Centre de Génétique et Centre de référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France.
Laboratoire de Génétique Moléculaire, UF Innovation en diagnostic génomique des maladies rares, Plateau Technique de Biologie, Centre Hospitalier Universitaire de Dijon, Dijon, France.
Eur J Hum Genet. 2020 Aug;28(8):1044-1055. doi: 10.1038/s41431-020-0582-3. Epub 2020 Feb 18.
Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.
早衰综合征的特征为智力障碍多变、行为障碍、大头畸形面容以及听力损失、异位钙化、远端肌肉萎缩和挛缩等进行性表型。2014 年，鉴定出 ZBTB20 变异体是导致该综合征的原因。实际上，ZBTB20 在认知、记忆、学习过程中发挥重要作用，对众多基因具有转录抑制作用。与携带大片段缺失的患者相比，携带错义单核苷酸变异的患者表现出更严重的表型。在此，我们报告了通过 AnDDI-Rares 网络招募的 14 名患者的临床和分子结果：6 名患者携带 ZBTB20 错义 SNV，1 名患者携带早期截断缺失，7 名患者携带 3q13.31 缺失。我们比较了他们的表型并回顾了文献数据，以建立更有力的表型-基因型相关性。所有 57 名患者均表现为轻度至重度智力障碍和/或精神运动发育迟缓。面部特征相似，表现为大头畸形、前额突出、眼睑下垂、上睑下垂和大耳朵。错义 SNV 患者更常发生听力损失（p=0.002），异位钙化、进行性肌肉萎缩和挛缩仅见于错义 SNV 患者（p 无显著性）。胼胝体发育不良（p=0.00004）、甲状腺功能减退（p=0.047）和糖尿病在该组中也更为常见。然而，缺失和截断变异患者的中位年龄为 9.4 岁，而错义 SNV 患者为 15.1 岁。需要更长的随访时间来确定缺失患者的表型是否也呈进行性。
