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CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum
Author(s) -
Palmer Elizabeth E.,
Whitton Chloe,
Hashem Mais O.,
Clark Robin D.,
Ramanathan Subhadra,
Starr Lois J.,
Velasco Danita,
De Dios John Karl,
Singh Emily,
CormierDaire Valerie,
Chopra Maya,
Rodan Lance H.,
Nellaker Christoffer,
Lakhani Shenela,
Mallack Eric J.,
Panzer Karin,
Sidhu Alpa,
Wentzensen Ingrid M.,
Lacombe Didier,
Michaud Vincent,
Alkuraya Fowzan S.
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.14022
Subject(s) - hypotonia , missense mutation , arthrogryposis , global developmental delay , genetics , exon , polymicrogyria , epilepsy , medicine , intellectual disability , pediatrics , phenotype , biology , bioinformatics , neuroscience , gene
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.