CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum,Clinical Genetics

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CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum
Clinical Genetics ( IF 2.9 ) Pub Date : 2021-07-01 , DOI: 10.1111/cge.14022
Elizabeth E Palmer _{1,

2} , Chloe Whitton ₃ , Mais O Hashem ₄ , Robin D Clark ₅ , Subhadra Ramanathan ₅ , Lois J Starr ₆ , Danita Velasco ₆ , John Karl De Dios ₇ , Emily Singh ₈ , Valerie Cormier-Daire ₉ , Maya Chopra ₁₀ , Lance H Rodan ₁₁ , Christoffer Nellaker _{12,

13,

14} , Shenela Lakhani ₁₅ , Eric J Mallack ₁₅ , Karin Panzer ₁₆ , Alpa Sidhu ₁₆ , Ingrid M Wentzensen ₁₇ , Didier Lacombe _{18,

19} , Vincent Michaud _{18,

19} , Fowzan S Alkuraya ₄

Affiliation

Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia.
School of Women's and Children's Health, University of New South Wales, Randwick, New South Wales, Australia.
Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia.
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Division of Medical Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Division of Medical Genetics, Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA, Omaha, Nebraska, USA.
Division of Medical Genetics, Department of Pediatrics, Dayton Children's Hospital, Dayton, Ohio, USA.
Division of Genetics, Medical College of Wisconsin with Children's Wisconsin, Milwaukee, Wisconsin, USA.
Service de Génétique Clinique, INSERM UMR 1163, Hôpital Necker-Enfants Malades, Institut IMAGINE, Université de Paris, Paris, France.
Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, Massachusetts, USA.
Department of Neurology, Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
Nuffield Department of Women's and Reproductive Health, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, UK.
Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK.
Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
Centre for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
GeneDx, Gaithersburg, Maryland, USA.
Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Bordeaux, Bordeaux, France.
Maladies Rares, Génétique et Métabolisme (MRGM), U 1211 INSERM/Université de Bordeaux, Bordeaux, France.

We describe the clinical features of nine unrelated individuals with rare de novo missense or in-frame deletions/duplications within the “HX motif” of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral-pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication.

中文翻译：

CHEDDA 综合征是一种未被充分认识的神经发育障碍，具有高度受限的 ATN1 突变谱

我们描述了九个无关个体的临床特征，这些个体在ATN1外显子 7 的“HX 基序”内具有罕见的从头错义或框内缺失/重复。我们之前提出，具有此类变异的个体应被视为受到先天性肌张力减退、癫痫、发育迟缓和指异常 (CHEDDA) 的综合征状况的影响，这与继发于外显子 5 中的扩张变异的牙颌-苍白球萎缩 (DRPLA) 不同ATN1的. 我们确认 CHEDDA 的普遍表型特征是独特的面部特征和整体发育迟缓。婴儿肌张力减退和轻微的手足差异很常见，可表现为关节弯曲。常见的合并症包括严重的喂养困难，通常需要胃造口术支持，以及视力和听力障碍。脑部、心脏和泌尿生殖系统的癫痫和先天性畸形很常见，但并不普遍。我们的研究证实了 CHEDDA 的临床实体继发于 ATN1 外显子 7 的突变特征。我们提出了一个临床计划，用于评估诊断、监测和早期干预，包括神经影像学预测的潜力。

更新日期：2021-09-03

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