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02 Sep 2026	Rare anaemia v4.10	HSPA9	Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
02 Sep 2026	Rare anaemia v4.10	HSPA9	Ida Ertmanska edited their review of gene: HSPA9: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
02 Sep 2026	Rare anaemia v4.10	HSPA9	Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
02 Sep 2026	Rare anaemia v4.10	HSPA9	Ida Ertmanska edited their review of gene: HSPA9: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
02 Sep 2026	Rare anaemia v4.10	HSPA9	Ida Ertmanska Phenotypes for gene: HSPA9 were changed from sideroblastic anaemia; 182170 Sideroblastic anaemia 4; 182170 sideroblastic anaemia type 4; Sideroblastic anaemia type 4, 182170 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194
02 Sep 2026	Rare anaemia v4.9	HSPA9	Ida Ertmanska Publications for gene: HSPA9 were set to 26491070
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a homozygous rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a homozygous rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population. 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (pC487Sfs3 & p.E577K in Family K; p.V296* & ?p.203_204ins3 in family L). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population. 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population. 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. Patient VA-39 - 9yo female, presented with pallor, weakness, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 26491070, 33398880, 36094340, 38360212
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. Patient VA-39 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. Patient VA-39 - 9yo female, presented with pallor, weakness, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. Patient VA-39 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 26491070, 33398880, 38360212
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska changed review comment from: PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in HSPA9.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.
02 Sep 2026	Rare anaemia v4.8	HSPA9	Ida Ertmanska reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 33398880, 38360212; Phenotypes: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
22 Jul 2019	Rare anaemia v0.74	HSPA9	Louise Daugherty Mode of inheritance for gene: HSPA9 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
18 Feb 2019	Rare anaemia v0.28	HSPA9	Louise Daugherty commented on gene: HSPA9: Initial gene list (Consensus Genes for SPEC HAEM Panels 31.01.19 North West v1 FINAL.xlsx) collated by Steve Keeney Molecular Diagnostics Centre Central Manchester NHS Foundation Trust January 2019 on behalf of North West GLH for the GMS Haematology specialist test group. Gene Symbol submitted: HSPA9; Suggested initial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? No; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Phenotypes: 182170 sideroblastic anaemia type 4; PMID(s): none submitted
18 Feb 2019	Rare anaemia v0.27	HSPA9	Steve Keeney reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Sideroblastic anaemia type 4, 182170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
18 Feb 2019	Rare anaemia v0.26	HSPA9	Louise Daugherty Added phenotypes Sideroblastic anaemia type 4, 182170 for gene: HSPA9
18 Feb 2019	Rare anaemia v0.22	HSPA9	Louise Daugherty Source North West GLH was added to HSPA9.
14 Feb 2019	Rare anaemia v0.17	HSPA9	Louise Daugherty commented on gene: HSPA9: Initial gene list (Consensus Genes for Panels_Haem_SHEFFIELD-29.01.2019.xlsx) collated by Mandy Nesbitt Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Trust January 2019 on behalf of Yorkshire and North East GLH for the GMS Haematology specialist test group. Gene Symbol submitted: HSPA9; Suggested intial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? No; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Phenotypes: 182170 sideroblastic anaemia type 4; PMID(s): none submitted
14 Feb 2019	Rare anaemia v0.16	HSPA9	Mandy nesbitt reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: 182170 sideroblastic anaemia type 4; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
14 Feb 2019	Rare anaemia v0.15	HSPA9	Louise Daugherty Added phenotypes 182170 sideroblastic anaemia type 4 for gene: HSPA9
14 Feb 2019	Rare anaemia v0.13	HSPA9	Louise Daugherty Source Yorkshire and North East GLH was added to HSPA9.
08 Feb 2019	Rare anaemia v0.11	HSPA9	Louise Daugherty commented on gene: HSPA9: Initial gene list (Consensus Genes for Haem Panels 17.12.18_KCH.xlsx) collated by Frances Smith Viapath Kings College Hospital February 2019 on behalf of London South GLH for the GMS Haematology specialist test group. Gene Symbol submitted: HSPA9; Suggested intial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? No; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Phenotypes: 182170 Sideroblastic anaemia 4; PMID(s): 26491070
08 Feb 2019	Rare anaemia v0.10	HSPA9	Frances Smith reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: ; Publications: 26491070; Phenotypes: 182170 Sideroblastic anaemia 4; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
08 Feb 2019	Rare anaemia v0.9	HSPA9	Louise Daugherty Added phenotypes 182170 Sideroblastic anaemia 4 for gene: HSPA9 Publications for gene HSPA9 were changed from to 26491070
08 Feb 2019	Rare anaemia v0.7	HSPA9	Louise Daugherty Source London South GLH was added to HSPA9.
06 Feb 2019	Rare anaemia v0.6	HSPA9	Louise Daugherty reviewed gene: HSPA9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
06 Feb 2019	Rare anaemia v0.5	HSPA9	Carl Fratter reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
06 Feb 2019	Rare anaemia v0.4	HSPA9	Louise Daugherty Source NHS GMS was added to HSPA9.
06 Feb 2019	Rare anaemia v0.3	HSPA9	Louise Daugherty Source Expert Review Green was added to HSPA9. Added phenotypes sideroblastic anaemia for gene: HSPA9 Rating Changed from Red List (low evidence) to Green List (high evidence)
06 Feb 2019	Rare anaemia v0.2	HSPA9	Louise Daugherty gene: HSPA9 was added gene: HSPA9 was added to Rare anaemia. Sources: Wessex and West Midlands GLH Mode of inheritance for gene: HSPA9 was set to