ClinVar Genomic variation as it relates to human health

In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to deletion of phenylalanine at codon 508 (delta-F508). The exon in which the delta-F508 mutation occurs has been corrected to exon 11; see, e.g., Sharma et al. (2014). The European Working Group on CF Genetics (1990) published information on the distribution of the delta-F508 mutation in Europe. The data, illustrated with a useful map, indicated a striking cline across Europe from low values of 30% in the southeast (in Turkey) to high values in the northwest (e.g., 88% in Denmark). The group suggested that the spread of the CF gene might have accompanied the migrations of early farmers starting from the Middle East and slowly progressing toward the northwest of Europe. The diffusion of the gene may have been favored by the selective advantage conferred by the gene. Strong association with the so-called haplotype B was demonstrated. The possibility of 'hitchhiking,' i.e., the influence of neighboring genes was discussed. Rozen et al. (1990) found the delta-F508 mutation in 71% of CF chromosomes from urban Quebec province French Canadian families, 55% of those from Saguenay-Lac-Saint-Jean region families and in 70% of those from Louisiana Acadian families. De Braekeleer (1991) estimated that the frequency at birth of cystic fibrosis is 1/926 in the Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the same region, Daigneault et al. (1991) reported a prevalence of CF at birth of 1/902 liveborns, and a carrier rate of 1/15. Rozen et al. (1992) found that the delta-F508 mutation was present in 58% of Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site mutation after codon 621 being found in 23%, and the A455E mutation (602421.0007) in 8%. The latter 2 mutations were not found in urban Quebec families. This provided further evidence of the role of founder effect. Among 293 patients, Kerem et al. (1990) found that those who were homozygous for the F508 deletion had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency. Pancreatic insufficiency was present in 99% of the homozygous patients, 72% of those heterozygous for the deletion, and only 36% of patients with other mutations. Wauters et al. (1991) studied the frequency of the delta-F508 mutation among Belgian patients with CF. The mutation was present in 80% of CF chromosomes from 36 unrelated families. Ninety-three percent of the CF chromosomes carrying the delta-F508 mutation also carried haplotype B in this population. Gille et al. (1991) described a strategy for efficient heterozygote screening for the delta-F508 mutation. They showed that PCR could detect a heterozygote in a pool of up to 49 unrelated DNA samples. Lerer et al. (1992) reported that the delta-F508 mutation accounts for 33.8% of Jewish CF alleles. The Basque population is thought to be one of the oldest in Europe, having been established in western Europe during the late Paleolithic Age. Euskera, the Basque language, is thought to be pre-Indo-European, originating from the first settlers of Europe. The variable distribution of the delF508 mutation in Europe, with higher frequencies in northern Europe and lower frequencies in southern Europe, has been attributed to a spread of the mutation by early farmers migrating from the Middle East during the Neolithic period. However, a very high frequency of this mutation was found in the Basque Provinces, where the incidence of CF is approximately 1 in 4,500. In a study of 45 CF families from the Basque Provinces, Casals et al. (1992) found that the frequency of the delF508 mutation was 87% in the chromosomes of individuals of pure Basque extraction and 58% in those of mixed Basque origin. Casals et al. (1992) proposed that the delF508 mutation was present in Europe more than 10,000 years ago, preceding the agricultural migrations which diluted the mutation rather than introducing it. Ballabio et al. (1990) described an allele-specific amplification method for diagnosing the phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of the U.S. Southwest, Grebe et al. (1992) found no instance of the delF508 mutation in 12 affected individuals. Clinically, 6 of the affected individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a severe CF phenotype. Four of the 6 Zunis with CF were also microcephalic, a finding not previously noted in CF patients. In an analysis of 640 Spanish cystic fibrosis families, Casals et al. (1997) found that 75 mutations accounted for 90.2% of CF chromosomes - an extraordinarily high heterozygosity. The frequency of the delta-F508 mutation was 53.2%. The next most frequent mutation was gly542 to ter (602421.0009) with a frequency of 8.43%. Using 3 intragenic microsatellites of the CFTR gene located in introns, Russo et al. (1995) evaluated linkage disequilibrium between each marker and various CF mutations on a total of 377 CF and 358 normal chromosomes from Italian subjects. Results were considered consistent with the hypothesis that all del508 chromosomes derived from a single mutational event. The same hypothesis was valid for 3 other mutations which might have originated more recently than del508. Grebe et al. (1994) performed molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States. Only 46% (59 of 129) carried mutation F508del (frequency in the general population 67.1%). In 69 Italian patients with CF due to homozygosity for the delF508 mutation, De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients. In a 62-year-old woman with idiopathic bronchiectasis (BESC1; 211400) and elevated sweat chloride but normal nasal potential difference, who carried a heterozygous F508del CFTR mutation, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The patient had a forced expiratory volume in 1 second (FEV1) that was 89% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology. Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30. Pankow et al. (2015) reported the first comprehensive analysis of the CFTR and delta-F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, they identified 638 individual high-confidence CFTR interactors and discovered a delta-F508 deletion-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promote delta-F508i CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. The results of Pankow et al. (2015) demonstrated that global remodeling of delta-F508 CFTR interactions is crucial for rescue, and provided comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508. Clinical Trials Wainwright et al. (2015) conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator. A total of 1,108 patients 12 years of age or older who were homozygous for the Phe508del CFTR mutation were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary endpoint was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. In both studies, there were significant improvements in the primary endpoint. The difference between active and placebo with respect to mean absolute improvement in the percentage FEV1 ranged from 2.6 to 4.0 percentage points (p less than 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (p less than 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the treated groups than in the placebo group. In addition, the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the treated groups. The incidence of adverse events was similar in the treated and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. Wainwright et al. (2015) concluded that the combination of a CFTR corrector and potentiator, designed to address the underlying cause of cystic fibrosis by targeting CFTR, can benefit the 45% of patients who are homozygous for the Phe508del mutation. (less)

In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to deletion of phenylalanine at codon 508 (delta-F508). The exon in which the delta-F508 mutation occurs has been corrected to exon 11; see, e.g., Sharma et al. (2014). The European Working Group on CF Genetics (1990) published information on the distribution of the delta-F508 mutation in Europe. The data, illustrated with a useful map, indicated a striking cline across Europe from low values of 30% in the southeast (in Turkey) to high values in the northwest (e.g., 88% in Denmark). The group suggested that the spread of the CF gene might have accompanied the migrations of early farmers starting from the Middle East and slowly progressing toward the northwest of Europe. The diffusion of the gene may have been favored by the selective advantage conferred by the gene. Strong association with the so-called haplotype B was demonstrated. The possibility of 'hitchhiking,' i.e., the influence of neighboring genes was discussed. Rozen et al. (1990) found the delta-F508 mutation in 71% of CF chromosomes from urban Quebec province French Canadian families, 55% of those from Saguenay-Lac-Saint-Jean region families and in 70% of those from Louisiana Acadian families. De Braekeleer (1991) estimated that the frequency at birth of cystic fibrosis is 1/926 in the Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the same region, Daigneault et al. (1991) reported a prevalence of CF at birth of 1/902 liveborns, and a carrier rate of 1/15. Rozen et al. (1992) found that the delta-F508 mutation was present in 58% of Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site mutation after codon 621 being found in 23%, and the A455E mutation (602421.0007) in 8%. The latter 2 mutations were not found in urban Quebec families. This provided further evidence of the role of founder effect. Among 293 patients, Kerem et al. (1990) found that those who were homozygous for the F508 deletion had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency. Pancreatic insufficiency was present in 99% of the homozygous patients, 72% of those heterozygous for the deletion, and only 36% of patients with other mutations. Wauters et al. (1991) studied the frequency of the delta-F508 mutation among Belgian patients with CF. The mutation was present in 80% of CF chromosomes from 36 unrelated families. Ninety-three percent of the CF chromosomes carrying the delta-F508 mutation also carried haplotype B in this population. Gille et al. (1991) described a strategy for efficient heterozygote screening for the delta-F508 mutation. They showed that PCR could detect a heterozygote in a pool of up to 49 unrelated DNA samples. Lerer et al. (1992) reported that the delta-F508 mutation accounts for 33.8% of Jewish CF alleles. The Basque population is thought to be one of the oldest in Europe, having been established in western Europe during the late Paleolithic Age. Euskera, the Basque language, is thought to be pre-Indo-European, originating from the first settlers of Europe. The variable distribution of the delF508 mutation in Europe, with higher frequencies in northern Europe and lower frequencies in southern Europe, has been attributed to a spread of the mutation by early farmers migrating from the Middle East during the Neolithic period. However, a very high frequency of this mutation was found in the Basque Provinces, where the incidence of CF is approximately 1 in 4,500. In a study of 45 CF families from the Basque Provinces, Casals et al. (1992) found that the frequency of the delF508 mutation was 87% in the chromosomes of individuals of pure Basque extraction and 58% in those of mixed Basque origin. Casals et al. (1992) proposed that the delF508 mutation was present in Europe more than 10,000 years ago, preceding the agricultural migrations which diluted the mutation rather than introducing it. Ballabio et al. (1990) described an allele-specific amplification method for diagnosing the phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of the U.S. Southwest, Grebe et al. (1992) found no instance of the delF508 mutation in 12 affected individuals. Clinically, 6 of the affected individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a severe CF phenotype. Four of the 6 Zunis with CF were also microcephalic, a finding not previously noted in CF patients. In an analysis of 640 Spanish cystic fibrosis families, Casals et al. (1997) found that 75 mutations accounted for 90.2% of CF chromosomes - an extraordinarily high heterozygosity. The frequency of the delta-F508 mutation was 53.2%. The next most frequent mutation was gly542 to ter (602421.0009) with a frequency of 8.43%. Using 3 intragenic microsatellites of the CFTR gene located in introns, Russo et al. (1995) evaluated linkage disequilibrium between each marker and various CF mutations on a total of 377 CF and 358 normal chromosomes from Italian subjects. Results were considered consistent with the hypothesis that all del508 chromosomes derived from a single mutational event. The same hypothesis was valid for 3 other mutations which might have originated more recently than del508. Grebe et al. (1994) performed molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States. Only 46% (59 of 129) carried mutation F508del (frequency in the general population 67.1%). In 69 Italian patients with CF due to homozygosity for the delF508 mutation, De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients. In a 62-year-old woman with idiopathic bronchiectasis (BESC1; 211400) and elevated sweat chloride but normal nasal potential difference, who carried a heterozygous F508del CFTR mutation, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The patient had a forced expiratory volume in 1 second (FEV1) that was 89% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology. Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30. Pankow et al. (2015) reported the first comprehensive analysis of the CFTR and delta-F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, they identified 638 individual high-confidence CFTR interactors and discovered a delta-F508 deletion-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promote delta-F508i CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. The results of Pankow et al. (2015) demonstrated that global remodeling of delta-F508 CFTR interactions is crucial for rescue, and provided comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508. Clinical Trials Wainwright et al. (2015) conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator. A total of 1,108 patients 12 years of age or older who were homozygous for the Phe508del CFTR mutation were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary endpoint was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. In both studies, there were significant improvements in the primary endpoint. The difference between active and placebo with respect to mean absolute improvement in the percentage FEV1 ranged from 2.6 to 4.0 percentage points (p less than 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (p less than 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the treated groups than in the placebo group. In addition, the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the treated groups. The incidence of adverse events was similar in the treated and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. Wainwright et al. (2015) concluded that the combination of a CFTR corrector and potentiator, designed to address the underlying cause of cystic fibrosis by targeting CFTR, can benefit the 45% of patients who are homozygous for the Phe508del mutation. (less)