ABC35; ABCC7; CF; CFTR; MRP; MRP7; TNR-CFTR; dJ760C5.1
The CFTR gene is associated with autosomal recessive cystic fibrosis (MedGen UID: 41393) and congenital bilateral absence of the vas deferens (CBAVD) (MedGen UID: 98021). Additionally, the CFTR gene is associated with an increased risk for chronic pancreatitis (PMID: 17003641, 11729110).
Order this gene as a single gene test.
CFTR: Analysis includes the intronic variants: NM_000492.3:c.3718-2477C>T (also known as 3849+10kbC>T), c.1210-34TGT (also known as T5TG12), c.1210-34TGT (also known as T5TG11), and c.1679+1634A>G.
Invitae tests that include this gene:
CFTR: Analysis includes the polymorphic TG/T tract within intron 9 as well as known promoter, 5’ UTR, 3’UTR, and intronic HGMD variants (including, but not limited to, c.3718-2477C>T, also known as 3849+10kbC>T and c.3717+12191C>T in the literature). Variants in these regions will be interpreted and only reported if classified as likely pathogenic or pathogenic. Polymorphisms and uncertain variants will be reported upon request.
The CFTR gene provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports negatively charged particles called chloride ions into and out of cells. The transport of chloride ions helps control the movement of water in tissues, which is necessary for the production of thin, freely flowing mucus. Mucus is a slippery substance that lubricates and protects the lining of the airways, digestive system, reproductive system, and other organs and tissues. The CFTR protein also regulates the function of other channels, such as those that transport positively charged particles called sodium ions across cell membranes. These channels are necessary for the normal function of organs such as the lungs and pancreas.
The CFTR gene is associated with autosomal recessive cystic fibrosis (MedGen UID: 41393). Other CFTR-related disorders include congenital bilateral absence of the vas deferens (CBAVD; MedGen UID: 98021) and an increased risk for pancreatitis (PMID: 17003641, 11729110).
Cystic fibrosis (CF) is characterized by the buildup of mucus that can damage the digestive, respiratory, and reproductive systems (PMID: 10872417). The severity of CF ranges from mild to severe and there is significant variability in presentation, even within a family (PMID: 10872417, 12124743, 19106752). Symptoms include chronic cough, recurring chest colds, wheezing, shortness of breath, recurring sinus infections, excessive sweating, and poor growth. In classic CF, symptoms begin in early childhood, with average life expectancy in the 40s. As the disease progresses, mucus buildup and recurring infections lead to irreparable lung damage and pulmonary complications, which are considered to be the primary cause of mortality (Cystic Fibrosis Foundation. www.cff.org. Accessed January 29, 2018). In addition to pulmonary disease, around 80-90% of individuals with classic CF have pancreatic insufficiency, which causes digestive problems, malnutrition, and poor growth (PMID: 27878805). Other symptoms include meconium ileus at birth (~20% of affected newborns), diabetes (20% of adolescents; 40-50% of adults), liver disease (5-10% of affected individuals in the first decade of life), and male infertility (>95% of affected males; PMID: 28986020,19542209, 21658639, 29216686).
In mild cases of CF, symptoms may present later in life, with less severity, and may not impact life expectancy (PMID: 16217177).
CBAVD is associated with male infertility and refers to bilateral hypoplasia or aplasia of the vas deferens and seminal vesicles. Men are typically azoospermic but have normal testicular function and spermatogenesis, and are therefore able to have biological children with assisted reproductive technology (PMID: 21658649).
Hereditary pancreatitis is characterized by recurring episodes of acute inflammation of the pancreas beginning in childhood or adolescence and leading to chronic pancreatitis. The clinical presentation is highly variable and may include chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, and diabetes (PMID:17204147). Pathogenic variants in CFTR may confer an approximately four- to ten-fold increased risk for chronic pancreatitis in heterozygous carriers. Other genetic and environmental risk factors are also known to modify this risk (PMID: 22942235, 9219780, 18059268, 18172691, 20977904, 21520337, 11729110). Chronic pancreatitis is a risk factor for pancreatic cancer (PMID: 25170203).
The CFTR gene, located on chromosome 7, encodes the cystic fibrosis transmembrane (CFTR) conductance regulator. This protein functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports negatively-charged chloride ions into and out of cells, which helps to control the movement of water in tissues, and is necessary for the production of thin, freely flowing mucus lining the airways, digestive system, reproductive system, and other organs and tissues. The CFTR protein also regulates the function of other channels, such as those that transport positively-charged sodium ions, which are necessary for the normal function of various organs (e.g., the lungs and pancreas). Variants in CFTR can cause the absence of the protein or a protein that doesn’t function properly (PMID:10454765, 10773783).
Cystic fibrosis and CBAVD exhibit autosomal recessive inheritance, and the affected individuals have two pathogenic variants-one in each copy of their CFTR genes. Affected individuals will pass one pathogenic CFTR variant to all of their children. For partners who each carry a pathogenic variant in CFTR, the risk of having have an affected child is 25% (per pregnancy).
The increased risk for hereditary pancreatitis follows an autosomal dominant pattern of inheritance. This means that an individual with a single pathogenic variant has a 50% chance of passing along that variant and the increased disease risk to their offspring.
Family members of individuals with pathogenic CFTR variants may consider genetic testing, as they may be carriers as well.
Management of affected individuals
While there is currently no cure for CF, early treatment can improve quality of life and increase life expectancy. Individuals with CF should be followed by a multi-disciplinary CF Foundation Accredited Care Center for monitoring and treatment. Symptom-specific and age-related management guidelines have been established (PMID: 17761616, 19914443, 19914445, 20675678, 27009033, 26452630, 26453627, 29106796, 29342367).
Treatments include nutritional supplements and respiratory therapies primarily focused on managing symptoms. Treatment is initiated upon diagnosis, and new prophylactic treatment options are continually evolving (PMID: 24932877, 29264936).
Additional treatment may include:
Monitoring recommendations include quarterly visits for physical exam and testing, including respiratory cultures, pulmonary function, liver function, radiographs, chest CTs, and various blood tests (PMID 27009033). Psychiatric evaluation annually is also recommended to check for depression and anxiety. (PMID: 26452630).
Additionally, affected individuals should avoid respiratory irritants (such as cigarette smoke), dehydration, and close contact with individuals with respiratory infections (PMID: 27009033). Family members and caregivers should also receive annual influenza vaccination (PMID: 27009033).
Management for carriers
Treatment for hereditary pancreatitis primarily focuses on pain management, maldigestion, and monitoring for diabetes and pancreatic cancer (PMID: 27555793). Adhering to a low-fat diet, eating small and frequent meals, taking enzyme supplements, keeping hydrated, and avoiding alcohol and smoking are advised (PMID: 27555793). In some cases, surgery (including total pancreatectomy with islet autotransplantation) may be warranted (PMID: 24555976). Specific recommendations exist for the treatment of pancreatic diabetes (PMID: 23890130).
Carriers are also at an increased risk of having a child affected with CF. For those of reproductive age, partners of known carriers should consider genetic testing to determine their reproductive risk. Around 1 in 31 people in the US are carriers of CF (Cystic Fibrosis Foundation. www.cff.org. Accessed January 29, 2018); however, this risk varies slightly based on ethnicity. Reproductive options are available for at-risk carrier couples, including prenatal diagnosis, IVF with preimplantation genetic diagnosis (PGD), gamete donation, and adoption. Additionally, newborn screening for CF is available in every state.
Review date: January 2018
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
*CFTR: Analysis includes the intronic variants: NM_000492.3:c.3718-2477C>T (also known as 3849+10kbC>T), c.1210-34TGT (also known as T5TG12), c.1210-34TGT (also known as T5TG11), and c.1679+1634A>G.