German Ryan J, Vuocolo Blake, Vossaert Liesbeth, Saba Lisa, Fletcher Robin, Tedder Matthew L, Sadikovic Bekim, Kerkhof Jennifer, Wangler Michael, Bacino Carlos A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
Am J Med Genet A. 2025 Jan;197(1):e63849. doi: 10.1002/ajmg.a.63849. Epub 2024 Aug 21.
We report a 40-year-old African American female with a novel variant in exon 8 of DNA methyltransferase 3 alpha (DNMT3A), (NM_022552.4: c.905G>C, p.G302A) who presented with a history of recurrent carotid paragangliomas, mediastinal mass, intellectual disability, dysarthria, cholelithiasis, diabetes mellitus, hypertension, and dysmorphic features. We interpret this novel variant as likely pathogenic and causative for the patient's syndromic features of Heyn-Sproul-Jackson syndrome. Heyn-Sproul-Jackson syndrome is a condition caused by gain-of-function genetic changes in DNMT3A. Paragangliomas have also been observed in non-syndromic patients with genetic alterations in DNMT3A. We describe a patient with clinical features of Heyn-Sproul-Jackson syndrome such as intellectual disability, dysarthria, brachydactyly, and lack of brain MRI findings to add evidence to associate paragangliomas with DNMT3A and draw particular attention to the potential involvement of the proline-tryptophan-tryptophan-proline domain of DNMT3A.
我们报告了一名40岁的非裔美国女性，其DNA甲基转移酶3α（DNMT3A）外显子8存在一种新的变异（NM_022552.4: c.905G>C, p.G302A），该患者有复发性颈动脉副神经节瘤、纵隔肿块、智力残疾、构音障碍、胆结石、糖尿病、高血压和畸形特征的病史。我们将这种新变异解释为可能致病，并导致患者出现海恩-斯普劳尔-杰克逊综合征的症状。海恩-斯普劳尔-杰克逊综合征是一种由DNMT3A功能获得性基因改变引起的疾病。在DNMT3A基因改变的非综合征患者中也观察到了副神经节瘤。我们描述了一名具有海恩-斯普劳尔-杰克逊综合征临床特征的患者，如智力残疾、构音障碍、短指畸形，且脑部MRI检查无异常发现，以补充将副神经节瘤与DNMT3A相关联的证据，并特别关注DNMT3A的脯氨酸-色氨酸-色氨酸-脯氨酸结构域的潜在作用。
