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Hum Mutat. 2019 May;40(5):532-538. doi: 10.1002/humu.23722. Epub 2019 Mar 12.

Kilquist syndrome: A novel syndromic hearing loss disorder caused by homozygous deletion of SLC12A2.

Author information

1
National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, Bethesda, Maryland.
2
Office of the Clinical Director, National Human Genome Research Institute National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
3
Division of Diagnostic Imaging and Radiology, Children's National Health System, Washington, District of Columbia.
4
Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland.
5
Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri.
6
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.

Abstract

Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next-generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22 kb homozygous deletion in SLC12A2, which encodes for sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia. Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein abundance when compared with control. Loss of Slc12a2 in mice has been shown to lead to deafness, abnormal neuronal growth and migration, severe gastrointestinal abnormalities, and absent salivation. Together with the described phenotype of the Slc12a2-knockout mouse model, our results suggest that the absence of functional SLC12A2 causes a new genetic syndrome and is crucial for the development of auditory, neurologic, and gastrointestinal tissues.

KEYWORDS:

NKCC1; absent salivation; cystic fibrosis; gut malrotation; uniparental isodisomy

PMID:
30740830
PMCID:
PMC6693334
[Available on 2020-05-01]
DOI:
10.1002/humu.23722

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