A novel SOX10 nonsense mutation in a patient with Kallmann syndrome and Waardenburg syndrome

Abstract

Summary: The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells.

Learning points: Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development. SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome. Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.

Figure 1

(A) Hypopigmentation of the right iris. (B). Representative images of the ophthalmoscopy test. The right panel shows the red colored fundus of this patient.

Figure 2

Representative images of brain MRI . The arrows indicate the aplastic olfactory bulb (left panel). No obvious abnormalities were noted in the hypothalamus or pituitary (right panel).

Figure 3

The chromatograms show the partial sequence of exon 3 in this patient. The arrow indicates the c.373C>T heterozygous mutation.

Figure 4

Schematic view of SOX10 gene and SOX10 protein. The purple areas of the SOX10 gene indicate the coding region. Dim, dimerization domain; HMG, high-mobility group; K2, K2 domain; TA, transactivation domain; NLS, nuclear localization signals; NES, nuclear export sequence. Numbers refer to amino-acid residues. The red lines and the blue line under the HMG domain represent the NLS and the NES sequences, respectively.