The median age was 33.0 years and mean age was 33.63 years. Most (n = 17,865) of the individuals were from 21–39 years of age. A small percentage was under 21 years (1.6%) or over 45 years (2.8%).
Disease carrier states
Alleles associated with 96 recessive diseases (excluding mild conditions) were identified in our 23,453 patients (Supplementary Table S1 online). Among the mild conditions, the most common was MTHFR deficiency, with a frequency of 1 in 1.9. Because these conditions typically have limited reproductive decision-making significance, they will not be considered further in this analysis. All subsequent analysis considers only those diseases listed in Supplementary Table S1online.
Of the total sample, 24.0% of individuals (n = 5,633) were heterozygous for at least one non-mild condition. A total of 7,067 heterozygous states were identified. Carrier statistics are fully reported in Supplementary Table S1 online.
Seventy-eight individuals were identified as homozygotes or compound heterozygotes for the following conditions: α-1-antitrypsin deficiency (n = 38), cystic fibrosis (n = 9), GJB2-related DFNB1 nonsyndromic hearing loss and deafness (n = 6), factor XI deficiency (n = 5), Gaucher disease (n = 4), familial Mediterranean fever (n = 3), carnitine palmitoyltransferase II deficiency (n= 2), medium chain acyl-CoA dehydrogenase deficiency (n = 2), sickle cell disease (n = 2), short chain acyl-CoA dehydrogenase deficiency (n = 2), achromatopsia (n = 1), β-thalassemia (n = 1), hexosaminidase A deficiency (n = 1), familial dysautonomia (n = 1), lipoamide dehydrogenase deficiency (n = 1), Niemann–Pick disease type C (n = 1), Pompe disease (n = 1), and spinal muscular atrophy (n = 1). The published specificity of the testing method suggests that these are “true positives” and merit further examination of clinical correlations.12 Review of clinical notes found at least two individuals with previously known diagnoses, for Gaucher disease and deafness. Another individual reported a history of sickle cell disease but did not specify whether this was familial or personal. All others did not report diagnosis information in their test requisitions and selected the routine carrier screening indication. For asymptomatic individuals with conditions such as α-1-antitrypsin deficiency, results could be used to guide appropriate surveillance.
Carrier rate variability by ethnicity
Frequencies of positive results varied by ethnic group (Table 1). On average, 24.0% of individuals were positive for at least one condition. When stratified by self-reported ethnicity, this frequency ranged from 43.6% of Ashkenazi Jewish individuals to 8.5% of East Asians. For ethnic groups like the Ashkenazi Jewish, this frequency is unsurprising given the availability of screening for many conditions found in this group.
Some individuals were heterozygous for multiple disorders (Table 2), with ~5.2% (n = 1,210) found to be carriers of two or more disorders. Most were heterozygous for only two conditions (4.3% of all screenees and 83.9% of multiple-disease carriers), although a small number were carriers of three (0.7 and 13.8%) or more than three conditions (0.1 and 2.3%). Ashkenazi Jewish individuals were most frequently identified as multiple carriers, with 13.3% of all tested Ashkenazi Jews carrying more than one genetic disorder. These values are unsurprising, as population geneticists have long known that individuals carry on average 4–5 recessive lethal alleles.10,15Put another way, the average number of positive results for recessive lethals in this panel is only (0 × 0.694 + 1 × 0.244 + 2 × 0.053 + 3 × 0.008 + 4 × 0.001) = 0.378; sequencing the entire genome of each patient would reveal ~10 times as many lethal recessives on average.
BRCA1 Hereditary Breast and Ovarian Cancer
Genetic testing is “the analysis of chromosomes (DNA), proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes.” It can provide information about a person‘s genes and chromosomes throughout life. Available types of testing include:
- Newborn screening: Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. A blood sample is collected with a heel prick from the newborn 24–48 hours after birth and sent to the lab for analysis. In the United States, newborn screening procedure varies state by state, but all states by law test for at least 21 disorders. If abnormal results are obtained, it does not necessarily mean the child has the disorder. Diagnostic tests must follow the initial screening to confirm the disease. The routine testing of infants for certain disorders is the most widespread use of genetic testing—millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental illness if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). People with PKU do not have an enzyme needed to process the amino acid phenylalanine, which is responsible for normal growth in kids and normal protein use throughout their lifetime. If there is a buildup of too much phenylalanine, brain tissue can be damaged, causing developmental delay. Newborn screening can detect the presence of PKU, allowing kids to get put on a special diet right away to avoid the effects of the disorder.
- Diagnostic testing: Diagnostic testing is used to diagnose or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical mutations and symptoms. Diagnostic testing can be performed at any time during a person’s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person’s choices about health care and the management of the disease. For example, people with a family history of polycystic kidney disease (PKD) who experience pain or tenderness in their abdomen, blood in their urine, frequent urination, pain in the sides, a urinary tract infection or kidney stones may decide to have their genes tested and the result could confirm the diagnosis of PKD.
- Carrier testing: Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition like cystic fibrosis.
- Preimplantation genetic diagnosis: Genetic testing procedures that are performed on human embryos prior to the implantation as part of an in vitro fertilizationprocedure. Pre-implantation testing is used when individuals try to conceive a child through in vitro fertilization. Eggs from the woman and sperm from the man are removed and fertilized outside the body to create multiple embryos. The embryos are individually screened for abnormalities, and the ones without abnormalities are implanted in the uterus.
- Prenatal diagnosis: Used to detect changes in a fetus‘s genes or chromosomes before birth. This type of testing is offered to couples with an increased risk of having a baby with a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them decide whether to abort the pregnancy. It cannot identify all possible inherited disorders and birth defects, however. One method of performing a prenatal genetic test involves an amniocentesis, which removes a sample of fluid from the mother’s amniotic sac 15 to 20 or more weeks into pregnancy. The fluid is then tested for chromosomal abnormalities such as Down syndrome (Trisomy 21) and Trisomy 18, which can result in neonatal or fetal death. Test results can be retrieved within 7–14 days after the test is done. This method is 99.4% accurate at detecting and diagnosing fetal chromosome abnormalities. Although there is a risk of miscarriage associated with an amniocentesis, the miscarriage rate is only 1/400. Another method of prenatal testing is Chorionic Villus Sampling (CVS). Chorionic villi are projections from the placenta that carry the same genetic makeup as the baby. During this method of prenatal testing, a sample of chorionic villi is removed from the placenta to be tested. This test is performed 10–13 weeks into pregnancy and results are ready 7–14 days after the test was done. Another test using blood taken from the fetal umbilical cord is percutaneous umbilical cord blood sampling.
- Predictive and presymptomatic testing: Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person’s chances of developing disorders with a genetic basis, such as certain types of cancer. For example, an individual with a mutation in BRCA1 has a 65% cumulative risk of breast cancer. Hereditary breast cancer along with ovarian cancer syndrome are caused by gene alterations in the genes BRCA1 and BRCA2. Major cancer types related to mutations in these genes are female breast cancer, ovarian, prostate, pancreatic, and male breast cancer. Li-Fraumeni syndrome is caused by a gene alteration on the gene TP53. Cancer types associated with a mutation on this gene include breast cancer, soft tissue sarcoma, osteosarcoma (bone cancer), leukemia and brain tumors. In the Cowden syndrome there is a mutation on the PTEN gene, causing potential breast, thyroid or endometrial cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder, help with making decisions about medical care and provide a better prognosis.
- Pharmacogenomics: type of genetic testing that determines the influence of genetic variation on drug response. When a person has a disease or health condition, pharmacogenomics can examine an individual’s genetic makeup to determine what medicine and what dosage would be the safest and most beneficial to the patient. In the human population, there are approximately 11 million single nucleotide polymorphisms (SNPs) in people’s genomes, making them the most common variations in the human genome. SNPs reveal information about an individual’s response to certain drugs. This type of genetic testing can be used for cancer patients undergoing chemotherapy. A sample of the cancer tissue can be sent in for genetic analysis by a specialized lab. After analysis, information retrieved can identify mutations in the tumor which can be used to determine the best treatment option.
Non-diagnostic testing includes:
- Forensic testing: Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).
- Paternity testing: This type of genetic test uses special DNA markers to identify the same or similar inheritance patterns between related individuals. Based on the fact that we all inherit half of our DNA from the father, and half from the mother, DNA scientists test individuals to find the match of DNA sequences at some highly differential markers to draw the conclusion of relatedness.
- Genealogical DNA test: To determine ancestry or ethnic heritage for genetic genealogy
- Research testing: Research testing includes finding unknown genes, learning how genes work and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers.
Many diseases have a genetic component with tests already available. This list is continuously changing with additions of new test availabilities. This list below is just a few of the thousands of tests available.
over-absorption of iron; accumulation of iron in vital organs (heart, liver, pancreas); organ damage; heart disease; cancer; liver disease; arthritis; diabetes; infertility; impotence
Obstructive lung disease in adults; liver cirrhosis during childhood; when a newborn or infant has jaundice that lasts for an extended period of time (more than a week or two), an enlarged spleen, ascites (fluid accumulation in the abdominal cavity), pruritus (itching), and other signs of liver injury; persons under 40 years of age that develops wheezing, a chronic cough or bronchitis, is short of breath after exertion and/or shows other signs of emphysema (especially when the patient is not a smoker, has not been exposed to known lung irritants, and when the lung damage appears to be located low in the lungs); when you have a close relative with alpha-1 antitrypsin deficiency; when a patient has a decreased level of A1AT.
- Apolipoprotein E-associated
Elevation of both serum cholesterol and triglycerides; accelerated atherosclerosis, coronary heart disease; cutaneous xanthomas; peripheral vascular disease; diabetes mellitus, obesity or hypothyroidism
Muscle weakness (rapidly progressive); frequent falls; difficulty with motor skills (running, hopping, jumping); progressive difficulty walking (ability to walk may be lost by age 12); fatigue; intellectual retardation (possible); skeletal deformities; chest and back (scoliosis); muscle deformities (contractures of heels, legs; pseudohypertrophy of calf muscles)
Reduced synthesis of the hemoglobin-beta chain; microcytic hypochromic anemia
Venous thrombosis; certain arterial thrombotic conditions; patients with deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, and premature ischemic stroke and also of women with premature myocardial infarction; family history of early onset stroke, deep vein thrombosis, thromboembolism, pregnancy associated with thrombosis/embolism, hyperhomocystinemia, and multiple miscarriage. Individuals with the mutation are at increased risk of thrombosis in the setting of oral contraceptive use, trauma, and surgery.
Venous thrombosis; pulmonary embolism; transient ischemic attack or premature stroke; peripheral vascular disease, particularly lower extremity; occlusive disease; cerebral vein thrombosis; multiple spontaneous abortions; intrauterine fetal demise
Venous thrombosis; increased plasma homocysteine levels
Independent risk factor for coronary artery disease, ischemic stroke, venous thrombosis (including osteonecrosis)
Breast, ovarian and prostate cancer
Uncontrolled division of cancer cells
Inflammation confined to the colon; abdominal pain and bloody diarrhea; anal fistulae and peri-rectal abscesses can also occur
Large amount of abnormally thick mucus in the lungs and intestines; leads to congestioni, pneumonia, diarrhea and poor growth
- Deafness (non-syndromic)
Congenital loss of hearing; -prelingual, non-syndromic deafness
Tendon xanthomas; elevated LDL cholesterol; premature heart disease
Predisposition of acute myeloid leukemia; skeletal abnormalities; radial hypoplasia and vertebral defect and other physical abnormalities, bone marrow failure (pancytopenia), endocrine dysfunction, early onset osteopenia/osteoporosis and lipid abnormalities, spontaneous chromosomal breakage exacerbated by exposure to DNA cross-linking agents.
Mental retardation or learning disabilities of unknown etiology; autism or autistic-like characteristics; women with premature menopause. Subtle dysmorphism, log face with prominent mandible and large ears, macroorchidism in postpubertal males, behavioral abnormalities, due to lack of FMR1 in areas such as the cerebral cortex, amygdala, hippocampus and cerebellum
Characterized by slowly progressive ataxia; typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration senses
over-absorption of iron; accumulation of iron in vital organs (heart, liver, pancreas); organ damage; heart disease; cancer; liver disease; arthritis; diabetes; infertility; impotence
Absence of ganglia in the gut
Progressive disorder of motor, cognitive, and psychiatric disturbances.
Hypolactasia; persistent diarrhea; abdominal cramps; bloating; nausea; flatus
MEN2A (which affects 60% to 90% of MEN2 families):Medullary thyroid carcinoma; Pheochromocytoma (tumor of the adrenal glands); Parathyroid adenomas (benign [noncancerous] tumors) or hyperplasia (increased size) of the parathyroid gland; MEN2B (which affects 5% of MEN2 families): Medullary thyroid carcinoma; Pheochromocytoma; Mucosal neuromas (benign tumors of nerve tissue on the tongue and lips); Digestive problems; Muscle, joint, and spinal problems; Typical facial features; Familial medullary thyroid carcinoma (FMTC) (which affects 5% to 35% of MEN2 families):Medullary thyroid carcinoma only
Affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system; clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital.
Pseudocholinesterase (also called butyrylcholinesterase or “BCHE”) hydrolyzes a number of choline-based compounds including cocaine, heroin, procaine, and succinylcholine, mivacurium, and other fast-acting muscle relaxants. Mutations in the BCHE gene lead to deficiency in the amount or function of the protein, which in turn results in a delay in the metabolism of these compounds, which prolongs their effects. Succinylcholine is commonly used as an anaesthetic in surgical procedures, and a person with BCHE mutations may suffer prolonged paraylasis. Between 1 in 3200 and 1 in 5000 people carry BCHE mutations; they are most prevalent in Persian Jews and Alaska Natives. As of 2013 there are 9 genetic tests available.
Variable degrees of hemolysis and intermittent episodes of vascular occlusion resulting in tissue ischemia and acute and chronic organ dysfunction; complications include anemia, jaundice, predisposition to aplastic crisis, sepsis, cholelithiasis, and delayed growth. Diagnosis suspected in infants or young children with painful swelling of the hands and feet, pallor, jaundice, pneumococcal sepsis or meningitis, severe anemia with splenic enlargement, or acute chest syndrome.
Lipids accumulate in the brain; neurological dysfunction; progressive weakness and loss of motor skills; decreased social interaction, seizures, blindness, and total debilitation
Cutaneous photosensitivity; acute neurovisceral crises