Leeds Institute of Medical Research, University of Leeds, St. James's University Hospital, Leeds, UK.
North East and Yorkshire Genomic Laboratory Hub, Central Lab, St. James's University Hospital, Leeds, UK.
J Med Genet. 2024 Mar 21;61(4):347-355. doi: 10.1136/jmg-2023-109510.
Collagen XVII is most typically associated with human disease when biallelic variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous variants causing dominant non-syndromic AI is not widely recognised.
Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth.
Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting.
These results indicate that variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous variants. We propose that patients with isolated AI or ERED, due to variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care.
当双等位基因变异体（>230）导致交界性大疱性表皮松解症（JEB）时，XVII 型胶原最常与人类疾病相关，JEB 是一种罕见的、遗传异质性的黏膜皮肤大疱性疾病，伴有牙釉质发育不全（AI），这是一种发育性牙釉质缺陷。尽管人们认识到 JEB 家族中的杂合子携带者可能患有 AI，并且杂合变体也会导致显性角膜上皮反复侵蚀性营养不良（ERED），但杂合变体导致显性非综合征性 AI 的重要性尚未得到广泛认可。
通过单分子分子反转探针或靶向杂交捕获（定制面板和全外显子组测序）对 AI 队列中的先证者进行筛查，以寻找变体。通过临床检查和受影响牙齿的分析来评估患者的表型。
19 名具有孤立 AI（无共分离特征）的无关先证者携带 17 种潜在致病性的杂合变体，包括错义、提前终止密码子、移码和剪接位点变体，这些变体位于蛋白的内域和外域。AI 表型与厚度接近正常、表面不规则（包括凹坑）的可变局灶性发育不全的釉质一致。
这些结果表明，变体是显性遗传性非综合征性 AI 的常见原因。在 AI 和 JEB 中涉及的变体进行比较，发现类型和分布相似，在两种情况下都有 5 种变体被确定，其中一种变体也可能导致 ERED。遗传检测的可用性增加意味着更多的人将收到杂合变体的报告。我们建议，由于变体导致孤立的 AI 或 ERED 的患者应被视为 JEB 的潜在携带者，并相应地进行咨询，这反映了多学科护理的重要性。
