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Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska Tag Q3_26_promote_green was removed from gene: ATP6AP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Changed rating: AMBER
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no recurrent infections noted. Hence, this gene should be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, based on cases with missense variants.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). However, only 2 probands presented with recurrent infections. Hence, this gene should remain Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. No immunodeficiency noted.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 ATP6AP2 Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.22 ATP6AP2 Ida Ertmanska Mode of pathogenicity for gene: ATP6AP2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v9.21 ATP6AP2 Ida Ertmanska Publications for gene: ATP6AP2 were set to 29127204; 41131679
Primary immunodeficiency or monogenic inflammatory bowel disease v9.20 ATP6AP2 Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no recurrent infections noted. Hence, this gene should be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, based on cases with missense variants.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Liver features reported: early-onset cirrhosis and steatosis, neonatal liver failure, hepatosplenomegaly, liver transplant before 1 year of age. Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska edited their review of gene: ATP6AP2: Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Liver features reported: early-onset cirrhosis and steatosis, neonatal liver failure, hepatosplenomegaly, liver transplant before 1 year of age. Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; Changed publications to: 29127204, 38075676, 41131679; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature; to: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients.

PMID: 38075676 Fang et al., 2023
11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation.
Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.

ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 ATP6AP2 Ida Ertmanska gene: ATP6AP2 was added
gene: ATP6AP2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Q3_26_promote_green tags were added to gene: ATP6AP2.
Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATP6AP2 were set to 29127204; 41131679
Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive
Review for gene: ATP6AP2 was set to GREEN
Added comment: PMID: 41131679 Raynor et al., 2026
Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities.

PMID: 29127204 Rujano et al., 2017
Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES.
P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted.
P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections.
Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects.
Sources: Literature