PC Ashkenazi 1 in 71 99% 1 in 7,100 Ashkenazi 1 in 110 95% 1 in 2,200 Joubert Syndrome 2 TMEM216 General <1 in 500 95% 1 in 10,000 Mennonite 1 in 10 99% 1 in 67 ♦ Maple Syrup Urine Disease Type 1a BCKDHA General 1 in 289 10% 1 in 482 Ashkenazi 1 in 97 99% 1 in 9,700 ♦ Maple Syrup Urine Disease Type 1b BCKDHB General 1 in 327 10% 1 in 363 Ashkenazi 1 in 107 87% 1 in 823 ♦ Maple Syrup Urine Disease Type 3 DLD General <1 in 500 60% 1 in 1,250 Ashkenazi 1 in 89 48% 1 in 171 ♦ Mucolipidosis Type IV MCOLN1 General <1 in 500 10% 1 in 556 Ashkenazi 1 in 279 95% 1 in 5,580 Multiple Sulfatase Deficiency SUMF1 General <1 in 500 18% 1 in 610 Ashkenazi 1 in 168 5% 1 in 177 ♦ Nemaline Myopathy NEB General 1 in 224 10% 1 in 249 Ashkenazi 1 in 115 97% 1 in 3,833 ♦ Niemann-Pick Disease, SMPD1-related SMPD1 General 1 in 196 20% 1 in 491 Ashkenazi 1 in 453 95% 1 in 9,060 Phosphoglycerate Dehydrogenase Deficiency, PHGDH-related PHGDH General <1 in 500 92% 1 in 6,250 Finland 1 in 70 60% 1 in 175 Polycystic Kidney Disease, Autosomal Recessive PKHD1 Ashkenazi 1 in 106 18% 1 in 129 General 1 in 144 19% 1 in 178 Retinitis Pigmentosa 59 DHDDS Ashkenazi
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