Institute of Human Genetics and.
Department of Pediatric Dermatology, University Children's Hospital Zurich, Zurich, Switzerland.
Br J Dermatol. 2023 Nov 16;189(6):741-749. doi: 10.1093/bjd/ljad314.
Short anagen hair (SAH) is a rare paediatric hair disorder characterized by a short anagen phase, an inability to grow long scalp hair and a negative psychological impact. The genetic basis of SAH is currently unknown.
To perform molecular genetic investigations in 48 individuals with a clinical phenotype suggestive of SAH to identify, if any, the genetic basis of this condition.
Exome sequencing was performed in 27 patients diagnosed with SAH or with a complaint of short, nongrowing hair. The cohort was screened for variants with a minor allele frequency (MAF) < 5% in the general population and a Combined Annotation Dependent Depletion (CADD) score > 15, to identify genes whose variants were enriched in this cohort. Sanger sequencing was used for variant validation and screening of 21 additional individuals with the same clinical diagnosis and their relatives. Genetic association testing of SAH-related variants for male pattern hair loss (MPHL) was performed using UK Biobank data.
Analyses revealed that 20 individuals (42%) carried mono- or biallelic pathogenic variants in WNT10A. Rare WNT10A variants are associated with a phenotypic spectrum ranging from no clinical signs to severe ectodermal dysplasia. A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-coloured hair and regression of the frontoparietal hairline. Notably, the most frequent variant in the cohort [c.682T>A;p.(Phe228Ile)] was in linkage disequilibrium with four common WNT10A variants, all of which have a known association with MPHL. Using UK Biobank data, our analyses showed that c.682T>A;p.(Phe228Ile) and one other variant identified in the SAH cohort are also associated with MPHL, and partially explain the known associations between WNT10A and MPHL.
Our results suggest that WNT10A is associated with SAH and that SAH has a genetic overlap with the common phenotype MPHL. The presumed shared biologic effect of WNT10A variants in SAH and MPHL is a shortening of the anagen phase. Other factors, such as modifier genes and sex, may also play a role in the clinical manifestation of hair phenotypes associated with the WNT10A locus.
短生长期毛发（SAH）是一种罕见的儿科毛发疾病，其特征为生长期短、无法生长长的头皮毛发以及带来负面的心理影响。SAH 的遗传基础目前尚不清楚。
对 48 名临床表型疑似 SAH 的个体进行分子遗传学研究，以确定是否存在这种情况的遗传基础。
对 27 名被诊断为 SAH 或头发短、不生长的患者进行外显子组测序。对人群中 MAF<5%和 CADD 评分>15 的变异进行筛选，以鉴定在该队列中富集的基因。对 21 名具有相同临床诊断的个体及其亲属进行 Sanger 测序验证和筛查。使用 UK Biobank 数据对与男性型脱发（MPHL）相关的 SAH 相关变异进行遗传关联测试。
分析表明，20 名个体（42%）携带 WNT10A 的单或双等位基因致病性变异。罕见的 WNT10A 变异与从无临床体征到严重外胚层发育不良的表型谱相关。WNT10A 与 SAH 之间存在显著关联，并且主要在浅色头发和额顶头发线后退的个体中观察到。值得注意的是，该队列中最常见的变异[c.682T>A;p.(Phe228Ile)]与四个常见的 WNT10A 变异处于连锁不平衡状态，所有这些变异均与 MPHL 有关。使用 UK Biobank 数据，我们的分析表明，c.682T>A;p.(Phe228Ile)和在 SAH 队列中发现的另一个变异也与 MPHL 相关，并且部分解释了 WNT10A 与 MPHL 之间已知的关联。
我们的研究结果表明，WNT10A 与 SAH 相关，SAH 与常见表型 MPHL 存在遗传重叠。WNT10A 变异在 SAH 和 MPHL 中的假定共同生物学效应是生长期缩短。其他因素，如修饰基因和性别，也可能在与 WNT10A 基因座相关的毛发表型的临床表现中发挥作用。
