ESPE Abstracts (2019) 92 P3-301

A Novel Heterozygous Mutation in The SLC5A2 Gene Causing Mild Failure to Thrive and Subclinical Hypoglycemia in a 2-year Old Girl

Eleni Dermitzaki1, Emmanouil Manolakos2, Fotini Filiousi3, Kleanthis Kleanthous1, Dimitrios T. Papadimitriou1

1Athens Medical Center, Athens, Greece. 2Access to Genome, Athens-Thessaloniki, Greece. 3Pediatrician, Chania, Greece

Patients: A 2-year old girl was referred due to glucosuria 1874 mg/dl. Fasting blood sugar was 71 mg/dl and HbA1c 4.8%. Examination of her growth charts revealed mild failure to thrive, since 15 months of age, as far as weight gain and height velocity. We used Flash technology (FreeStyle Libre) to identify hypoglycemic episodes. In 9 days, 8% of the time was < 70 mg/dl, with 11 hypoglycemic events: mean duration 94 min, lowest 52 mg/dl.

Treatment: We started the child on cornflower 1 g/Kg, with her milk at bedtime and advised for frequent feedings every 3-hours during the day. There was significant improvement in height velocity and weight gain within the next semester, with the BMI completely normalizing. HbA1c did not change but subsequent Libre scans showed elimination of all hypoglycemic excursions.

Methods: We decided to sequence the SLC5A2 gene, as most probable genetic cause. Genomic DNA extracted from peripheral blood. The sample was analyzed using the SeqCap EZ HyperCAp Library (Roche), followed by next generation sequencing (IlluminaNovaSeq 6000). The bioinformatics analysis has been performed using software packages (bcltofastq version 2.20, Isaac Aligner version 4, GATK "Genome Analysis Toolkit" version 4, Samtools version 1.9 and Bedtools version 2). Data analysis and interpretation were done based on patient's clinical information and filtered for a requested gene panel. Variants with a minor allele frequency greater than or equal to 1% were not evaluated. Variants in genes lacking evidence of clinical significance and variants in genes unrelated to the patient's characteristic were not evaluated, unless present in genes assessed for medically actionable secondary findings, in accordance with ACMG recommendations.

Results: The following nucleotide variant is reported: c.[1021+1G>A]+[=] exon 8 in SLC5A2 gene. Variant c.1021+1G>A in heterozygous state is identified in exon 8 in SLC5A2 gene; this variation causes the elimination of canonical splice site. This variant has not a resident no frequency data are reported (gnomAD, dbSNP, ExAC). The variant is not reported in scientific literature and in ClinVar. Mother was also carrier but with no glucosuria.

Conclusions: Heterozygous mutations in the SLC5A2 gene may cause subclinical hypoglycemia and mild failure to thrive in early infancy. Given the mother's state, this novel mutation may be behaving as dominant in early infancy, or there may be an imprinting mechanism involved. Early detection and treatment of this rare disorder may prevent neurological sequelae of undetected hypoglycemia while restoring weight gain and height velocity.

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