High rate of molecular diagnosis among individuals with alopecia with known or suspected inborn errors of immunity

Alopecia is a multifactorial disorder causing hair loss of the scalp, face, and/or body. It affects an estimated 0.1–0.2% of individuals worldwide and can be visually stigmatizing and have significant quality of life consequences. While most cases of alopecia lack an identifiable genetic explanation, this condition is enriched in individuals with Mendelian inborn errors of immunity (IEI). The purpose of this study was to determine Mendelian contributions to alopecia in a mixed cohort of patients with suspected IEI. The cohort was comprised of 3,072 unrelated participants with suspected IEI or related inflammatory disorders who underwent exome and/or genome sequencing from 2017–2022. From this pool, we identified 110 (3.58%) probands with alopecia. Probands were predominantly adult (mean 37.2 years, range 4–76), female (67%), and of European ancestry (64.5%). Alopecia was characterized as universalis (3/110, 2.7%), totalis (4/110, 3.6%), areata (5/110, 4.5%), scarring alopecia of the scalp (2/110, 1.8%), and other or not otherwise specified (96/100, 87.3%). Overall, 33/110 probands (30.0%) were found to have a Mendelian molecular diagnosis. Almost half of the participants with molecular diagnoses (15/33, 45%) had biallelic defects in AIRE, consistent with a molecular diagnosis of autoimmune polyendo-crinopathy-candidiasis-ectodermal dystrophy (APECED). In addition, 4/33 (12.1%) had a molecular diagnosis of STAT3-related hyper-IgE syndrome, 2/33 (6.1%) had STAT1 deficiency, and 2/33 (6.1%) had RAG1 deficiency. The remaining 10/33 (30.3%) included defects in the following genes: CXCR4, FAM111B, FOXN1, GATA2, IL2RG, GJB2, NFKB2, PIK3CD, PLCG2, and PSMB8. Multiple linear regression found that when controlling for sex and ancestry, younger age and greater phenotypic complexity was significantly associated with the likelihood of receiving a molecular diagnosis related to alopecia (OR = 0.93, p-value = 0.004 and OR = 1.27, p-value = 0.034, respectively). In summary, a high proportion of individuals with alopecia in an IEI cohort received a molecular diagnosis via WES/WGS. Further, there was a small but significant association between younger age and higher phenotypic complexity and likelihood of receiving a molecular diagnosis. Most molecular diagnoses for alopecia in this cohort were disorders of the immune system, while two (hereditary fibrosing poikiloderma and keratitis-ichthyosis deafness syndrome) involved primarily non-immune etiologies.