ClinVar Genomic variation as it relates to human health

Visual impairment (present) , Reduced visual acuity (present) , Caesarian section (present) , Delayed ability to walk (present) , Moderate global developmental delay (present) , Premature birth (present) , Generalized hypotonia (present) , Increased fetal movement (present) , Abnormal delivery (present) , Delayed fine motor development (present) , Intellectual disability, moderate (present) , Global developmental delay (present) , Delayed ability to stand (present) , Delayed gross motor development (present) , Horizontal nystagmus (present) , Sensorineural hearing loss disorder (present) , Focal-onset seizure (present) , Oligohydramnios (present) , Seizure (present) , Congenital nystagmus (present) , Nocturnal seizures (present) , Cerebellar ataxia (present) , Delayed ability to sit (present) , Vertical nystagmus (present) , Nystagmus (present) (less)

See Itano and Neel (1950), Neel et al. (1953), Ranney et al. (1953), Hunt and Ingram (1959), Smith and Krevans (1959), Baglioni and Ingram (1961), River et al. (1961), and Fabry et al. (1981). By restriction haplotyping, Boehm et al. (1985) concluded that the beta-C-globin gene in blacks had a single origin followed by spread of the mutation to other haplotypes through meiotic recombination 5-prime to the beta-globin gene. On 22 of 25 chromosomes studied, they found the same haplotype (defined by 8 polymorphic restriction sites), a haplotype seen only rarely among beta-A-bearing chromosomes. The 3 exceptions showed identity to the typical beta-C allele in the 3-prime end of the beta-globin gene cluster. Trabuchet et al. (1991) presented haplotyping information suggesting a unicentric origin of the HbC mutation in sub-Saharan Africa. Rapid detection of the sickle cell mutation is possible by amplifying the region of codon 6 by PCR and digesting the amplification product by a restriction endonuclease whose recognition site is abolished by the A-to-T mutation, the resulting abnormal fragment being detected with ethidium bromide staining after electrophoresis. Detection of the HbC mutation is more difficult since no known restriction-endonuclease site is abolished or created by the mutation. Fischel-Ghodsian et al. (1990) described a rapid allele-specific PCR amplification technique that allowed detection of the HbC mutation in an even shorter time span than the one required for detecting the HbS mutation (141900.0243). To test the hypothesis that hemoglobin C protects against severe malaria (611162), Agarwal et al. (2000) conducted a study in the predominantly Dogon population of Bandiagara, Mali, in West Africa, where the frequency of HbC is high (0.087) and that of HbS is low (0.016). They found evidence for an association between HbC and protection against severe malaria in the Dogon population. Indeed, the data suggested less selection for the HbAS state in this group than for HbAC. In many children with sickle cell disease (603903), functional asplenia develops during the first year of life and septicemia is the leading cause of death in childhood. The risk of septicemia in sickle cell anemia is greatest during the first 3 years of life and is reduced markedly by prophylactic penicillin therapy. Less is known about splenic dysfunction and the risk of overwhelming sepsis in children with SC disease, although functional asplenia has been documented by radionuclide liver-spleen scans in some adult patients (Ballas et al., 1982) and an elevated erythrocyte pit count, a finding that indicates functional asplenia in children with sickle cell anemia, also has been found in some children with SC disease (Pearson et al., 1985). Lane et al. (1994) reported 7 fatal cases of pneumococcal septicemia in children with SC disease. The earliest death occurred in a 1-year-old child who had cyanotic congenital heart; the other children were aged 3.5 to 15 years. Only 1 child had received pneumococcal vaccine or prophylactic penicillin therapy. All 7 children had an acute febrile illness and rapid deterioration despite parenterally administered antibiotic therapy and intensive medical support. Erythrocyte pit counts in 2 patients were 40.3 and 41.7%, respectively (normal, less than 3.6%). Autopsy findings in 5 cases included splenic congestion without infarction in 5, splenomegaly in 4, and bilateral adrenal hemorrhage in 3. Lane et al. (1994) concluded that pneumococcal vaccine should be administered in all children with SC disease. The routine use of prophylactic penicillin therapy in infants and children with SC disease remained controversial. The mutation in codon 6 of HBB in HbS is GAG (glu) to GTG (val); the mutation in HbC is GAG (glu) to AAG (lys). See also 141900.0039 and 141900.0040. Modiano et al. (2001) performed a large case-control study in Burkina Faso on 4,348 Mossi subjects, and demonstrated that hemoglobin C is associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011). These findings, together with the limited pathology of HbAC and HbCC compared to the severely disadvantaged HbSS and HbSC genotypes and the low HbS gene frequency in the geographic epicenter of HbC, support the hypothesis that, in the long-term and in the absence of malarial control, HbC would replace HbS in central West Africa. Rihet et al. (2004) surveyed 256 individuals (71 parents and 185 sibs) from 53 families in Burkina Faso over 2 years and found that hemoglobin C carriers were found to have less frequent malaria attacks than AA individuals within the same age group (P = 0.01). Analysis of individual hemoglobin alleles yielded a negative association between HbC and malaria attack (P = 0.00013). Analyses that took into account confounding factors confirmed the negative association of HbC with malaria attack (P = 0.0074) and evidenced a negative correlation between HbC and parasitemia (P = 0.0009). Fairhurst et al. (2005) reported a marked effect of hemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (HbAA), parasitized AC and CC erythrocytes showed reduced adhesion to endothelial monolayers expressing CD36 (173510) and intercellular adhesion molecule-1 (ICAM1; 147840). They also showed impaired rosetting interactions with nonparasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlated with these findings. The abnormalities in PfEMP-1 display were associated with markers of erythrocyte senescence, and were greater in CC than in AC erythrocytes. Fairhurst et al. (2005) suggested that hemoglobin C might protect against malaria by reducing PfEMP1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature. Recombinational hotspots are a ubiquitous feature of the human genome, occurring every 60 to 200 kb, and likely contribute to the observed pattern of large haplotypic blocks punctuated by low linkage disequilibrium (LD) over very short (1 to 2 kb) distances. Recombination breaks up ancestral LD and produces new combinations of alleles on which natural selection can act. Positive selection increases the frequency of beneficial mutations, creating LD via genetic 'hitchhiking.' The beta-globin hotspot spans approximately 1 kb and is located approximately 500 bp from the selected site at the beta-globin gene. The close proximity of these beta-globin regions allowed Wood et al. (2005) to empirically examine the signature of selection across a region that recombines at a rate 50 to 90 times higher than the genomic average of 1.1 cM/Mb. Early studies of the HbC polymorphism suggested that this allele was, like the hemoglobin S allele (141900.0243), also subject to balancing selection (Allison, 1954). Subsequently, it was shown that HbC provides protection against Plasmodium falciparum without significantly reducing fitness, indicating that this allele is increasing in frequency as a result of positive directional selection (Agarwal et al., 2000; Modiano et al., 2001; Hedrick, 2004; Rihet et al., 2004). Because the African HbC allele rarely exceeds frequencies of 20% and is geographically concentrated in central West Africa, it is thought that this mutation is very young. Wood et al. (2005) examined the extent of LD surrounding the African HbC allele to estimate its age and the strength of selection acting on this mutation and tested the hypothesis that the beta-globin recombinational hotspot decouples the selected HbC allele from nearby upstream regions. They estimated that the HbC mutation originated less than 5,000 years ago and that selection coefficients are between 0.04 and 0.09. Despite strong selection and the recent origin of the HbC allele, recombination (crossing-over or gene conversion) is observed within 1 kb 5-prime of the selected site on more than one-third of the Hb chromosomes sampled. The rapid decay in LD upstream of the HbC allele demonstrates the large effect the beta-globin hotspot has in mitigating the effects of positive selection on linked variation, in other words a reduction in 'hitchhiking.' Modiano et al. (2008) adopted 2 partially independent haplotypic approaches to study the Mossi population in Burkina Faso, where both the HbS and HbC alleles are common. They showed that both alleles are monophyletic, but that the HbC allele has acquired higher recombinatorial and DNA slippage haplotypic variability or linkage disequilibrium decay and is likely older than HbS. Modiano et al. (2008) inferred that the HbC allele has accumulated mainly through recessive rather than a semidominant mechanism of selection. Gouagna et al. (2010) used cross-sectional surveys of 3,739 human subjects and transmission experiments involving 60 children and over 6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB variants HbC and HbS, which are protective against malaria, are associated with transmission of the parasite from the human host to the Anopheles mosquito vector. They found that HbC and HbS were associated with significant 2-fold in vivo (P = 1.0 x 10(-6)) and 4-fold ex vivo (P = 7.0 x 10(-5)) increases of parasite transmission from host to vector. In addition, the HbC allele was consistently associated with higher gametocyte rate. Cyrklaff et al. (2011) found that HbS (141900.0243) and HbC affect the trafficking system that directs parasite-encoded proteins to the surface of infected erythrocytes. Cryoelectron tomography revealed that P. falciparum generates a host-derived actin cytoskeleton within the cytoplasm of wildtype red blood cells that connects the Maurer clefts with the host cell membrane and to which transport vesicles are attached. The actin cytoskeleton and the Maurer clefts were aberrant in erythrocytes containing HbS or HbC. Hemoglobin oxidation products, enriched in HbS and HbC erythrocytes, inhibited actin polymerization in vitro and may account for the protective role in malaria. (less)

See Itano and Neel (1950), Neel et al. (1953), Ranney et al. (1953), Hunt and Ingram (1959), Smith and Krevans (1959), Baglioni and Ingram (1961), River et al. (1961), and Fabry et al. (1981). By restriction haplotyping, Boehm et al. (1985) concluded that the beta-C-globin gene in blacks had a single origin followed by spread of the mutation to other haplotypes through meiotic recombination 5-prime to the beta-globin gene. On 22 of 25 chromosomes studied, they found the same haplotype (defined by 8 polymorphic restriction sites), a haplotype seen only rarely among beta-A-bearing chromosomes. The 3 exceptions showed identity to the typical beta-C allele in the 3-prime end of the beta-globin gene cluster. Trabuchet et al. (1991) presented haplotyping information suggesting a unicentric origin of the HbC mutation in sub-Saharan Africa. Rapid detection of the sickle cell mutation is possible by amplifying the region of codon 6 by PCR and digesting the amplification product by a restriction endonuclease whose recognition site is abolished by the A-to-T mutation, the resulting abnormal fragment being detected with ethidium bromide staining after electrophoresis. Detection of the HbC mutation is more difficult since no known restriction-endonuclease site is abolished or created by the mutation. Fischel-Ghodsian et al. (1990) described a rapid allele-specific PCR amplification technique that allowed detection of the HbC mutation in an even shorter time span than the one required for detecting the HbS mutation (141900.0243). To test the hypothesis that hemoglobin C protects against severe malaria (611162), Agarwal et al. (2000) conducted a study in the predominantly Dogon population of Bandiagara, Mali, in West Africa, where the frequency of HbC is high (0.087) and that of HbS is low (0.016). They found evidence for an association between HbC and protection against severe malaria in the Dogon population. Indeed, the data suggested less selection for the HbAS state in this group than for HbAC. In many children with sickle cell disease (603903), functional asplenia develops during the first year of life and septicemia is the leading cause of death in childhood. The risk of septicemia in sickle cell anemia is greatest during the first 3 years of life and is reduced markedly by prophylactic penicillin therapy. Less is known about splenic dysfunction and the risk of overwhelming sepsis in children with SC disease, although functional asplenia has been documented by radionuclide liver-spleen scans in some adult patients (Ballas et al., 1982) and an elevated erythrocyte pit count, a finding that indicates functional asplenia in children with sickle cell anemia, also has been found in some children with SC disease (Pearson et al., 1985). Lane et al. (1994) reported 7 fatal cases of pneumococcal septicemia in children with SC disease. The earliest death occurred in a 1-year-old child who had cyanotic congenital heart; the other children were aged 3.5 to 15 years. Only 1 child had received pneumococcal vaccine or prophylactic penicillin therapy. All 7 children had an acute febrile illness and rapid deterioration despite parenterally administered antibiotic therapy and intensive medical support. Erythrocyte pit counts in 2 patients were 40.3 and 41.7%, respectively (normal, less than 3.6%). Autopsy findings in 5 cases included splenic congestion without infarction in 5, splenomegaly in 4, and bilateral adrenal hemorrhage in 3. Lane et al. (1994) concluded that pneumococcal vaccine should be administered in all children with SC disease. The routine use of prophylactic penicillin therapy in infants and children with SC disease remained controversial. The mutation in codon 6 of HBB in HbS is GAG (glu) to GTG (val); the mutation in HbC is GAG (glu) to AAG (lys). See also 141900.0039 and 141900.0040. Modiano et al. (2001) performed a large case-control study in Burkina Faso on 4,348 Mossi subjects, and demonstrated that hemoglobin C is associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011). These findings, together with the limited pathology of HbAC and HbCC compared to the severely disadvantaged HbSS and HbSC genotypes and the low HbS gene frequency in the geographic epicenter of HbC, support the hypothesis that, in the long-term and in the absence of malarial control, HbC would replace HbS in central West Africa. Rihet et al. (2004) surveyed 256 individuals (71 parents and 185 sibs) from 53 families in Burkina Faso over 2 years and found that hemoglobin C carriers were found to have less frequent malaria attacks than AA individuals within the same age group (P = 0.01). Analysis of individual hemoglobin alleles yielded a negative association between HbC and malaria attack (P = 0.00013). Analyses that took into account confounding factors confirmed the negative association of HbC with malaria attack (P = 0.0074) and evidenced a negative correlation between HbC and parasitemia (P = 0.0009). Fairhurst et al. (2005) reported a marked effect of hemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (HbAA), parasitized AC and CC erythrocytes showed reduced adhesion to endothelial monolayers expressing CD36 (173510) and intercellular adhesion molecule-1 (ICAM1; 147840). They also showed impaired rosetting interactions with nonparasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlated with these findings. The abnormalities in PfEMP-1 display were associated with markers of erythrocyte senescence, and were greater in CC than in AC erythrocytes. Fairhurst et al. (2005) suggested that hemoglobin C might protect against malaria by reducing PfEMP1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature. Recombinational hotspots are a ubiquitous feature of the human genome, occurring every 60 to 200 kb, and likely contribute to the observed pattern of large haplotypic blocks punctuated by low linkage disequilibrium (LD) over very short (1 to 2 kb) distances. Recombination breaks up ancestral LD and produces new combinations of alleles on which natural selection can act. Positive selection increases the frequency of beneficial mutations, creating LD via genetic 'hitchhiking.' The beta-globin hotspot spans approximately 1 kb and is located approximately 500 bp from the selected site at the beta-globin gene. The close proximity of these beta-globin regions allowed Wood et al. (2005) to empirically examine the signature of selection across a region that recombines at a rate 50 to 90 times higher than the genomic average of 1.1 cM/Mb. Early studies of the HbC polymorphism suggested that this allele was, like the hemoglobin S allele (141900.0243), also subject to balancing selection (Allison, 1954). Subsequently, it was shown that HbC provides protection against Plasmodium falciparum without significantly reducing fitness, indicating that this allele is increasing in frequency as a result of positive directional selection (Agarwal et al., 2000; Modiano et al., 2001; Hedrick, 2004; Rihet et al., 2004). Because the African HbC allele rarely exceeds frequencies of 20% and is geographically concentrated in central West Africa, it is thought that this mutation is very young. Wood et al. (2005) examined the extent of LD surrounding the African HbC allele to estimate its age and the strength of selection acting on this mutation and tested the hypothesis that the beta-globin recombinational hotspot decouples the selected HbC allele from nearby upstream regions. They estimated that the HbC mutation originated less than 5,000 years ago and that selection coefficients are between 0.04 and 0.09. Despite strong selection and the recent origin of the HbC allele, recombination (crossing-over or gene conversion) is observed within 1 kb 5-prime of the selected site on more than one-third of the Hb chromosomes sampled. The rapid decay in LD upstream of the HbC allele demonstrates the large effect the beta-globin hotspot has in mitigating the effects of positive selection on linked variation, in other words a reduction in 'hitchhiking.' Modiano et al. (2008) adopted 2 partially independent haplotypic approaches to study the Mossi population in Burkina Faso, where both the HbS and HbC alleles are common. They showed that both alleles are monophyletic, but that the HbC allele has acquired higher recombinatorial and DNA slippage haplotypic variability or linkage disequilibrium decay and is likely older than HbS. Modiano et al. (2008) inferred that the HbC allele has accumulated mainly through recessive rather than a semidominant mechanism of selection. Gouagna et al. (2010) used cross-sectional surveys of 3,739 human subjects and transmission experiments involving 60 children and over 6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB variants HbC and HbS, which are protective against malaria, are associated with transmission of the parasite from the human host to the Anopheles mosquito vector. They found that HbC and HbS were associated with significant 2-fold in vivo (P = 1.0 x 10(-6)) and 4-fold ex vivo (P = 7.0 x 10(-5)) increases of parasite transmission from host to vector. In addition, the HbC allele was consistently associated with higher gametocyte rate. Cyrklaff et al. (2011) found that HbS (141900.0243) and HbC affect the trafficking system that directs parasite-encoded proteins to the surface of infected erythrocytes. Cryoelectron tomography revealed that P. falciparum generates a host-derived actin cytoskeleton within the cytoplasm of wildtype red blood cells that connects the Maurer clefts with the host cell membrane and to which transport vesicles are attached. The actin cytoskeleton and the Maurer clefts were aberrant in erythrocytes containing HbS or HbC. Hemoglobin oxidation products, enriched in HbS and HbC erythrocytes, inhibited actin polymerization in vitro and may account for the protective role in malaria. (less)