A New Case of Kilquist's Syndrome with a Novel Variant in SLC12A2 and a Brief Review of the Literature

Abstract

Background Kilquist's syndrome is a recently described rare disease characterized by hearing loss, secretory dysfunction, gastrointestinal system abnormalities, and neurological anomalies including hypotonia and global developmental delay. It is caused by mutations in the solute carrier family 12 member 2 (SLC12A2) gene, which encodes the Na-K-2Cl cotransporter isoform 1 (NKCC1).

Objective The aim of this study was to contribute to understanding the genotype–phenotype correlations of SLC12A2 variants.

Material and Methods We evaluated a Turkish patient with a novel variant in SLC12A2 and reviewed all previously reported cases with Kilquist's syndrome. Whole exome sequencing and Sanger sequencing were used as molecular genetic testing methods.

Results Whole exome sequencing revealed a nonsense homozygous NM_001046.3: c.2534G > A (pW845*) variant in the SLC12A2 gene. Sanger sequencing confirmed the variant. The patient was homozygous for this variant; the parents were heterozygous.

Conclusion This is the first Turkish patient with a novel variant in SLC12A2 reported in the literature. With this report, we have contributed to expanding the clinical and mutation spectrum of SLC12A2.

Keywords

SLC12A2 - Kilquist's syndrome - NKCC1 - novel - developmental delay

Ethical Statement

Samples from the patient were obtained in accordance with the Helsinki Declaration. The paper is exempt from ethical committee approval. Ethical approval was not required for this study in accordance with local/national guidelines. Written informed consent for genetic testing was obtained from the patient's parents. Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images.

Data Availability Statement

All data generated or analyzed during this study are included in the references. Further inquiries can be directed to the corresponding author.

Publication History

Received: 03 July 2024

Accepted: 25 November 2024

Article published online:
28 December 2024

• References

• 1 Bilal Shamsi M, Saleh M, Almuntashri M. et al. Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease. J Hum Genet 2021; 66 (07) 689-695
• 2 Koumangoye R, Bastarache L, Delpire E. NKCC1: newly found as a human disease-causing ion transporter. Function 2020; 2 (01) zqaa028
• 3 Szymanski J, Minichiello L. NKCC1 deficiency in forming hippocampal circuits triggers neurodevelopmental disorder: role of BDNF-TrkB signalling. Brain Sci 2022; 12 (04) 502
• 4 Delpire E, Wolfe L, Flores B. et al. A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1. Cold Spring Harbor Laboratory Mol Case Stud 2016; 2 (06) a0001289
• 5 Virtanen MA, Uvarov P, Hübner CA, Kaila K. NKCC1, an elusive molecular target in brain development: making sense of the existing data. Cells 2020; 9 (12) 2607
• 6 Zhang S, Zhou J, Zhang Y. et al. The structural basis of function and regulation of neuronal cotransporters NKCC1 and KCC2. Commun Biol 2021; 4 (01) 226
• 7 Kaila K, Price TJ, Payne JA, Puskarjov M, Voipio J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci 2014; 15 (10) 637-654
• 8 Watanabe M, Fukuda A. Development and regulation of chloride homeostasis in the central nervous system. Front Cell Neurosci 2015; 9: 371
• 9 Peerboom C, Wierenga CJ. The postnatal GABA shift: a developmental perspective. Neurosci Biobehav Rev 2021; 124: 179-192
• 10 Badurek S, Griguoli M, Asif-Malik A. et al. Immature dentate granule cells require Ntrk2/Trkb for the formation of functional hippocampal circuitry. iScience 2020; 23 (05) 101078
• 11 LOVD. The SLC12A2 gene homepage. Accessed December 13, 2024 at: https://databases.lovd.nl/shared/genes/SLC12A2
• 12 Macnamara EF, Koehler AE, D'Souza P. et al. Kilquist syndrome: a novel syndromic hearing loss disorder caused by homozygous deletion of SLC12A2. Human Mutat 2019; 40 (05) 532-538
• 13 Stödberg T, Magnusson M, Lesko N. et al. SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia. Neurol Genet 2020; 6 (04) e478
• 14 Delpire E, Koumangoye R. NKCC1 in human diseases: is the SLC12A2 gene haploinsufficient?. Am J Physiol Cell Physiol 2023; 325 (02) C385-C390