The Genetics and Prenatal Diagnosis Center, The Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
The Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
BMC Med Genomics. 2023 Feb 16;16(1):24. doi: 10.1186/s12920-022-01424-4.
Rubinstein-Taybi syndrome (RSTS) is an extremely rare autosomal dominant inheritable disorder caused by CREBBP and EP300 mutations, while atypical RSTS harbouring variant from the same genes but not obvious resembling RSTS. There are only a few cases of Menke-Hennekam syndrome (MKHK) with variant of exon 30 or 31 of CREBBP or EP300 gene have been reported that not resembling RSTS recent years. Atypical RSTS cannot be accurately classified as MKHK, nor is it easy to identify the obvious classic characteristics of RSTS. The clinical manifestations and genetic variation of atypical RSTS are not fully understood.
We present a Chinese core family with a girl had recurrent respiratory tract infection and developmental delay. The patient with language and motor mild development retardation, she has slight abnormal facial features, mild hirsutism and post-axial hexadactylia of left foot. Her cisterna magna is enlarged to connect with the fourth ventricle, and the ventricular system is enlarged. She has a malacia beside the posterior horn of the left lateral ventricle. The patient has primary low immunoglobulin G and A, but her level of immunoglobulin M content in blood is normal. The patient harbors a novel heterozygous frameshift variant of c.2499dupG in exon 14 of EP300 gene, that it is proved to de novo origin. The mutation is judged to be a pathogenic mutation, and it has high-grade pathogenic evidence.
The clinical and genetic evaluation of this case corroborates that clinical features caused by c.2499dupG in exon 14 of EP300 are less marked than RSTS2 patient although it is difficult to establish an accurate genotype-phenotype correlation. Our additional case also helps to deepen the clinical and genetic spectrum in this disorder. The case provides a novel mutation of EP300 and enriches the phenotypes related with the gene. We have contributed new variation and disease information for guardians and doctors to broaden the knowledge about EP300-RSTS genotype and phenotype, this may contribute to ameliorate the health management of patients and improve the genetic counseling to the families.
Rubinstein-Taybi 综合征（RSTS）是一种极其罕见的常染色体显性遗传性疾病，由 CREBBP 和 EP300 基因突变引起，而具有相同基因但不具有明显 RSTS 表型的非典型 RSTS。近年来，仅有少数 Menke-Hennekam 综合征（MKHK）病例报道，其 CREBBP 或 EP300 基因外显子 30 或 31 存在变异，但不具有 RSTS 表型。非典型 RSTS 不能准确归类为 MKHK，也不容易识别 RSTS 的明显经典特征。非典型 RSTS 的临床表现和遗传变异尚不完全清楚。
我们报告了一个中国核心家庭，其中一个女孩反复呼吸道感染和发育迟缓。该患者语言和运动发育轻度迟缓，具有轻微的面部异常、轻度多毛症和左足的后轴六指。她的小脑延髓池扩大并与第四脑室相通，脑室系统扩大。左外侧脑室后角旁有软化灶。患者的免疫球蛋白 G 和 A 水平较低，但血液中免疫球蛋白 M 含量正常。患者携带 EP300 基因外显子 14 中的 c.2499dupG 杂合移码变异，证实其为新生突变。该突变被判断为致病性突变，具有高度致病性证据。
该病例的临床和遗传学评估证实，尽管难以建立准确的基因型-表型相关性，但 EP300 基因外显子 14 中的 c.2499dupG 引起的临床特征不如 RSTS2 患者明显。我们的附加病例也有助于加深对该疾病的临床和遗传谱的认识。该病例提供了 EP300 的新突变，并丰富了与该基因相关的表型。我们为监护人和医生提供了新的变异和疾病信息，以拓宽他们对 EP300-RSTS 基因型和表型的认识，这有助于改善患者的健康管理并提高对家庭的遗传咨询。
