A NOVEL MUTATION OF SLC12A3 GENE CAUSING GITELMAN SYNDROME /CASE REPORT/

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A NOVEL MUTATION OF SLC12A3 GENE CAUSING GITELMAN SYNDROME /CASE REPORT/

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Co-author 1

Byamba Altangerel byamba.aa0219@gmail.com State Second Central Hospital of Mongolia Department of Nephrology and Endocrinology Ulaanbaatar Mongolia *

Co-author 2

Baigalmaa Sodnomdarjaa sodbaigalmaa@gmail.com State Second Central Hospital of Mongolia Department of Nephrology and Endocrinology Ulaanbaatar Mongolia -

Co-author 3

Janibek Baimurat janibekb@hotmail.com State Second Central Hospital of Mongolia Department of Nephrology and Endocrinology Ulaanbaatar Mongolia -

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Introduction

Gitelman syndrome is a manifestation of a mutation in the SLC12A3 gene that encodes the thiazide-sensitive sodium chloride cotransporter (NCC) present in the apical membrane of cells on the distal convoluted tubule. More than 350 mutations in SLC12A3 have been identified in these patients. Gitelman syndrome is an autosomal recessive tubular disorder.

Gitelman Syndrome is a rare genetic disorder characterized by renal potassium wasting, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyperreninemic hyperaldosteronism.

Case presentation:

Patient's information: Age: 26, Sex: Fеmale

Body weight: 34kg, Height: 145cm

BMI: 16.6kg/m2, Occaption:Chef

Pregnancy: 1, Delivery: C-section

Chief complaint:

Low blood pressure, Cramps, muscle weakness, Unable to walk by herself, Carpopedal spasm, Excessive thirst, Increased urination, Severe fatigue

Past Medical History:

Since childhood: there were occasional weakness in the arms and legs. These symptoms improved spontaneously within 2-3 days, so she never sought medical attention. She lost 9kg within a month Nov to Dec/2022. A month ago, her legs and arms started to get weak. She hospitalized in her soum and provincial hospital, but she did not improve, On 19/Dec/2022 she came at ED of our hospital with symptoms as muscle weakness, and unable to walk.

Physical examination: Blood pressure: 70/40mmHg

Physical examination of all organ systems were normal

Joint structure and function were normal

Arms and legs muscle strength: 2-3 scale.

Urine Output: 2500ml/day

Laboratory analysis

CBC: Leukocytosis, Thrombocytosis /WBC 11.1 10^9/L , PLT 609 10^9/mL/

Biochemistry: Severe Hypokalemia К 1.79mmol/l, Hypomagnesemia Mg 0.6mmol/l, Hypochloremia Cl 92.6mmol/l, Hyponatremia Na 134mmol/l, Crea 64umol/l, Ca 2.4mmol/l

Arterial Blood Gas: Metabolic alkalosis pH7.482↑, cHCO3 25.3↑

Urine analysis- pH 7.5

24hour urine electrolytes analysis:

К 18.8mmol/l, Ca 0.3mmol/l, Cl 92.2mmol/l, Crea 1.4mmol/l

FE K+ 27%, TTKG 16, FE Ca+ 0.003, FE Cl- 2.4%

Urine K/Cr= 18.8meq/l/0.25g/l= 75meq/g confirming renal potassium wasting.

Urine Ca/Crea(mg/mg) = 1.2mg/dL/ 25.2mg/dL= 0.047 hypocalciuria

Medical test:

ECG:T wave flattening, ST-segment depression, Prominent U waves , Long QT intervals in all leads.

Abdominal US: Renal size normal, 1.0-2.0cm multiple cysts in the both kidney

Karyotype Test: A normal female karyotype (46XX)

Genetic Test: Potential compound heterozygous pathogenic and likely pathogenic variants were identified in SLC12A3. SLC12A3 is associated with autosomal recessive 'Gitelman syndrome (OMIM: 263800)'. As one of the variants/SLC12A3 NM_001126108.2:c.1964G>A (NP_001119580.2:p.Arg655His)/ has never been reported in other patients. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset(total allele frequency: 0.008%).

Diagnosis: Gitelman syndrome confirmed by genetic test (OMIM: 263800)

Treatment: Gitelman syndrome KDIGO 2017 guideline /Potassium and Magnesium replacement therapy/

Methods

Genomic DNA was extracted from EDTA blood specimen using standard protocol. Exome capture was performed using xGen Exome Research Panel v2, supplemented with xGen human mtDNA panel and xGen Custom Hyb Panel v1 (Integrated DNA Technologies, Coralville, Iowa, USA). Sequencing was performed using NovaSeq 6000 (Illumina, San Diego, CA, USA). /Institution: Seoul National University Hospital/

Results

Genetic test result: POSITIVE

Gitelman syndrome (OMIM: 263800)

Gene

Variant

Classification

SLC12A3

Genomic Position: 16-56920314-G-A (GRCh37)
DNA: NM_001126108.2:c.1964G>A
Protein: NP_001119580.2:p.Arg655His
Zygosity: Heterozygous
Inheritance: Unknown

Pathogenic

SLC12A3

Genomic Position: 16-56924229-CG-C (GRCh37)
DNA: NM_001126108.2:c.2332del
Protein: NP_001119580.2:p.Glu778ArgfsTer8
Zygosity: Heterozygous
Inheritance: Unknown

Likely pathogenic

Potential compound heterozygous pathogenic and likely pathogenic variants were identified in SLC12A3. SLC12A3 is associated with autosomal recessive 'Gitelman syndrome (OMIM: 263800)'. As one of the variants has never been reported in other patients, functional analysis is recommended. Parental testing is also recommended to check if the two variants are in trans.

SLC12A3 NM_001126108.2:c.1964G>A (NP_001119580.2:p.Arg655His)

Population Data	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%).
Predicted Consequence/Location	Missense variant
Segregation Data	None
Computation and Functional Data	In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.54 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.86 (>=0.6, sensitivity 0.72 and precision 0.9)].
Previously Reported Variant Data	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008588 / PMID: 8528245). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 11168953, 22934535, 24776766). Different missense changes at the same codon (p.Arg655Cys, p.Arg655Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008589, VCV000840885 / PMID: 8528245, 9734597).
Disease Association	Gitelman syndrome (OMIM: 263800)
Variant Classification	Pathogenic

Conclusion

Gitelman syndrome should be considered in patients with hypokalemia complicated with hypomagnesemia and hypocalciuria. Genetic testing is essential to confirm the diagnosis.

Kewords