Hypomagnesemia and seizures in a patient with an SOS1 mutation

Noonan syndrome (NS) is an autosomal dominant multisystem disorder. The son of sevenless homolog 1 (symbolized SOS1) gene encodes a guanine nucleotide exchange factor (GEF) for Ras proteins.[] Genetic disorders in which the SOS1 mutation has been confirmed include NS. Missense mutations in SOS1 account for roughly 10% of NS.[]

Alteration of the electrolyte gradient across cellular membranes exerts effects on neuronal excitability, and seizures are frequently observed in electrolyte imbalance.[] Magnesium has membrane-stabilizing effects, and seizures usually occur in neonates with severe hypomagnesemia (<1 mEq/L).[] Hypomagnesemia is very rare, but it could be one of the symptomatic causes of seizures.[]

Herein, we report a patient presenting with seizures, who harbored a variant of the SOS1 gene and had isolated hypomagnesemia.

A 38-year-old man has presented to us with seizures. He had visited another hospital with two events of generalized tonic-clonic seizures, 1 and 3 months earlier, respectively. The etiology of the seizures had been evaluated, but the cause was not revealed. The patient had undergone a workup for any causes of loss of consciousness, including autonomic function test, echocardiography, and 24-hour holter monitoring, which revealed no abnormalities.

He was right-handed and had a short stature (156.9 cm) and he had mild intellectual disability. He does not regularly drink alcohol and he has no history of hypertension or diabetes. Lumbar spine radiography revealed scoliosis. There were no family history of any neurological disorders. Neurological examination revealed no focal neurological deficits. His-awake and sleep electroencephalography showed no epileptiform discharges. Brain MRI revealed no structural abnormalities. We checked his serum magnesium levels to investigate the etiology of the seizures and found remarkably low levels (0.9 mg/dl; reference range: 1.6–2.6 for reference). Other electrolytes, including sodium, potassium, and calcium, were in the normal range. He did not complain of diarrhea and had no history of taking any medications that could cause hypomagnesemia, such as loop and thiazide diuretics, cyclosporines, aminoglycoside antibiotics, laxatives, or proton pump inhibitors. The electrocardiogram results were within normal limits. Additional laboratory tests were performed for the evaluation of hypomagnesemia, namely, plasma renin activity (2.86 ng/ml; reference range: 0.6–4.18), intact-parathyroid hormone (9.4 pg/ml; reference range: 15–65), 1,25-dihydroxycholecalciferol (33.83 pg/ml; reference range: 19.6–54.3), and 24-h urine magnesium (321.3 mg/day; reference range: 72.9–121.5). The fractional excretion of magnesium was 10.67%. We confirmed that he had hypomagnesemia due to renal magnesium wasting. However, we could not identify the cause of renal magnesium wasting. Abdominal CT revealed no structural lesions.

Subsequently, whole-exome sequencing (WES) was performed. For WES, genomic DNA was extracted from a buccal swab sample of the proband. All exon regions of all human genes were captured using the xGen Exome Research Panel v2 (Integrated DNA Technologies, Coralville, IA, USA). The captured regions of the genome were sequenced using Novaseq 6000 (Illumina, San Diego, CA, USA). Raw genome sequencing data analysis, including alignment to the GRCh37/hg19 human reference genome, variant calling, and annotation, were conducted with open-source bioinformatics tools and inhouse software. To estimate allele frequency, gnomAD (http://gnomad.broadinstitute.org/) was used as a population genome database, and a 3 billion genome database was used. Common variants with minor allele frequencies of >5% were filtered out in accordance with the BA1 criterion of the American College of Medical Genetics and Genomics (ACMG) guidelines. Then, we extracted evidence data on the pathogenicity of variants from the scientific literature and disease databases, including ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and UniProt (https://www.uniprot.org/). The proband's clinical information profile was accessed to measure the similarity with ∼7000 rare genetic diseases (https://omim.org/ and https://www.orpha.net/consor/cgi-bin/index.php).

In the patient's WES results, a heterozygous missense mutation was identified in the SOS1 gene of chromosome 2p22.1, NM_005633.3:c.305C>T (NP_005624.2:p.Pro102Leu). It is a likely pathogenic variant underlying Noonan syndrome type 4 (NS4; MIM#610,733) and has not been reported before. The patient was diagnosed with NS (Table 1) and was treated with an injection of 2 g magnesium sulfate as the loading dose, followed by infusion of 6 g for 24 h. He was discharged from the hospital with a prescription of 1500 mg/day magnesium. His-serum magnesium level returned to the normal range, and seizures did not recur till the 6 month follow-up.

According to the ACMG/AMP guidelines, the identified mutation from WES results was interpreted as likely pathogenic. This was based on the fulfillment of three lines of evidence under moderate pathogenic criteria (PM), as follows. (1) This is located in a mutational hot spot and critical and well-established functional domain without benign variation (PM1) (2) It is absent from the population database, both gnomAD v2.1.1 and v3 datasets (PM2). (3) The missense variants of SOS1 are commonly associated with NS4, and the rate of benign missense variants is relatively low. Different pathogenic amino acid changes have been reported with sufficient evidence for the same codon (ClinVar ID: VCV000477721) (PM5). Moreover, evidence of an additional supporting criteria was provided: in silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure and function (PP3).

Mutations in proteins involved in the RAS–MAPK signaling pathway are known to cause NS. The SOS1 gene encodes GEF for Ras proteins, which may regulate Ras proteins by facilitating the change between inactive (GDP-bound) and active (GTP-bound) states. On the basis of the reports of SOS1 missense mutations, six variants have been identified as being correlated with NS.

We could not definitely exclude the possibility that hypomagnesemia was not associated with NS. However, his cause of hypomagnesemia was renal magnesium wasting, and renal abnormalities are well-known symptom in NS.[] Additionally, he could not get out of the hypomagnesemia without a continuous supply of magnesium. Thus, hypomagnesemia was considered to be related to the NS.

We report a man presenting with seizures, which are probably caused by hypomagnesemia. He was found to harbor a variant of the SOS1 gene. A mutation in NS is a potential hereditary disease that can cause hypomagnesemia and seizure, which is significant finding in this case report.

None

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.