Novel de novo ZBTB20 mutations in three cases with Primrose syndrome and constant corpus callosum anomalies

被引:17
作者
Alby, Caroline [1 ,2 ,3 ]
Boutaud, Lucile [1 ,2 ,3 ]
Bessieres, Bettina [3 ]
Serre, Valerie [4 ]
Rio, Marlene [3 ]
Cormier-Daire, Valerie [2 ,3 ,5 ]
de Oliveira, Judith [1 ,3 ]
Ichkou, Amale [3 ]
Mouthon, Linda [3 ]
Gordon, Christopher T. [1 ,2 ,3 ]
Bonniere, Maryse [3 ]
Mechler, Charlotte [3 ]
Nitschke, Patrick [2 ,6 ]
Bole, Christine [2 ,7 ]
Lyonnet, Stanislas [1 ,2 ,3 ]
Bahi-Buisson, Nadia [1 ,2 ,3 ]
Boddaert, Nathalie [2 ,3 ,8 ]
Colleaux, Laurence [2 ,9 ]
Roth, Philippe [10 ]
Ville, Yves [10 ]
Vekemans, Michel [1 ,2 ,3 ]
Encha-Razavi, Ferechte [1 ,2 ,3 ]
Attie-Bitach, Tania [1 ,2 ,3 ]
Thomas, Sophie [1 ,2 ]
机构
[1] INSERM, UMR1163, Inst Imagine, Lab Embryol & Genet Congenital Malformat, 24 Blvd Montparnasse, F-75015 Paris, France
[2] Paris Descartes Sorbonne Paris Cite, Paris, France
[3] Hosp Necker Enfants Malad, AP HP, Dept Genet, Paris, France
[4] Paris Diderot Univ, Inst Jacques Monod, CNRS, UMR7592, Paris, France
[5] INSERM, UMR1163, Inst Imagine, Lab Mol & Physiopathol Bases Osteochondrodysplasi, Paris, France
[6] Paris Descartes Sorbonne Paris Cite Univ, Inst Imagine, Bioinformat Core Facil, Paris, France
[7] Paris Descartes Sorbonne Paris Cite Univ, Inst Imagine, Genom Core Facil, Paris, France
[8] Hosp Necker Enfants Malad, AP HP, Dept Pediat Radiol, Paris, France
[9] INSERM, UMR1163, Inst Imagine, Lab Mol & Pathophysiol Bases Cognit Disorders, Paris, France
[10] Hosp Necker Enfants Malad, AP HP, Dept Obstet & Fetal Med, Paris, France
关键词
MEF2C HAPLOINSUFFICIENCY; IDENTITY; ABNORMALITIES; MICRODELETION; TRANSCRIPTION; PHENOTYPE; AGENESIS; FEATURES; NEURONS; GENES;
D O I
10.1002/ajmg.a.38684
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.
引用
收藏
页码:1091 / 1098
页数:8
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