PADI3 – Uncombable Hair Syndrome

Uncombable hair syndrome (UHS) is a rare congenital hair shaft disorder characterized by dry, straw‐colored, frizzy hair that cannot be flattened due to longitudinal grooves in the hair shafts. Biallelic mutations in PADI3, encoding peptidylarginine deiminase 3, underlie an autosomal recessive form of UHS 27866708. PADI3 collaborates with TGM3 and TCHH in posttranslational modification of hair shaft proteins, and pathogenic variants disrupt this process.

Genetic analyses of 107 unrelated UHS index patients identified biallelic PADI3 variants in 76 individuals, establishing autosomal recessive inheritance 36044230. Additional case reports include two siblings harboring c.1374dup (p.Val459ArgfsTer15) detected by Sanger sequencing in a consanguineous family 38456245 and a singleton case due to maternal uniparental disomy of chromosome 1 implicating PADI3 loss of function 36541401.

The PADI3 variant spectrum comprises missense, nonsense, frameshift, and splice variants. Notable recurrent alleles in European and Asian cohorts include c.652G>A (p.Gly218Ser), c.556C>T (p.Arg186Trp), c.505C>T (p.Gln169Ter), c.1868C>T (p.Pro623Leu), c.1183del (p.Glu395AsnfsTer7), c.1115G>T (p.Arg372Met), and c.1114A>G (p.Arg372Gly) 36044230. We report here c.652G>A (p.Gly218Ser) as a representative pathogenic allele.

Segregation analysis is limited, with only one sib‐pair reported; no additional affected relatives have been documented. Carrier frequency estimates are lacking, but the high detection rate in referral cohorts suggests a prevalence of PADI3‐related UHS is underrecognized.

Functional studies demonstrate that PADI3 mutations impair enzyme activity and disrupt hair shaft architecture. Cell culture assays reveal diminished citrullination of trichohyalin substrates, and scanning electron microscopy of Padi3 knockout mice recapitulates the characteristic grooved hair phenotype, confirming loss‐of‐function pathomechanism 27866708.

Overall, the evidence meets ClinGen Strong criteria for PADI3–UHS association based on 79 probands, autosomal recessive inheritance, and concordant functional models. Molecular testing of PADI3 is recommended for definitive diagnosis of UHS, enabling accurate genetic counseling and potential future therapeutic development.

References

• American Journal of Human Genetics • 2016 • Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome PMID:27866708
• Journal of the American Academy of Dermatology • 2022 • Genetic Spectrum of Uncombable Hair Syndrome in a Worldwide Cohort PMID:36044230
• Pediatric Dermatology • 2024 • Two siblings with uncombable hair syndrome: A new pathogenic variant PMID:38456245
• American Journal of Medical Genetics Part A • 2023 • Uncombable hair syndrome due to maternal uniparental disomy of chromosome 1 PMID:36541401

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