KITLG – Waardenburg syndrome type 2

Heterozygous variants in KITLG have been implicated in autosomal dominant Waardenburg syndrome type 2 (Waardenburg syndrome type 2). In a small pedigree, linkage analysis and exome sequencing identified a c.310C>G (p.Leu104Val) variant that co-segregated with sensorineural hearing loss and pigmentary anomalies across multiple affected individuals ([PMID:26522471]). No additional unrelated WS2 cases with KITLG variants have been reported to date.

In vitro studies of the p.Leu104Val transmembrane isoform showed normal membrane localization, but secretion of the soluble KITLG form was significantly reduced, supporting a dominant-negative or gain-of-function effect on KITLG–KIT signaling ([PMID:26522471]). This functional evidence concords with the human phenotype and underscores the role of impaired KITLG secretion in WS2 pathogenesis.

Key take-home: KITLG sequencing is warranted in WS2 patients, particularly those with sensorineural hearing loss and pigmentary abnormalities, to guide diagnosis and genetic counseling.

References

• American journal of human genetics • 2015 • Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2. PMID:26522471

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