diagnosis of CF may be delayed . Sometimes , CF diagnosis may be delayed despite classical symptoms , significant lung disease , and pancreatic insufficiency . In addition , clinicians may have a less suspicion of CF since CFNBS is practiced extensively . This article will discuss CFTR mutations , genotype and phenotype relationship , and modulators of CFTR gene expression . Then , briefly CFNBS will be reviewed .
CFTR Mutations and Disease Heterogeneity in CF
Currently , there are more than 2000 CFTR mutations described ; however , only 85 % of the identified genetic variants are associated with the disease ( www . cftr2 . org ). CFTR mutations are classified into five classes according to their effects on molecular mechanism and functional CFTR protein production . 4 Class I-III mutations result in either no CFTR protein production , truncated protein that is destroyed before reaching the cell membrane , or non-functional protein at the cell surface . In class IV and V mutations , while full length CFTR is located at the cell surface , either its conductance or amount would be insufficient . 5 Since there will be some functioning CFTR protein at the cell surface , Class IV and V mutations are mild mutations associated with pancreatic sufficiency . Recently , the Clinical and Functional Translation of CFTR initiative ( www . CFTR2 . org ) was established to determine the clinical and functional impact of various CFTR mutations .
Genotype-phenotype Relationship and Modifiers of CFTR Function
The heterogeneity of the CF phenotype within the same mutation suggests that there are more factors involved in the determination of clinical phenotype than CFTR genotype alone . Although class I-III CFTR mutations are associated with pancreatic insufficiency and significant lung disease , individuals with these mutations show a high degree of variability in disease severity , complications , and survival . 4 For example , the F508del mutation , the most common CFTR mutation , is mostly associated with severe clinical phenotype . However , observations have shown that F508del phenotype can be variable , even in the same family and between siblings .
A recent Canadian report showed that 362 individuals received a diagnosis of CF as adults between 1990 and 2014 . Median age at the diagnosis was 34.3 years , and these individuals had milder disease . Around 5 % of 362 individuals were found to be homozygous for the F508del mutation , highlighting the heterogeneity in phenotype for this genotype . 2 Variability in CF lung disease even among siblings who have identical mutations was supported by a study of a pair of dizygotic twins with compound CFTR genotypes . 5 Although both twins had pancreatic insufficiency , the severity of the pulmonary disease varied considerably : while one twin had chronic P . aeruginosa infection with significant lung disease , the other twin had normal lung functions without chronic respiratory infection . 5 A European twin study demonstrated that monozygotic twins had a significantly higher concordance in severity of lung disease than did dizygotic twins , suggesting a strong genetic contribution to variability in severity of CF lung disease . A U . S . twins study also confirmed these observations , as long as twins lived in the same environment . 5
Researchers have investigated several genes with respect to pulmonary CF disease modifiers . These potential gene modifiers include polymorphism in the promoter region of the tumor necrosis factor α gene , polymorphism in the transforming growth factor β gene , and variant alleles of mannose binding lectin . 5 Functional CFTR gene expression is controlled by transcriptional , post-transcriptional , translational and post-translational regulatory mechanisms . Therefore , CFTR gene expression can also be modulated through mechanisms such as epigenetic changes that also may influence CFTR expression in different tissues . 6
Although CF prevalence varies in different ethnicities , it should be noted that no ethnic group is protected from the disease . 7 CF is quite rare in Asian populations , and an epidemiological study of the Japanese population found the incidence of CF to be about 1 in 350,000 . In China , there are no epidemiological statistics regarding incidence of this disease and there have been only 36 cases reported today , excluding our patient ( case # 2 ). 8 Since CF is extremely rare in Chinese individuals , our patient ’ s parents refused to acknowledge that their child had CF .
CF Diagnosis
Arkansas initiated CFNBS in July 2017 . By 2010 , all 50 states and the District of Columbia had passed legislation requiring that all newborns be screened for CF . Although there are differences between countries and even in the U . S . regarding CFNBS protocols , there are essentially three steps ( tiers ) involved :
• IRT : Measuring immunoreactive trypsinogen ( IRT ) level from Guthrie cards is the first step of CFNBS . IRT screening is performed by state health departments ; if this initial screening is abnormal , then the second tier is proceeded . 7
• DNA Mutation Analysis : Most CF- NBS protocols utilize analysis of a panel of CF-causing mutations based on the population genetics . If this limited panel identifies at least one CFTR mutation , then the screening is considered “ positive ” and infants are subjected to sweat chloride testing .
• Sweat chloride testing : Following the positive CFNBS , infants undergo sweat testing at CF Foundation accredited laboratories . Although molecular analysis of CFTR gene is useful in confirming the diagnosis , quantitative analysis of sweat Cl- concentration has been the gold standard for the diagnosis of CF . 1 , 7 CF is diagnosed when sweat Cl- level is > 60 mmol / L . Until recently , negative sweat Cl- concentration cut off level was different between adults and infants : Negative sweat Cl- level was < 30 mmol / L in infants up to 6 months of age and < 40mmol / L in individuals > 6months old ( 22 ). In 2017 , CFF consensus guideline has changed the definition of negative sweat test to Cl- levels < 30 mmol / L in any age group . 1 , 7
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