Clinical characteristics.

Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include recurrent sinusitis and bronchitis, progressive obstructive pulmonary disease with bronchiectasis, exocrine pancreatic deficiency and malnutrition, pancreatitis, gastrointestinal manifestations (meconium ileus, rectal prolapse, distal intestinal obstructive syndrome), liver disease, diabetes, male infertility due to hypoplasia or aplasia of the vas deferens, and reduced fertility or infertility in some women. Pulmonary disease is the major cause of morbidity and mortality in CF.

Diagnosis/testing.

The diagnosis of CF is established in a proband with:

• Elevated immunoreactive trypsinogen on newborn screen, signs and/or symptoms suggestive of CF, or family history of CF; AND
• Evidence of an abnormality in cystic fibrosis transmembrane conductance regulator (CFTR) function: sweat chloride ≥60 mmol/L on sweat chloride testing, biallelic CFTR CF-causing pathogenic variants, or nasal transmembrane epithelial potential difference measurement consistent with CF.

Management.

Treatment – targeted therapy: CFTR modulator therapy is available for individuals with responsive CFTR variants.

Treatment – supportive care: Newborns: management by a CF specialist or CF care center; airway clearance instruction; encouraging feeding with breast milk; routine vaccinations; contact precautions with every encounter; antibiotics for bacterial suppression and treatment; nutrition management; pancreatic enzyme replacement; nutrient-dense food and supplements; fat-soluble vitamin supplements; laxative treatment as needed with surgical management for bowel obstruction; and salt and water supplementation.

After the newborn period: airway clearance; pulmonary treatment (bronchodilator, hypertonic saline, dornase alfa, airway clearance, inhaled corticosteroids and/or long-acting beta agonist, and aerosolized antibiotic); standard treatments for pneumothorax or hemoptysis; double lung transplant for those with advanced lung disease; routine vaccinations including influenza; contact precautions; antibiotics for bacterial suppression and treatment; antibiotics and/or surgical intervention for nasal/sinus symptoms; nutrition management; pancreatic enzyme replacement; nutrient-dense food and supplements; fat-soluble vitamin supplements; laxative treatment as needed with surgical management for bowel obstruction; standard treatments for gastroesophageal reflux disease; oral ursodiol for biliary sludging/obstruction; liver transplant when indicated; management of CF-related diabetes mellitus by an endocrinologist; assisted reproductive technologies (ART) for infertility; salt and water supplementation; standard treatments for associated mental health issues.

Surveillance: Frequent assessment by a CF specialist to monitor for new or worsening manifestations; pulmonary function testing frequently after age five years; chest x-ray or chest CT examination to assess for bronchiectasis every two years or as needed; cultures of respiratory tract secretions at least every three months; non-tuberculosis mycobacterium culture and serum IgE annually or as indicated; annual CBC with differential; annual ENT assessment; monitoring growth and GI manifestations at each visit; fecal elastase as needed; annual serum vitamin A, D, E, and PT (as a marker of vitamin K); annual liver function tests; annual random glucose, annual two-hour glucose tolerance test beginning at age ten years; DXA scan as needed in adolescence; infertility assessment as needed; annual electrolytes, BUN, and creatinine; annual assessment of depression and anxiety.

Agents/circumstances to avoid: Environmental smoke, exposure to respiratory infections, dehydration.

Evaluation of relatives at risk: Molecular genetic testing of at-risk sibs (if the pathogenic variants in the family are known) or sweat chloride testing of at-risk sibs (if the pathogenic variants in the family are not known) to identify as early as possible those who should be referred to a CF center for initiation of early treatment.

Genetic counseling.

CF is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CFTR pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the CFTR pathogenic variants have been identified in an affected family member, targeted heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing for CF are possible.

Suggestive Findings

Scenario 1: Abnormal newborn screening (NBS) result

• NBS for CF is based on quantification of immunoreactive trypsinogen (IRT) and subsequent molecular testing including either CFTR targeted analysis or sequence analysis on dried blood spots.
• Elevated IRT values with or without the presence of CFTR pathogenic variants are considered out of range and require diagnostic sweat chloride testing.

Scenario 2: Symptomatic individual not diagnosed during the newborn period. NBS was not universal in the United States until 2010; individuals not diagnosed following NBS may have: (1) been born prior to NBS implementation; (2) not had NBS for other reasons; (3) had a false negative NBS result; or (4) had caregivers who did not follow up with recommended diagnostic testing after abnormal NBS.

Suggestive clinical and laboratory findings in symptomatic individuals include:

• Clinical findings [Rosenfeld et al 2016]
  • Sinopulmonary: chronic wet or productive cough, recurrent pneumonia, bronchiectasis, nasal polyposis
  • Musculoskeletal: digital clubbing
  • Infectious: respiratory infection with Pseudomonas aeruginosa or other atypical gram-negative organisms, allergic bronchopulmonary aspergillosis
  • Nutritional/metabolic: poor weight gain, growth deficiency
  • Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
  • Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome, steatorrhea
  • Hepatic: protracted neonatal jaundice, biliary cirrhosis
  • Genitourinary: obstructive azoospermia
• Laboratory findings
  • Hyponatremia, hypochloremia, hypokalemia, hypoproteinemia, chronic metabolic alkalosis
  • Deficiency of fat-soluble vitamins (vitamins A, D, E, and K)

Establishing the Diagnosis

The diagnosis of CF is established in a proband with one of the following:

• Positive newborn screen (NBS) for CF (elevated immunoreactive trypsinogen [IRT])
• Signs and/or symptoms suggestive of CF (See Suggestive Findings.)
• Family history of CF in a first-degree relative (typically a sib)

AND one of the following:

• Elevated sweat chloride value ≥60 mmol/L on sweat chloride testing
• Identification of biallelic CFTR CF-causing pathogenic (or likely pathogenic) variants on molecular genetic testing
• Nasal transmembrane epithelial potential difference measurement consistent with CF (See Nasal Transmembrane Epithelial Potential Difference.)

Note: (1) A sweat chloride value ≥60 mmol/L establishes the diagnosis; however, an intermediate sweat chloride of 30-59 mmol/L should prompt further evaluation with a CF specialist. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) Identification of biallelic CFTR variants of uncertain significance (or of one known CF-causing CFTR variant and one CFTR variant of uncertain significance) does not establish or rule out the diagnosis (see Nasal Transmembrane Epithelial Potential Difference).

Clinical Description

Cystic fibrosis (CF) affects the epithelia in several organs resulting in a complex, multisystem disease primarily involving the respiratory, gastrointestinal, genitourinary, and endocrine systems and the sweat glands.

Heterozygotes

Individuals with bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, atypical mycobacterial infections, and aquagenic palmoplantar keratoderma are more likely to be heterozygous for a CFTR pathogenic variant [Hsu et al 2013, Gamaletsou et al 2018, Raynal et al 2019, Çolak et al 2020, Izquierdo et al 2022]. Approximately 15% of individuals with acute recurrent pancreatitis (24/155 individuals) or chronic pancreatitis (22/146 individuals) were heterozygous for a CFTR pathogenic variant [Kumar et al 2016].

Genotype-Phenotype Correlations

The Clinical and Functional Translation of CFTR website provides genotype-phenotype information for CFTR pathogenic variants including sweat chloride, lung function, pancreatic status, and pseudomonas infection rates.

The strongest genotype-phenotype correlations have been identified in the context of pancreatic function. The most common CFTR pathogenic variants have been classified as pancreatic sufficient (PS) or pancreatic insufficient (PI). Individuals who are PS usually have one or two PS alleles, indicating that PS alleles are dominant with respect to pancreatic phenotype [Rueda-Nieto et al 2022].

Beyond pancreatic function, genotype does not consistently predict phenotype. Pulmonary disease severity varies widely among individuals with identical genotypes (see Molecular Genetics, Genetic Modifiers).

CFTR pathogenic variants associated with protein trafficking, channel gating, and channel conductance have approved targeted therapies. See Table 5a and Jia & Taylor-Cousar [2023].

Prevalence

CF affects at least 100,000 individuals worldwide, with 40,000 individuals in the US [Guo et al 2022]. CF affects individuals of all ages, with more than 50% of people with CF in the US being older than age 18 years [Cystic Fibrosis Foundation Patient Registry 2020].

The incidence of CF is increased in several populations (e.g., Amish, Ashkenazi Jewish, Hutterite) due to the presence of pathogenic founder variants (see Table 7). However, CF occurs in individuals of all ethnicities.

Other Disorders

Primary dysphagia with chronic descending tracheal aspiration and primary gastroesophageal reflux (GER) with or without ascending tracheal aspiration. Both conditions can cause chronic cough in infancy and may be associated with poor weight gain and growth deficiency. However, in infants with primary dysphagia or primary GER, the cough is often temporally associated with feedings; steatorrhea is not associated with primary dysphagia or primary GER.

Asthma. CF and asthma both present with chronic cough and persistent wheeze following respiratory viral infections, allergen exposure, or exertion. However, individuals with asthma typically improve on asthma therapy, do not experience recurrent pneumonia, are not colonized with CF-related bacteria, have normal growth and weight gain, and do not have steatorrhea.

Congenital airway anomalies, like CF, can cause chronic cough and wheezing during infancy. Gastrointestinal or nutritional manifestations that are typically present in infants with CF are not seen in children with congenital airway anomalies.

Primary biliary atresia. Rarely, individuals with CF may present in infancy with symptoms of biliary obstruction without other clinically apparent GI or respiratory manifestations. Serum levels of immunoreactive trypsinogen and stool levels of elastase should be normal in infants with primary biliary atresia, whereas CF liver disease is invariably associated with evidence of pancreatic duct obstruction.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a newborn diagnosed with cystic fibrosis (CF), the evaluations summarized in Table 4a (if not performed as part of the evaluation that led to the diagnosis) are recommended. For those individuals diagnosed after the newborn period, the evaluations summarized in Table 4b are recommended [Borowitz et al 2009b, Lahiri et al 2016].

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations, partnership with a CF specialist is critical in addition to the following recommended surveillance.

Agents/Circumstances to Avoid

Avoid the following:

• Environmental smoke
• Exposure to respiratory infections
• Dehydration

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband and at-risk relatives to identify as early as possible those who should be referred to a CF center for initiation of treatment.

Evaluations can include the following:

• If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
• If the pathogenic variants in the family are not known, sweat chloride testing can be used to clarify the disease status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with CF tolerate pregnancy well. Key factors for an optimal pregnancy include nutrition management, pulmonary clearance treatments, aggressive management of infections, and treatment by a multidisciplinary care team, especially in women with mild-to-moderate disease [Shteinberg et al 2021]. In all studies published to date, the most important predictors of pregnancy outcome are the severity of maternal pulmonary impairment and nutritional status. Women with more severe disease, such as cystic fibrosis-related diabetes (CFRD) and poor pulmonary function (FEV1 <50% predicted) should undergo pregnancy with caution [Taylor-Cousar 2020]. Increased rates of pulmonary exacerbations can be observed, and deterioration during pregnancy may precipitate preterm delivery [Shteinberg et al 2021]. Additionally, case reports of women with Burkholderia cepacia have been associated with more rapid rates of lung function decline during pregnancy [Jain et al 2022]. Pregnancy is not associated with long-term negative effects on pulmonary and nutritional outcomes or an increased risk of death [Schechter et al 2013, Taylor-Cousar 2020].

Preconception

• Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy.
• Maternal and fetal complications are high in women with CF who have received lung transplantation. Open and extensive discussions should be held between the transplant recipient and her care team prior to conception [Jain et al 2022].
• As in pregnancies of women with other forms of diabetes mellitus, fetal outcome is optimized when glycemic control is achieved prior to pregnancy.

During pregnancy

• The management of pregnancy and the immediate postpartum period for a woman with CF requires a maternal fetal medicine specialist, CF pulmonologist, dietician, and other members of the CF team [Jain et al 2022].
• Special attention should also be paid to supplementation of the fat-soluble vitamin A during pregnancy, as supratherapeutic levels may be teratogenic. Iron and folate supplementation recommendations in pregnant women with CF are similar to those in women without CF [Jain et al 2022].
• While there are no concerning signals in animal reproductive models for CFTR modulator therapy, human data are currently limited to case reports and physician surveys [Nash et al 2020, Taylor-Cousar 2020]. Risks and benefits of continuing CFTR modulator therapy during pregnancy should be discussed with a CF specialist [Taylor-Cousar 2020]. The multicenter prospective observational study entitled Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS; NCT04828382) is currently enrolling subjects to further address the effect of CFTR modulators on pregnancy and postpartum outcomes.
• Maternal nutritional status and weight gain should be monitored and optimized aggressively, and pulmonary exacerbations should be treated early.
• Gestational diabetes is common in pregnancies of women with CF. Traditional screening paradigms for gestational diabetes mellitus may not be useful in pregnancies of women with CF; therefore, screening at each trimester of pregnancy has been suggested to improve the detection of diabetes mellitus [Jain et al 2022]. Insulin is the first-line agent for glycemic control in CFRD and in gestational diabetes in women with CF [Jain et al 2022].

Delivery

• Mode of delivery is based on usual obstetric indications, with vaginal delivery being the most common mode of delivery in women with CF [Shteinberg et al 2021].
• During the postpartum period, it is important to support early mobilization and maintain good airway clearance practices, which can continue to be challenging with the demands of childcare [Taylor-Cousar 2020, Shteinberg et al 2021]. Adequate pain management and airway clearance must also be a focus for women who deliver by cæsarean section.

Breastfeeding

• Review medications for risk of transfer in breast milk. Most medications used in the long-term management of CF are considered safe. The major exceptions to this are immunosuppressants (importantly, in transplant recipients), azoles, and tetracyclines. Animal reproductive models have shown the presence of modulators in the breast milk of lactating animals [Taylor-Cousar 2020].
• Women with CF will need to consider the choice of breastfeeding based on the ability to maintain weight in the face of the high caloric demands associated with breastfeeding and the need to resume medications that may be transferred to the infant through breast milk [Taylor-Cousar 2020].

Therapies Under Investigation

Therapeutic interventions for CF are continually evolving (see cff.org). Restoration of CFTR function continues to advance with improved modulators and gene therapy. Modulator therapy studies include using approved medications in individuals of younger ages and testing new modulators, once-daily dosing, and new combination therapies.

Therapies under study that focus specifically on the approximately 10% of individuals who are not eligible for current therapy due to nonsense or rare variants that do not produce any CFTR protein include read-through agents and gene therapy. Read-through agents are particularly interesting as a treatment for those with nonsense variants. Gene therapy is an area of active research, ranging from DNA based (both integrating and nonintegrating), RNA therapy, gene editing (such as CRISPR), and antisense oligonucleotide therapy.

The Infection Research Initiative from the Cystic Fibrosis Foundation is investigating a range of topics, including understanding CF-specific microorganisms, improving diagnosis and detection, optimizing current treatment, developing new antimicrobials, and evaluating the long-term effects of antimicrobial use. One exciting area of infection research related to bacteriophage therapy is the use of viruses to target difficult-to-treat bacteria.

Many other areas of CF research are also under way, such as mucociliary clearance modalities, anti-inflammatory agents, and nutritional treatments.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Cystic fibrosis (CF) is inherited in an autosomal recessive manner.

Risk to Family Members of a Proband with CF

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a CFTR pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a CFTR pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband not detected by sequence analysis that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [Hsu et al 2013, Gamaletsou et al 2018, Raynal et al 2019, Çolak et al 2020, Izquierdo et al 2022, Polgreen & Comellas 2022]. (See Clinical Description, Heterozygotes.)

Sibs of a proband

• If both parents are known to be heterozygous for a CFTR pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes are at increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis [Hsu et al 2013, Gamaletsou et al 2018, Raynal et al 2019, Çolak et al 2020, Izquierdo et al 2022, Polgreen & Comellas 2022]. (See Clinical Description, Heterozygotes.)

Offspring of a proband

• An individual with CF will transmit a CFTR pathogenic variant to all offspring. The risk that offspring will inherit a second CFTR pathogenic variant depends on the genetic status of the reproductive partner.
• If the reproductive partner of a proband is heterozygous for a CFTR pathogenic variant, offspring are at a 50% risk of being affected and a 50% risk of being heterozygous.
• It is appropriate to offer carrier testing to the reproductive partner of an individual with CF (see Population Screening).
  Note: While CF occurs in individuals of all ethnicities, the incidence of CF is increased in several populations (e.g., Amish, Ashkenazi Jewish, Hutterite) due to the presence of pathogenic founder variants (see Table 7).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CFTR pathogenic variant.

Heterozygote Detection

Targeted heterozygote testing for at-risk relatives requires prior identification of the CFTR pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of carrier testing, potential risks to offspring, and reproductive options) to young adults who are affected, are carriers (heterozygotes), or are at risk of being carriers.
• Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy (see Pregnancy Management).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Population Screening

Carrier screening for CF is offered to all women who are pregnant.

Per NSGC Practice Guidelines, carrier (heterozygote) testing for CF should also be offered preconceptionally to women of all ancestries who are of reproductive age, to the reproductive partners of individuals who are heterozygous for a CFTR pathogenic variant or who are affected with CF, and to family members of an individual with CF.

A core panel of 23 CFTR pathogenic variants has been recommended by the ACMG for pan ethnic targeted carrier screening. Comprehensive CF testing can also be considered for pan ethnic carrier screening, particularly for individuals of non-northern European descent [Deignan et al 2020].

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancies. Once the CFTR pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for CF are possible [Kessels et al 2020].

Note: Noninvasive prenatal testing for CF is also becoming more common.

Low-risk pregnancies. The finding of fetal echogenic bowel and/or intestinal loop dilatation and nonvisualization of the fetal gallbladder (NVFGB) on ultrasound examination is associated with an increased risk for CF in a pregnancy previously not known to be at increased risk for CF. The risk for CF ranges from 0.5% to 9.9% in fetuses with hyperechogenic bowel [Ameratunga et al 2012, Masini et al 2018, D'Amico et al 2021]. Fetuses with NVFGB and associated anomalies have a 16-fold higher risk for CF [Di Pasquo et al 2019]. In this situation, genetic counseling of the parents regarding the risk for CF is appropriate, followed by CFTR molecular genetic testing of the parents and/or the fetus, depending on the gestational age of the pregnancy and the decision of the parents.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CFTR encodes cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein that functions as a regulated chloride channel located at the apical membrane of epithelia, transporting chloride ions into and out of cells. Once chloride is transported out of the cell, sodium will join, forming sodium chloride (salt), which attracts water. CFTR maintains the balance of salt and water. CFTR is important in many organs, most specifically the respiratory, gastrointestinal, genitourinary, and endocrine systems and the sweat ducts.

Loss-of-function CFTR variants disrupt transepithelial chloride transport. Without chloride, sodium will not form salt and water will not be attracted. In most organs, this leads to excessively thick secretions and tissue damage. For example, in the lungs, thick mucus is an excellent milieu for bacteria, which the body attempts to fight with inflammation, leading to the vicious cycle of mucus production, infection, inflammation, and pulmonary damage (e.g., bronchiectasis). In the pancreas, thick secretions block the exocrine pancreatic ducts, preventing passage of pancreatic enzymes and creating pancreatic insufficiency. Secretion blockage causes pathology in many organs (e.g., liver disease, infertility/subfertility, bowel obstruction, pansinusitis).

The CFTR chloride channel is unique in the sweat glands, as it is reversed. In a person unaffected by CF, the CFTR chloride channel in sweat glands helps to reabsorb chloride (and thus salt and water). In people with CF, the channel is not functional, chloride is not reabsorbed, and the sweat is salty (resulting in an abnormal sweat test).

Mechanism of disease causation. Loss of function

CFTR-specific laboratory technical considerations. Intronic variants including the poly T and poly TG tract in intron 8, c.2657+5G>A, and c.3718-2477C>T are included in the ACMG 23-variant panel. Deep intronic variants are not typically detected by exome sequencing. If deep intronic variants are not detected by the laboratory's methodology, additional testing to identify these variants should be performed [Deignan et al 2020].

Genetic Modifiers

CFTR poly T tract. A poly T tract, a string of thymidine bases located in intron 8 of CFTR, can be associated with CFTR-related disorders depending on its size. The three common variants of the poly T tract are 5T, 7T, and 9T. Both 7T and 9T are benign variants, and 5T is a variably penetrant variant. The 5T variant is predicted to decrease the efficiency of intron 8 splicing, such that approximately 50% of full-length CFTR is produced (compared to almost 75% of full-length CFTR in those with 7T and 9T alleles) [Nykamp et al 2021]. The 5T variant is further modified by the TG tract.

CFTR poly TG tract. A TG tract lies just 5' of the poly T tract. It consists of a short string of TG (thymidine-guanine) repeats that commonly number 11, 12, or 13. The number of TG repeats modulate phenotype in individuals with a 5T allele. Individuals with a longer TG tract (12 or 13 TG repeats) in cis with a shorter poly T tract (5T) have a full-length CFTR reduction to approximately 25%, which has the strongest adverse effect on proper intron 8 splicing [Salinas et al 2016, Nykamp et al 2021].

Acknowledgments

The authors would like to acknowledge the Cystic Fibrosis Foundation and most importantly all of the people with CF and their families who have contributed to improving care for those with CF.

Author History

Christine Bojanowski, MD, MSCR (2022-present)
Edith Cheng, MS, MD; University of Washington School of Medicine (2001-2022)
James F Chmiel, MD; Case Western Reserve University School of Medicine (2008-2017)
Garry R Cutting, MD; Johns Hopkins University School of Medicine (2001-2022)
Ronald L Gibson, MD, PhD; University of Washington (2001-2008)
Barbara A Karczeski, MS, CGC, MA; Johns Hopkins University School of Medicine (2017-2022)
Benjamin Lyman, DO (2022-present)
Susan G Marshall, MD; Seattle Children's Hospital (2001-2004; 2017-2022)
Samuel M Moskowitz, MD; Massachusetts General Hospital (2004-2017)
Thida Ong, MD; Seattle Children's Hospital (2017-2022)
Adrienne Savant, MD, MS (2022-present)
Darci Sternen, MS, LGC; Seattle Children's Hospital (2001-2022)
Jonathan F Tait, MD, PhD; University of Washington (2001-2004)
Jariya Upadia, MD (2022-present)

Revision History

• 9 March 2023 (aa) Revision: Targeted Therapy linked as a Key Section
• 10 November 2022 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 19 February 2008 (me) Comprehensive update posted live
• 24 August 2005 (cd) Revision: changes to ACMG-recommended mutation panel
• 24 August 2004 (me) Comprehensive update posted live
• 26 March 2001 (me) Review posted live
• 6 October 1998 (jt) Original submission

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• Barben J, Castellani C, Munck A, Davies JC, de Winter-de Groot KM, Gartner S, Kashirskaya N, Linnane B, Mayell SJ, McColley S, Ooi CY, Proesmans M, Ren CL, Salinas D, Sands D, Sermet-Gaudelus I, Sommerburg O, Southern KW, et al. Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros. 2021;20:810-9. [PubMed]
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• Sosnay PR, Salinas DB, White TB, Ren CL, Farrell PM, Raraigh KS, Girodon E, Castellani C. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses. J Pediatr. 2017;181S:S27-S32.e1. [PubMed]
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