ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder,Clinical Genetics

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ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder
Clinical Genetics ( IF 2.9 ) Pub Date : 2021-07-03 , DOI: 10.1111/cge.14023
Stephanie Oates _{1,

2} , Michael Absoud _{3,

4} , Sushma Goyal ₃ , Sophie Bayley ₂ , Jennifer Baulcomb ₃ , Annemarie Sims ₃ , Amy Riddett ₃ , Katrina Allis ₅ , Charlotte Brasch-Andersen _{6,

7} , Meena Balasubramanian _{8,

9} , Renkui Bai ₅ , Bert Callewaert ₁₀ , Ulrike Hüffmeier ₁₁ , Diana Le Duc ₁₂ , Maximilian Radtke ₁₂ , Christian Korff ₁₃ , Joanna Kennedy ₁₄ , Karen Low ₁₄ , Rikke S Møller _{15,

16} , Jens Erik Klint Nielsen ₁₇ , Bernt Popp ₁₁ , Lina Quteineh _{13,

18} , Gitte Rønde ₁₇ , Bitten Schönewolf-Greulich ₁₇ , Amelle Shillington ₁₉ , Matthew Rg Taylor ₂₀ , Emily Todd ₂₀ , Pernille M Torring ₆ , Zeynep Tümer _{14,

21} , Georgia Vasileiou ₁₁ , T Michael Yates _{8,

9} , Christiane Zweier ₂₁ , Richard Rosch ₂₂ , M Albert Basson _{23,

24} , Deb K Pal _{1,

2,

3,

23}

Affiliation

Department of Paediatric Neuroscience, King's College Hospital, London, UK.
Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, London, UK.
Newcomen Children's Neurosciences Centre, Evelina London Children's Hospital, London, UK.
Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London, UK.
Genetic Counselor, Mitochondrial and Metabolic Genetics, GeneDx, Gaithersburg, Maryland, USA.
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.
Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Institute of Human Genetics, Friedrich-Alexander Universitat of Erlangen-Nurnberg, Erlangen, Germany.
Institute of Human Genetics, University of Leipzig Medical Centre, Leipzig, Germany.
Pediatric Neurology Unit, University Hospitals, Geneva, Switzerland.
Department of Genetics, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK.
Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre, Dianalund, Denmark.
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Service of Genetic Medicine, Geneva University Hospitals, Geneva, Switzerland.
Pediatric Genetics, Cincinnati Children's Hospital Medical Centre, USA.
University of Colorado Anschutz Medical Campus, Adult Medical Genetics Program, Aurora, Colorado, USA.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.
Centre for Craniofacial and Regenerative Biology, King's College London, London, UK.

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype–phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype–phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.

中文翻译：

ZMYND11 变异是导致中央颞叶癫痫和全身性癫痫伴神经发育障碍的新原因

ZMYND11是染色体 10p15.3 微缺失综合征的关键基因，该综合征是导致智力障碍的综合征原因。 ZMYND11变体的表型最近已扩展到自闭症和癫痫发作。我们对 20 名具有ZMYND11致病性变异的个体的癫痫表型进行了扩展。我们获得了 16 名新个体和 9 名已发表个体的临床描述，以及两名儿童的详细病史。通过 GeneMatcher、ClinVar 和欧洲罕见癫痫治疗网络 (NETRE) 确定了新个体。使用基因组或外显子组测序进行遗传评估；使用美国医学遗传学学院 (ACMG) 标准对变异进行分类。患有ZMYND11相关癫痫的个体分为三组：（i）非典型良性部分性癫痫或特发性局灶性癫痫（n = 8）； (ii) 全身性癫痫/婴儿癫痫性脑病（n = 4）； (iii) 未分类（n = 8）。癫痫预后范围从自发缓解到耐药。神经发育缺陷是不变的。畸形特征是可变的。变异分布在整个基因中，并且大多是从头开始的，没有精确的基因型-表型相关性。 ZMYND11是一小群与癫痫（尤其是 ABPE）发病机制相关的染色质读取基因之一。对更大的队列和功能研究进行更详细的癫痫描述可能会揭示基因型与表型的相关性。致癫痫机制可能与组蛋白 H3.3 的相互作用有关。

更新日期：2021-09-03

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