Poisson Alice, Lesca Gaetan, Chatron Nicolas, Favre Emilie, Cottin Vincent, Gamondes Delphine, Sanlaville Damien, Edery Patrick, Giraud Sophie, Demily Caroline, Dupuis-Girod Sophie
GénoPsy, Center for Diagnosis and Management of Genetic Psychiatric Disorders, Centre Hospitalier le Vinatier, Lyon, France; Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon 2, France.
Hospices Civils de Lyon, Genetic Department and Molecular Biology Laboratory, Centre de Biologie Est, Bron, F-69677, France; Université Claude Bernard Lyon 1, F-69100, Villeurbanne, France.
Eur J Med Genet. 2019 Nov;62(11):103565. doi: 10.1016/j.ejmg.2018.10.017. Epub 2018 Oct 30.
Hereditary hemorrhagic telangiectasia is usually linked to the presence of a pathogenic mutation ACVRL1 or ENG. Thus, apparently there is no benefit to perform an array CGH in case of HHT. However, ENG has been involved in a contiguous gene syndrome due to a de novo 9q33.3q34.11 microdeletion. We describe here a new contiguous gene syndrome involving ACVRL1 gene. A 50-year-old female patient had a typical clinical presentation of hereditary hemorrhagic telangiectasia (HHT) with epistaxis, cutaneous-mucous telangiectases, arteriovenous malformation. She also presented a cognitive disability. Cognitive assessment showed a heterogeneous cognitive disorder predominating in the executive sphere without intellectual deficiency. She had no peculiar morphological feature. Neurological examination disclosed the presence of contralateral mirror movements during voluntary movement of each hand. A heterozygous deletion of the whole ACVRL1 gene (exons 1 to 10) was found to be responsible for the HHT features. To investigate further the dysexecutive syndrome and the mirror movements, we performed oligonucleotide array comparative genomic hybridization (array CGH) study (180K, Agilent, Santa-Clara, CA, USA). This study revealed a de novo 1.58 Mb deletion on chromosome 12q13.12q13.13 encompassing the ACVRL1 and SCN8A genes. To our knowledge, this deletion has not been previously reported and defines a new contiguous gene syndrome. The loss of one ACVRL1 allele is likely to be responsible for the HHT phenotype, while the deletion of the SCN8A gene is likely to be the cause of the mild cognitive disorder. SCN8A haploinsufficiency might also be involved in the occurrence of mirror movements. This report highlights the benefit of searching for large rearrangements in cases including unusual symptoms in association with HHT. On the other hand, an early diagnosis of 12q13.12q13.13 microdeletion based on the presence of a dysexecutive syndrome and/or mirror movement may allow to prevent HHT complications.
遗传性出血性毛细血管扩张症通常与致病性突变ACVRL1或ENG的存在有关。因此，对于遗传性出血性毛细血管扩张症患者，进行阵列比较基因组杂交（array CGH）显然没有益处。然而，由于新发的9q33.3q34.11微缺失，ENG已涉及一种相邻基因综合征。我们在此描述一种涉及ACVRL1基因的新的相邻基因综合征。一名50岁女性患者有遗传性出血性毛细血管扩张症（HHT）的典型临床表现，包括鼻出血、皮肤黏膜毛细血管扩张、动静脉畸形。她还存在认知障碍。认知评估显示存在以执行功能领域为主的异质性认知障碍，无智力缺陷。她没有特殊的形态特征。神经系统检查发现，每只手在自主运动时出现对侧镜像运动。发现整个ACVRL1基因（外显子1至10）的杂合缺失是导致HHT特征的原因。为了进一步研究执行功能障碍综合征和镜像运动，我们进行了寡核苷酸阵列比较基因组杂交（array CGH）研究（180K，安捷伦公司，美国加利福尼亚州圣克拉拉）。这项研究揭示了12号染色体q13.12q13.13上有一个1.58 Mb的新发缺失，包含ACVRL1和SCN8A基因。据我们所知，这种缺失此前尚未见报道，它定义了一种新的相邻基因综合征。一个ACVRL1等位基因的缺失可能是导致HHT表型的原因，而SCN8A基因的缺失可能是轻度认知障碍的病因。SCN8A单倍体不足也可能与镜像运动的发生有关。本报告强调了在伴有HHT且有异常症状的病例中寻找大片段重排的益处。另一方面，基于执行功能障碍综合征和/或镜像运动的存在对12q13.12q13.13微缺失进行早期诊断，可能有助于预防HHT并发症。
