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Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch‐up Development
Author(s) -
Platzer Konrad,
Cogné Benjamin,
Hague Jennifer,
Marcelis Carlo L.,
Mitter Diana,
Oberndorff Katrin,
Park SooMi,
Ploos van Amstel Hans K.,
Simonic Ingrid,
van der Smagt Jasper J.,
Stegmann Alexander P.A.,
Stevens Servi J.C.,
Stumpel Constance T.R.M.,
Vincent Marie,
Lemke Johannes R.,
Jamra Rami
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25278
Subject(s) - haploinsufficiency , exome sequencing , genetics , global developmental delay , biology , allele , intellectual disability , phenotype , homeobox , transcription factor , gene , bioinformatics
Objective Developmental delay (DD) with favorable intellectual outcome and mild intellectual disability (ID) are mostly considered to be of complex genetic and environmental origin, but, in fact, often remain unclear. We aimed at proving our assumption that also mild cases of DD and ID may be of monogenic etiology. Methods We clinically evaluated 8 individuals and performed exome sequencing or array copy number analysis and identified variants in CUX1 as the likely cause. In addition, we included a case from the public database, DECIPHER. Results All 9 individuals harbored heterozygous null‐allele variants in CUX1 , encoding the Cut‐homeobox 1 transcription factor that is involved in regulation of dendritogenesis and cortical synapse formation in layer II to IV cortical neurons. Six variants arose de novo, while in one family the variant segregated with ID. Of the 9 included individuals, 2 were diagnosed with moderate ID, 3 with mild ID, and 3 showed a normal age‐related intelligence at ages 4, 6, and 8 years after a previous history of significant DD. Interpretation Our results suggest that null‐allele variants, and thus haploinsufficiency of CUX1 , cause an isolated phenotype of DD or ID with possible catch‐up development. This illustrates that such a developmental course is not necessarily genetic complex, but may also be attributed to a monogenic cause. Ann Neurol 2018;84:200–207