Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch-up Development

Diana Mitter, Johannes R. Lemke, Konrad Platzer*, Rami Jamra, Hans K. Ploos van Amstel, Jasper J. van der Smagt, Alexander P. A. Stegmann, Constance T. R. M. Stumpel, Servi J. C. Stevens, Katrin Oberndorff, Carlo L. Marcelis, Benjamin Cogne, Marie Vincent, Ingrid Simonic, Jennifer Hague, Soo-Mi Park

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


ObjectiveDevelopmental 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.

MethodsWe 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.

ResultsAll 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.

InterpretationOur 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

Original languageEnglish
Pages (from-to)200-207
Number of pages8
JournalAnnals of Neurology
Issue number2
Publication statusPublished - Aug 2018




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