ClinVar Genomic variation as it relates to human health

PHOAR2-Enteropathy Syndrome For discussion of the c.1807C-T transition (c.1807C-T, NM_005630) in exon 13 of the SLCO2A1 gene, resulting in an arg603-to-ter (R603X) substitution, that was found in compound heterozygous state in 2 Japanese sisters (patients 4 and 5) with chronic nonspecific ulcers (CNSU) of the stomach, duodenum, and ileum, who also exhibited acne, large joint arthralgias, and hyperhidrosis (PHOAR2E; 614441) by Umeno et al. (2015), see 601460.0004. Umeno et al. (2015) also reported an 18-year-old Japanese girl (patient 15) with anemia and CNSU of the duodenum and ileum who was compound heterozygous for R603X and a splice site mutation in SLCO2A1 (c.940+1G-A; 601460.0005), and a 59-year-old Japanese woman (patient 10) with CNSU of the ileum who was compound heterozygous for R603X and a c.421G-T transversion in exon 4, resulting in a glu141-to-ter (E141X; 601460.0023) substitution. The latter 2 patients did not exhibit features of PHO. Functional analysis in transfected HEK293 cells demonstrated that none of the mutants was able to take up PGE, indicating loss of function as a PGE transporter. For discussion of the c.1807C-T transition (c.1807C-T, NM_005630.2) in exon 13 of the SLCO2A1 gene, resulting in an arg603-to-ter (R603X) substitution, that was found in compound heterozygous state in a 19-year-old Korean man (family 2) with primary hypertrophic osteoarthropathy (PHO) by Lee et al. (2016), see 601460.0005. In 2 Chinese men (P17 and P33) with features of PHO, including digital clubbing and periostosis, Li et al. (2017) identified compound heterozygosity for the R603X substitution and another mutation in the SLCO2A1 gene: in P17, the second mutation was a c.1624C-T transition in exon 11, resulting in an arg542-to-cys (R542C; 601460.0024) substitution at a highly conserved residue; and in P33, the second mutation was a c.1106-1G-A transition in intron 8 (601460.0025). The R542C variant was present at very low minor allele frequency (0.0002221) in the ExAC database. Neither man was reported to have gastrointestinal symptoms. In a review of 46 Japanese patients from 43 families with CNSU and mutation in the SLCO2A1 gene, Umeno et al. (2018) noted that the R603X variant was present in 20 (22%) of 92 alleles, making it the second most frequent mutation identified. In a Chinese man (family 12) with PHO, Xu et al. (2021) identified homozygosity for the R603X substitution. His heterozygous father exhibited only pachydermia and periostosis, whereas his heterozygous mother was clinically unaffected. The proband in family 12 had been previously studied by Li et al. (2017) as P15, and was reported to have gastrointestinal hemorrhage and anemia. Autosomal Dominant Primary Hypertrophic Osteoarthropathy In affected individuals from 2 Chinese families (6 and 7) segregating autosomal dominant PHO (PHOAD; 167100), Xu et al. (2021) identified heterozygosity for the R603X substitution (c.1807C-T, NM_005630.2) in the SLCO2A1 gene, which was not found in 250 Chinese controls. In family 6, the male proband had complete PHO, with pachydermia, digital clubbing, periostosis, and joint swelling, as well as gastrointestinal abnormalities, whereas his sister and mother, who also carried the R603X variant, exhibited only pachydermia. In family 7, the male proband and his maternal uncle had digital clubbing and periostosis, whereas the proband's mother had only periostosis. (less)

PHOAR2-Enteropathy Syndrome For discussion of the c.1807C-T transition (c.1807C-T, NM_005630) in exon 13 of the SLCO2A1 gene, resulting in an arg603-to-ter (R603X) substitution, that was found in compound heterozygous state in 2 Japanese sisters (patients 4 and 5) with chronic nonspecific ulcers (CNSU) of the stomach, duodenum, and ileum, who also exhibited acne, large joint arthralgias, and hyperhidrosis (PHOAR2E; 614441) by Umeno et al. (2015), see 601460.0004. Umeno et al. (2015) also reported an 18-year-old Japanese girl (patient 15) with anemia and CNSU of the duodenum and ileum who was compound heterozygous for R603X and a splice site mutation in SLCO2A1 (c.940+1G-A; 601460.0005), and a 59-year-old Japanese woman (patient 10) with CNSU of the ileum who was compound heterozygous for R603X and a c.421G-T transversion in exon 4, resulting in a glu141-to-ter (E141X; 601460.0023) substitution. The latter 2 patients did not exhibit features of PHO. Functional analysis in transfected HEK293 cells demonstrated that none of the mutants was able to take up PGE, indicating loss of function as a PGE transporter. For discussion of the c.1807C-T transition (c.1807C-T, NM_005630.2) in exon 13 of the SLCO2A1 gene, resulting in an arg603-to-ter (R603X) substitution, that was found in compound heterozygous state in a 19-year-old Korean man (family 2) with primary hypertrophic osteoarthropathy (PHO) by Lee et al. (2016), see 601460.0005. In 2 Chinese men (P17 and P33) with features of PHO, including digital clubbing and periostosis, Li et al. (2017) identified compound heterozygosity for the R603X substitution and another mutation in the SLCO2A1 gene: in P17, the second mutation was a c.1624C-T transition in exon 11, resulting in an arg542-to-cys (R542C; 601460.0024) substitution at a highly conserved residue; and in P33, the second mutation was a c.1106-1G-A transition in intron 8 (601460.0025). The R542C variant was present at very low minor allele frequency (0.0002221) in the ExAC database. Neither man was reported to have gastrointestinal symptoms. In a review of 46 Japanese patients from 43 families with CNSU and mutation in the SLCO2A1 gene, Umeno et al. (2018) noted that the R603X variant was present in 20 (22%) of 92 alleles, making it the second most frequent mutation identified. In a Chinese man (family 12) with PHO, Xu et al. (2021) identified homozygosity for the R603X substitution. His heterozygous father exhibited only pachydermia and periostosis, whereas his heterozygous mother was clinically unaffected. The proband in family 12 had been previously studied by Li et al. (2017) as P15, and was reported to have gastrointestinal hemorrhage and anemia. Autosomal Dominant Primary Hypertrophic Osteoarthropathy In affected individuals from 2 Chinese families (6 and 7) segregating autosomal dominant PHO (PHOAD; 167100), Xu et al. (2021) identified heterozygosity for the R603X substitution (c.1807C-T, NM_005630.2) in the SLCO2A1 gene, which was not found in 250 Chinese controls. In family 6, the male proband had complete PHO, with pachydermia, digital clubbing, periostosis, and joint swelling, as well as gastrointestinal abnormalities, whereas his sister and mother, who also carried the R603X variant, exhibited only pachydermia. In family 7, the male proband and his maternal uncle had digital clubbing and periostosis, whereas the proband's mother had only periostosis. (less)