SOX10 – Kallmann Syndrome

Kallmann syndrome (KS) is an idiopathic form of hypogonadotropic hypogonadism characterized by anosmia and failure of pubertal development. While KS is genetically heterogeneous, heterozygous mutations in SOX10 (HGNC:11190) have emerged as a contributor to KS with sensorineural hearing loss and iris hypopigmentation, expanding its phenotypic spectrum beyond Waardenburg syndrome. Clinical reports now describe six unrelated KS probands ([PMID:26228106]) carrying SOX10 variants, underscoring a reproducible gene–disease link. The overall association meets a Strong ClinGen classification based on multiple de novo or segregating variants and concordant functional data. No studies have refuted this link or implicated alternative mechanisms in KS. SOX10 analysis should be considered in KS cases with hearing impairment.

Heterozygous SOX10 variants show an autosomal dominant inheritance pattern in KS. Of the six reported probands, five carried de novo truncating or missense mutations and one family demonstrated mother–daughter transmission ([PMID:39680495]). One recurrent nonsense variant, c.565G>T (p.Glu189Ter), recurred in a Chinese male with KS, deafness, iris hypopigmentation, and hyperthyroidism ([PMID:29678855]). Segregation analysis confirmed variant co-occurrence with KS in a maternal lineage (one affected relative). The variant spectrum includes nonsense, frameshift, and pathogenic missense alleles absent from population controls.

The SOX10 allelic series in KS comprises loss-of-function variants: frameshifts such as c.124delC (p.Leu42CysfsTer67) and c.1179_1180insACTATGGCTCAGCCTTCCCC (p.Ser394ThrfsTer?), alongside missense changes within the HMG domain. Most variants truncate or disrupt the C-terminal transactivation domain. The pathogenic c.565G>T (p.Glu189Ter) variant abolishes DNA-binding and transactivation capability in vitro. Recurrent alleles suggest a common haploinsufficiency mechanism across KS and Waardenburg phenotypes.

Functional assays consistently demonstrate that KS-associated SOX10 variants exhibit markedly reduced transcriptional activation of downstream targets. In vitro studies showed that p.Leu145Pro and p.Gly41Val mutations nearly eliminate MITF promoter activation, both alone and in synergy with PAX3 ([PMID:30914325]). Similarly, c.565G>T (p.Glu189Ter) yields a truncated protein with minimal transactivating activity. These data align with a haploinsufficiency model whereby reduced SOX10 dosage impairs neural crest-derived olfactory ensheathing cell differentiation and gonadotropin-releasing hormone neuron migration.

No conflicting evidence disputes SOX10’s role in KS. Reported KS patients lacked other Waardenburg features such as Hirschsprung disease, indicating phenotype modulation by allelic context or modifier genes. The KS-linked SOX10 variants all impair a shared molecular pathway critical for neural crest cell development.

Integration of genetic and functional data supports a coherent model: SOX10 haploinsufficiency disrupts olfactory axon targeting and GnRH neuron migration, leading to KS with deafness and hypopigmentation. Additional rare missense variants may underlie subtler phenotypes and warrant deeper investigation. Key take-home: SOX10 mutation analysis is clinically valuable for diagnosing KS patients with co-occurring hearing loss and anosmia.

References

• Hormone research in paediatrics • 2015 • Loss-of-Function SOX10 Mutation in a Patient with Kallmann Syndrome, Hearing Loss, and Iris Hypopigmentation. [PMID:26228106]
• Gene • 2019 • Functional analysis of SOX10 mutations identified in Chinese patients with Kallmann syndrome. [PMID:30914325]

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