Overhydrated Hereditary Stomatocytosis (OHSt): research report

Scope and verification. I ran three web searches and read search summaries only. I did not open the full text of any paper. These items came back from search results: - Bruce 2009, PMID 18931342. - The Haematologica 2011 metabolomics report. - The 2018 Frontiers review. - The 2019 J Blood Med review (PMC6613601). - The GeneBe/ClinGen-style gene summary.

Everything else is background knowledge and is marked [unverified]. Treat it as a lead until a snippet has been checked with just fetch-reference. I did not retrieve exact abstract quotes, so none appear below. I did not look up any ontology identifier, so every HP, GO, CL, UBERON, CHEBI and NCIT term is a search suggestion by label only and has no CURIE. Look each one up with OAK or the term caches before binding it.

1. Disease information

• OHSt is a rare, autosomal dominant congenital hemolytic anemia. It belongs to the "cation-leak" hereditary stomatocytoses, together with dehydrated stomatocytosis (xerocytosis, mainly PIEZO1) and the other leak forms. (Frontiers 2018)
• Red cells are swollen (high MCV, low MCHC). A summary of the pathogenesis says: "The influx of Na+ exceeds the loss of K+ causing water influx and resulting in swollen erythrocytes, hemolysis, and stomatocyte formation." (Frontiers 2018)
• Identifiers. The MONDO ID you gave (MONDO:0008493) was not checked. OMIM, Orphanet, ICD-10/11 and MeSH identifiers are not verified either; look them up directly. KEGG has an entry (H01979), found by search: KEGG.
• Synonyms: overhydrated stomatocytosis; hydrocytosis; OHSt; hereditary stomatocytosis with overhydration. Related labels you will meet in the same sources are "Rh-null disease, regulator type" and "Rh deficiency syndrome". These are separate recessive conditions, not synonyms.
• Data level: the evidence is aggregated disease-level resources and case series. It is not EHR-derived.

2. Etiology

• Cause: heterozygous missense variants in RHAG, which encodes the Rh-associated glycoprotein. Search results describe overhydrated stomatocytosis as "mainly caused by RHAG gene mutations, and milder forms have been linked to SLC4A1 variants". (J Blood Med 2019, PMC6613601)
• Landmark paper: Bruce LJ et al., Blood 2009, PMID 18931342, "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein." (abstract mirror)
• Search results report that "DNA analysis revealed that the OHSt patients have 1 of 2 heterozygous mutations (t182g, t194c) in RHAG that lead to substitutions of 2 highly conserved amino acids (Ile61Arg, Phe65Ser)."
• They also report that expressing the mutant proteins in Xenopus oocytes gave a cation leak about six times greater than wild type.
• Further variants: later reports describe additional RHAG missense variants (for example p.Phe65Ser and others) [unverified]. Please search ClinVar and the literature for the current list.
• Risk and protective factors:
• No environmental risk factors or protective factors are known [unverified].
• No gene–environment interaction data were found.
• Inheritance is dominant, and many cases are reported as de novo [unverified].
• Modifiers: not characterised in anything I retrieved.

3. Phenotypes

Clinical features reported for the stomatocytosis group (J Blood Med 2019): - jaundice - pallor - fatigue - splenomegaly - gallstones

Suggested HPO labels (look up IDs): - Hemolytic anemia - Macrocytosis, with high MCV - Low MCHC - Stomatocytosis / abnormal erythrocyte morphology - Splenomegaly - Jaundice - Cholelithiasis - Reticulocytosis - Neonatal hyperbilirubinemia [unverified] - Iron overload [unverified]

Other points: - Severity is variable, from compensated hemolysis to transfusion-dependent anemia. - Onset is neonatal to childhood. - Frequencies and quality-of-life data were not found. Do not invent them. - Perinatal fluid effusions and thrombosis are mentioned in the 2019 review for the stomatocytosis group. I could not tell from the summary which subtype each applies to.

4. Genetic and molecular information

• Gene: RHAG (chromosome 6p21.3 [unverified]). Use the lowercase hgnc: form in the KB, and look up the HGNC ID rather than writing it from memory.
• Variants: Ile61Arg (c.182T>G) and Phe65Ser (c.194T>C), both affecting conserved transmembrane residues. (Bruce 2009)
• Functional consequence: the mutant protein induces a monovalent cation leak. The authors note that RhAG belongs to the ammonium transporter family, whose members form pore-like structures. Their modelling suggested the mutations open that pore. (Bruce 2009)
• Candidate class: a gain-of-function neomorphic leak, not simple loss of function. Bind functional_impact_category only if a source states it.
• Allelic disease: biallelic RHAG variants cause Rh-null (regulator type) hemolytic anemia, which is autosomal recessive and a different entity. (GeneBe summary)
• Origin: germline.
• Allele frequency: not retrieved.
• Other genes: SLC4A1 has been linked to milder overhydrated-like phenotypes. (J Blood Med 2019) A second report says OHSt is "frequently linked to mutations in genes that encode components of the band 3 complex, such as RHAG". (Haematologica 2011) Check whether any of these belong in separate entries.
• Epigenetic or chromosomal features: none identified.

5. Environmental information

None are known. There are no established toxin, lifestyle or infectious triggers in anything retrieved.

6. Mechanism and pathophysiology

Ordered causal chain 1. A heterozygous missense variant in RHAG (Ile61Arg or Phe65Ser) alters a conserved transmembrane residue. This is demonstrated. (Bruce 2009) 2. The altered Rh-associated glycoprotein, which is part of the Rh/ankyrin-R/band 3 complex, forms or opens a pore-like cation pathway. This is demonstrated by Xenopus oocyte expression (about 6-fold leak) and supported by structural modelling. 3. The pathway lets monovalent cations (Na⁺ and K⁺) cross the red cell membrane. 4. Na⁺ influx exceeds K⁺ loss, so net cation gain draws water into the cell. This is demonstrated. (Frontiers 2018) 5. Compensatory Na⁺/K⁺-ATPase activity rises. It consumes ATP and glycolytic capacity, and a 2011 metabolomic study of four patients reported "glycolysis is exhausted", with ADP, pyruvate, lactate and malate accumulating. (Haematologica 2011) That study also suggests transporter abnormalities or unrecognised oxidative stress. This step is inferred from small-sample data. 6. The cells swell, take a cup shape (stomatocytes) and have reduced deformability. Why the cup shape forms is unknown. 7. The spleen removes the abnormal cells, which leads to extravascular hemolysis. This is inferred. 8. Chronic hemolysis causes anemia, jaundice, splenomegaly and pigment gallstones. Iron overload can follow [unverified].

Suggested terms (labels only): - GO: monovalent inorganic cation transport; ammonium transmembrane transport; cell volume homeostasis; potassium ion import across plasma membrane. - CL: erythrocyte. - Cellular component: plasma membrane, and the Rh complex if a GO term exists.

Not available: no transcriptomics, proteomics, single-cell or CRISPR-screen data were found.

7. Anatomical structures affected

• Primary: red blood cell membrane. Blood and bone marrow are the main systems involved.
• Secondary: spleen (extravascular hemolysis), liver and biliary tract (gallstones), and liver, heart and endocrine organs if iron overload develops [unverified].
• Subcellular: plasma membrane.
• Suggested UBERON terms (labels): blood, spleen, gallbladder.
• Lateralization: not applicable.

8. Temporal development

• Onset: congenital, with variable presentation from neonatal to childhood.
• Course: lifelong, chronic, and stable or episodic with infections [unverified].
• Remission: none.
• Critical periods: not described in the retrieved material.

9. Inheritance and population

• Inheritance: autosomal dominant. Bind the HPO mode-of-inheritance term after looking it up.
• Prevalence: very rare. The prevalence of the stomatocytosis disorders is uncertain because diagnosis is difficult. (Marcello, Pediatr Blood Cancer 2023) Do not put a number in rate_per_100000 unless Orphanet gives one. Orphanet was not reached.
• Penetrance, expressivity, founder effects, sex ratio: not retrieved.

10. Diagnostics

• Blood film: stomatocytes. Reported lab findings, which I did not verify in detail, are high MCV, low MCHC, reticulocytosis and raised bilirubin.
• Osmotic fragility / ektacytometry: the osmotic gradient ektacytometry curve is shifted. Specialised tests are needed to separate this from other stomatocytoses [unverified].
• Red cell cation content and flux: high Na⁺ with low K⁺ is described for the group [unverified].
• Genetic testing: a gene panel for hereditary hemolytic anemia including RHAG, PIEZO1, KCNN4, GARDOS-related genes and SLC4A1 is the usual approach [unverified]. Check GTR and ClinGen for panels.
• Differential diagnosis: dehydrated stomatocytosis (PIEZO1), hereditary spherocytosis, Rh-null disease, and acquired stomatocytosis (for example alcohol-related).
• Screening: no newborn screening program is known.

11. Outcome and prognosis

• Prognosis is variable and survival data were not retrieved.
• Complications reported for the group include gallstones, iron overload and thrombosis. (J Blood Med 2019)
• Prognostic factors and biomarkers: not found.

12. Treatment

• Supportive care: transfusion when needed, folate supplementation [unverified], monitoring for iron overload, and chelation if iron overload develops [unverified]. Suggested NCIT labels: Supportive Care, Red Blood Cell Transfusion, Iron Chelation Therapy.
• Splenectomy should be avoided. A 2019 review says no specific treatment for symptomatic hemolysis exists and that splenectomy "should be avoided as it seems to aggravate the risk of thrombosis". (J Blood Med 2019) A 1999 case report describes portal vein thrombosis after splenectomy in a child with dehydrated stomatocytosis. (PMID 10445340) A gene summary notes that individuals with OHSt may be prone to iron overload and post-splenectomy thrombotic complications, and that splenectomy may be less beneficial in this form. (GeneBe) The evidence is mostly case reports and case series.
• No gene therapy, targeted therapy or clinical trial was identified. I did not search ClinicalTrials.gov.
• Do not add a therapeutic_agent unless a source names one.

13. Prevention

• Genetic counselling for an autosomal dominant condition.
• Avoid splenectomy as above, and use thrombosis precautions if it cannot be avoided [unverified].
• Iron-overload surveillance.
• No vaccination or public health measures are known to be relevant.

14. Other species

I did not search OMIA, so nothing is established here. A naturally occurring stomatocytosis exists in dogs (Alaskan malamute and Drentse patrijshond) with a different mechanism [unverified]. Check OMIA before using it.

15. Model organisms

• The Xenopus laevis oocyte expression system was used to show the 6-fold cation leak. This is a heterologous in vitro system, so grade it IN_VITRO and not MODEL_ORGANISM. (Bruce 2009)
• I found no knockin mouse, zebrafish or iPSC model of OHSt. Check MGI and the Alliance of Genome Resources before stating that none exists.
• Limitations to record: oocytes lack the red cell cytoskeleton and Rh/ankyrin-R/band 3 complex context, so they are a boundary-omission divergence.

Gaps to close before curation

1. Pull the Bruce 2009 abstract with just fetch-reference PMID:18931342 and quote it verbatim.
2. Look up the Orphanet and OMIM entries for the identifiers, prevalence and phenotype frequencies.
3. Read GeneReviews and ClinGen for the RHAG gene–disease validity tier. Copy the tier, do not assign it.
4. Look up every ontology CURIE with OAK.
5. Confirm the splenectomy claims with abstract-level snippets. The 2019 review and the 1999 case report concern the wider stomatocytosis group, so check what applies to OHSt specifically.

Sources

• Bruce et al., Blood 2009 (PMID 18931342)
• Haematologica 2011 report
• Frontiers in Physiology 2018 review
• J Blood Med 2019 review (PMC6613601)
• J Blood Med 2019, full text
• Splenectomy case report, 1999 (PMID 10445340)
• Marcello, Pediatr Blood Cancer 2023
• GeneBe, RHAG
• KEGG H01979

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Quotes that could not be checked

There was no text to compare these against, so they are neither confirmed nor contradicted:

• DOI:10.3389/fphys.2018.00367: "The influx of Na+ exceeds the loss of K+ causing water influx and resulting in swollen erythrocytes, hemolysis, and stomatocyte formation."
• Reference resolved but exposes no abstract or full text to search

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Every term resolved, and every label the report gave matched.