Abstract
Loss-of-function variants in the melanocortin 1 receptor (MC1R) gene are a well-established cause of red hair in European populations. However, the genetic spectrum and phenotypic effects of MC1R variants in East Asians remain poorly defined, as red hair is exceedingly rare in this population. To characterize the clinical and genetic features of MC1R-associated red hair and hypopigmentation in Chinese pediatric patients and to expand the genotypic spectrum of MC1R in East Asian populations, four unrelated Chinese children with red or reddish-brown hair underwent comprehensive dermatologic and ophthalmologic assessments and whole-exome sequencing. All MC1R variants were confirmed by Sanger sequencing, and parental samples were analyzed to determine inheritance. In silico prediction tools and structural modeling were used to assess potential pathogenicity and protein-level impact. Seven MC1R variants were identified, including three novel variants: one frameshift (p.Ala28Thrfs*23) and two missense variants (p.Pro295Leu and p.Ser90Asn). Patients carrying compound heterozygous variants showed more pronounced hypopigmentation with bright red hair, whereas the heterozygous carrier of p.Thr157Ile exhibited a milder phenotype. Structural modeling suggested that these variants likely affect transmembrane or intracellular regions of the receptor, potentially altering protein conformation and impairing signaling function. No pathogenic variants in classic oculocutaneous albinism genes were detected. This study expands the genotypic spectrum of MC1R and demonstrates that MC1R deficiency alone can result in an "albinism-like" red hair phenotype in East Asian populations. These findings support including MC1R in the differential diagnosis for Asian patients with unexplained red hair and mild hypopigmentation.