Rare anaemia

Gene: SLC4A1

Green List (high evidence)

Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - some had mild hematological incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.

Created: 20 May 2026, 10:25 a.m. | Last Modified: 20 May 2026, 10:59 a.m.

Panel Version: 4.2

Biallelic anaemia cases:
PMID: 37448902 Shaikh, Suratkal, and Bhave, 2023
Report of an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia. The patient was treated for suspicion of autoimmune hemolytic anemia but was recalcitrant to treatment. Genetic analysis revealed the patient to be homozygous for SLC4A1 c.2573C>A (p.Ala858Asp). The patient’s parents and siblings had no clinical history of hematological or renal disease.

PMID: 36776909 Yang et al., 2023 - literature review
"almost half of the patients with AR dRTA had hematological abnormalities, while it was uncommon in patients with AD dRTA'
dRTA = distal renal tubular acidosis
"Autosomal recessive inheritance was more often found in Asian patients (P < 0.05)."

PMID: 29483102 Yang et al., 2018
Patient with anemia and distal renal tubular acidosis, homozygous for SLC4A1 c.2173A>C, p.Ser725Arg. 6-day-old male infant presented with tachypnea, intermittent hypoxia, scleral icterus, splenomegaly, and severe anemia, hemoglobin 6.6 g/dL, and marked spherocytosis. Mother and father (first cousins from Pakistan) were het for the variant, also had Band 3 deficiency and a level of hemolysis, though much lower than in the proband.

PMID: 22126643 Fawaz et al., 2012
Study of 7 children from 5 consanguineous Omani families presenting with hyperchloremic normal anion gap metabolic acidosis, failure to thrive, and mild to moderate compensated hemolytic anemia, homozygous for c.2573C>A; p.Ala858Asp (confirmed het in all parents). Reported striking acanthocytosis in the homozygous state and only a mild acanthocytosis in parents.

PMID: 18174378 Toye et al., 2008
Proband developed a transfusion-dependent, hemolytic anemia following birth. Immunoblotting showed band 3 was reduced to approximately 35% of wildtype. Homozygous SLC4A1 c.2000C>T, p.Ser667Phe variant detected. Parents are first cousins from Algerina, both het for the variant - showed compensated hemolysis and spherocytosis, which they were unaware of.

PMID: 16252102 Choo et al., 2005
Patient 2, Sarawak boy with profound hemolytic anemia - comp het for SLC4A1 p.Q759H and p.Ala400_Ala408del variants. Admitted to hospital at 3 weeks due to anemia and failure to thrive, required blood transfusions.

Created: 20 May 2026, 10:19 a.m. | Last Modified: 20 May 2026, 10:57 a.m.

Panel Version: 4.2

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Distal renal tubular acidosis 4 with hemolytic anemia, OMIM:611590; Cryohydrocytosis, OMIM:185020; Spherocytosis, type 4, OMIM:612653

Publications

• 37448902
• 36776909
• 29483102
• 18174378
• 16252102

Green List (high evidence)

Gene rating submitted 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.

Created: 18 Feb 2019, 2:24 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Haemolytic Anemia; RBC membrane abnormality; Cryohydrocytosis,185020; Ovalocytosis, SA type, 166900; Spherocytosis, type 4, 612653

Green List (high evidence)

Gene rating submitted 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.

Created: 14 Feb 2019, 4:04 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
612653 Spherocytosis, type 4; 166900 Ovalocytosis, SA type

Green List (high evidence)

Gene rating submitted by Frances Smith Viapath Kings College Hospital February 2019 on behalf of London South GLH for the GMS Haematology specialist test group.

Created: 8 Feb 2019, 3:46 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
166900 Ovalocytosis, SA type, 185020 Cryohydrocytosis; 612653 Spherocytosis, type 4

Publications

• 1722314

Variants in this GENE are reported as part of current diagnostic practice

I don't know

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: SLC4A1; Suggested initial 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, imprinted status unknown; Phenotypes: Haemolytic Anemia;RBC membrane abnormality;Cryohydrocytosis,185020;Ovalocytosis, SA type, 166900;Spherocytosis, type 4, 612653; PMID(s): none submitted

Created: 18 Feb 2019, 2:28 p.m.

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: SLC4A1; 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, imprinted status unknown; Phenotypes: 612653 Spherocytosis, type 4;166900 Ovalocytosis, SA type; PMID(s): none submitted

Created: 14 Feb 2019, 4:05 p.m.

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: SLC4A1; Suggested intial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? Yes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Phenotypes: 166900 Ovalocytosis, SA type, 185020 Cryohydrocytosis;612653 Spherocytosis, type 4; PMID(s): 1722314

Created: 8 Feb 2019, 3:49 p.m.

Initial gene list (Consensus Genes for Panels 17.12.18_Haem_WWMGLH_v3.xlxs) collated by Carl Fratter Oxford Medical Genetics Laboratories January 2019 on behalf of Wessex and the West Midlands GLH for the GMS Haematology specialist test group. Gene Symbol submitted: SLC4A1; Suggested intial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? Yes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Phenotypes: Haemolytic Anemia;RBC membrane abnormality;Cryohydrocytosis,185020;Ovalocytosis, SA type, 166900;Spherocytosis, type 4, 612653; PMID(s): 16227998;8608262;7949112;2146504;1722314;8471774;8282779;8547122

Created: 6 Feb 2019, 12:14 p.m.

Green List (high evidence)

Gene rating submitted by Carl Fratter Oxford Medical Genetics Laboratories January 2019 on behalf of Wessex and the West Midlands GLH for the GMS Haematology specialist test group.

Created: 6 Feb 2019, 12:13 p.m.

Variants in this GENE are reported as part of current diagnostic practice