TY - JOUR
T1 - Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy
AU - Undiagnosed Diseases Network
AU - Parenti, Ilaria
AU - Lehalle, Daphné
AU - Nava, Caroline
AU - Torti, Erin
AU - Leitão, Elsa
AU - Person, Richard
AU - Mizuguchi, Takeshi
AU - Matsumoto, Naomichi
AU - Kato, Mitsuhiro
AU - Nakamura, Kazuyuki
AU - de Man, Stella A.
AU - Cope, Heidi
AU - Shashi, Vandana
AU - Friedman, Jennifer
AU - Joset, Pascal
AU - Steindl, Katharina
AU - Rauch, Anita
AU - Muffels, Irena
AU - van Hasselt, Peter M.
AU - Petit, Florence
AU - Smol, Thomas
AU - Le Guyader, Gwenaël
AU - Bilan, Frédéric
AU - Sorlin, Arthur
AU - Vitobello, Antonio
AU - Philippe, Christophe
AU - van de Laar, Ingrid M.B.H.
AU - van Slegtenhorst, Marjon A.
AU - Campeau, Philippe M.
AU - Au, Ping Yee Billie
AU - Nakashima, Mitsuko
AU - Saitsu, Hirotomo
AU - Yamamoto, Tatsuya
AU - Nomura, Yumiko
AU - Louie, Raymond J.
AU - Lyons, Michael J.
AU - Dobson, Amy
AU - Plomp, Astrid S.
AU - Motazacker, M. Mahdi
AU - Kaiser, Frank J.
AU - Timberlake, Andrew T.
AU - Fuchs, Sabine A.
AU - Depienne, Christel
AU - Mignot, Cyril
AU - Acosta, Maria T.
AU - Adam, Margaret
AU - Adams, David R.
AU - Agrawal, Pankaj B.
AU - Alejandro, Mercedes E.
AU - Alvey, Justin
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7
Y1 - 2021/7
N2 - Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
AB - Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
UR - http://www.scopus.com/inward/record.url?scp=85108208546&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/c86ca15c-fb8d-3e00-a414-57f264fd7523/
U2 - 10.1007/s00439-021-02283-2
DO - 10.1007/s00439-021-02283-2
M3 - Journal articles
C2 - 33944996
AN - SCOPUS:85108208546
SN - 0340-6717
VL - 140
SP - 1109
EP - 1120
JO - Human Genetics
JF - Human Genetics
IS - 7
ER -