Deafness, Autosomal Dominant 69 (DFNA69), and Familial Progressive Hyperpigmentation with or without Hypopigmentation via the KITLG Gene

Nonsyndromic hearing loss is characterized by difficulty or inability to hear that is not associated with any visible defects involving the external ear, other organs, or any other medical condition. Nonsyndromic hearing loss may be associated with abnormalities involving the middle ear and/or the inner ear (Ciuman 2013; Dodson et al. 2011; Hilgert et al. 2009). At least 70% of cases involving hearing loss are nonsyndromic (Van Camp et al. 1997).

Nonsyndromic hearing loss and deafness due to pathogenic variants in the KITLG gene is associated with congenital or prelingual, mild to profound, asymetric, unilateral or bilateral, non-progressive sensorineural hearing impairment with overall variable penetrance. No vestibular abnormalities are present. Furthermore, no pigmentation effects were detected in two families with hearing loss due to variants in the KITLG gene (Zazo Seco et al. 2015).

Pathogenic variants in the KITLG gene also cause familial progressive hyperpigmentation with or without hypopigmentation, associated with diffuse hyperpigmentation, cafe-au-lait macules and larger hypopigmented ash-leaf macules on the face, neck, trunk and limbs. Onset is congenital or early infancy and progressive with large areas of the skin becoming hyperpigmented. Hearing was not reported as being affected in patients with pigmentation effects (Wang et al. 2009; Amyere et al. 2011).

The KITLG gene has also been suggested as the cause of hearing loss, heterochromia iridum with skin hyper- and hypopigmentation in a single Dutch family. These features along with the absence of dystopia canthorum in this family had resulted in a diagnosis of Waardenburg syndrome type II prior to genetic testing, indicating that variants in the KITLG gene may also cause this auditory-pigmentary disorder (Zazo Seco et al. 2015).

The KIT ligand (KITLG) gene is located on chromosome 12q21.32 and spans 91.7 kb, consisting of 9 coding exons that produce a 273 amino acid protein. The KITLG protein (also known as steel factor, stem cell factor, and mast cell growth factor) is the ligand for the KIT tyrosine-kinase receptor. KITLG is involved in proliferation and migration of neural crest cells as well as survival and differentiation of hematopoietic precursor cells, primordial germ cells and melanoblasts (Zazo Seco et al. 2015). KIT signaling causes post-translational modification of the MITF protein, a key transcription factor involved in the survival, proliferation and differentiation of melanoblasts as well as regulating the expression of genes involved in pigment production (Zazo Seco et al. 2015; Lin and Fisher 2007).

The mechanism by which KITLG variants cause sensorineural hearing loss is not completely understood, although it is thought to be mediated by melanocytes in the stria vascularis of the inner ear that are necessary for generating the endocochlear potential involved in the detection of sound (Kim et al. 2015; Cable et al. 1992).

Six missense, one small deletion and one premature protein termination variant in the KITLG gene have been reported as pathogenic, all of which were inherited in an autosomal dominant manner (Wang et al. 2009; Amyere et al. 2011; Cuell et al. 2015; Zazo Seco et al. 2015).

The clinical sensitivity of this sequencing test is not precisely known. Only six point and two small insertion/deletion variants in the KITLG gene have been reported as pathogenic (Human Gene Mutation Database). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

This test provides full coverage of all coding exons of the KITLG gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).