Major brain malformations: corpus callosum dysgenesis, agenesis of septum pellucidum and polymicrogyria in patients with BCORL1-related disorders,Journal of Human Genetics

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Major brain malformations: corpus callosum dysgenesis, agenesis of septum pellucidum and polymicrogyria in patients with BCORL1-related disorders
Journal of Human Genetics ( IF 3.5 ) Pub Date : 2021-08-16 , DOI: 10.1038/s10038-021-00971-5
Michal Gafner _{1,

2} , Marina Michelson _{2,

3,

4} , Emanuela Argilli _{5,

6} , Keren Yosovich _{2,

3,

7} , Elliott H Sherr _{5,

6} , Kendall C Parks _{5,

6} , Eleina M England ₈ , Ronen Hady-Cohen _{2,

3,

9} , Zvi Leibovitz _{10,

11} , Dorit Lev _{2,

3,

4} , Yael Michaeli-Yosef _{2,

3,

9} , Tally Lerman-Sagie _{2,

3,

9} , Lubov Blumkin _{2,

3,

9,

12}

Affiliation

Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Magen Center for Rare Diseases, Wolfson Medical Center, Holon, Israel.
The Rina Mor Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel.
Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel.
Fetal Neurology Clinic, Wolfson Medical Center, Holon, Israel.
Obstetrics-Gynecology Ultrasound Unit, Rappaport Faculty of Medicine, Bnai-Zion Medical Center, The Technion, Haifa, Israel.
Pediatric Movement Disorders Service, Wolfson Medical Center, Holon, Israel.

Objective

BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations.

Methods and results

We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients’ charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development.

Conclusions

We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis.

中文翻译：

主要脑畸形：BCORL1 相关疾病患者的胼胝体发育不全、透明隔发育不全和多小脑回

客观的

BCORL1是一种转录辅抑制因子，在皮层迁移、神经元分化、成熟和小脑发育中发挥作用。我们将BCORL1描述为主要脑畸形的新遗传原因。

方法和结果

我们报告了来自两个无关家庭的三名患者，他们患有新生儿发作的顽固性癫痫和严重的整体发育迟缓。来自第一个家庭的两个兄弟姐妹的脑部 MRI 显示，哥哥有胼胝体发育不全和隔膜发育不全 (ASP)，弟弟有单侧外侧裂多小脑回 (PMG)。来自第二个家庭的患者的 MRI 显示胼胝体 (CC) 完全发育不全。全外显子组测序揭示了 NM_021946.5 ( BCORL1 ) 中的一个新的半合子变异：c.796C>T (p.Pro266Ser) 在来自第一个家族的两个兄弟姐妹和 NM_021946.5 (BCORL1) 中：c.3376G>A；患者的 p.Asp1126Asn 变异来自第二个家庭，这两个变异都遗传自健康的母亲。我们审查了患者的图表和 MRI，并将表型与其他已发表的表型进行了比较BCORL1相关案例。以前没有描述过与BCORL1表型相关的脑畸形。我们讨论了BCORL1对大脑发育的潜在影响。