School of Clinical Medicine, Cambridge University, Cambridge, UK.
Department of Clinical Genetics, Addenbrooke's Hospital, Cambridge, UK.
Mol Genet Genomic Med. 2021 Dec;9(12):e1708. doi: 10.1002/mgg3.1708. Epub 2021 Jun 10.
Coats plus syndrome (CP) is a rare autosomal recessive disorder, characterised by retinal telangiectasia exudates (Coats disease), leukodystrophy, distinctive intracranial calcification and cysts, as well as extra-neurological features including abnormal vasculature of the gastrointestinal tract, portal hypertension and osteopenia with a tendency to fractures. CP most frequently occurs due to loss-of-function mutations in CTC1. The encoded protein CTC1 constitutes part of the CST (CTC1-STN1-TEN1) complex, and three patients have been described with CP due to biallelic mutations in STN1. Together with the identification of homozygosity for a specific loss-of-function mutation in POT1 in a sibling pair, these observations highlight a defect in the maintenance of telomere integrity as the cause of CP, although the precise mechanism leading to the micro-vasculopathy seen at a pathological level remains unclear. Here, we present the investigation of a fourth child who presented to us with retinal exudates, intracranial calcifications and developmental delay, in keeping with a diagnosis of CP, and later went on to develop pancytopenia and gastrointestinal bleeding. Genome sequencing revealed compound heterozygous variants in STN1 as the likely genetic cause of CP in this present case.
We assessed the phenotype to be CP and undertook targeted sequencing.
Whilst sequencing of CTC1 and POT1 was normal, we identified novel compound heterozygous variants in STN1 (previous gene symbol OBFC1): one loss-of-function--c.894dup (p.(Asp299Argfs*58)); and one missense--c.707T>C (p.(Leu236Pro)).
Given the clinical phenotype and identified variants we suggest that this is only the fourth patient reported to date with CP due to mutations in STN1.
coats 综合征（CP）是一种罕见的常染色体隐性遗传病，其特征为视网膜毛细血管扩张渗出（Coats 病）、脑白质营养不良、特征性颅内钙化和囊肿，以及胃肠道血管异常、门静脉高压和骨质疏松症伴骨折倾向等神经外表现。CP 最常由 CTC1 功能丧失突变引起。编码蛋白 CTC1 构成 CST（CTC1-STN1-TEN1）复合物的一部分，已有 3 例 CP 患者由于 STN1 的双等位基因突变引起。结合 POT1 特定功能丧失突变纯合子在一对同胞兄妹中的鉴定，这些观察结果强调了端粒完整性维持缺陷是 CP 的原因，尽管导致病理水平微血管病变的确切机制仍不清楚。在这里，我们介绍了第四位患儿的研究情况，该患儿以视网膜渗出、颅内钙化和发育迟缓就诊，符合 CP 的诊断，随后出现全血细胞减少和胃肠道出血。基因组测序显示 STN1 的复合杂合变异可能是该患儿 CP 的遗传原因。
我们评估了 CP 的表型并进行了靶向测序。
虽然 CTC1 和 POT1 的测序正常，但我们在 STN1 中发现了新的复合杂合变异（先前的基因符号 OBFC1）：一个功能丧失--c.894dup（p.（Asp299Argfs*58））；一个错义--c.707T>C（p.（Leu236Pro））。
鉴于临床表型和鉴定的变异，我们建议这是迄今为止第四例由于 STN1 突变导致 CP 的患者。
