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De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome


Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

Type Journal
ISBN 1537-6605 (Electronic) 0002-9297 (Linking)
Authors Palmer, E. E.; Hong, S.; Al Zahrani, F.; Hashem, M. O.; Aleisa, F. A.; Ahmed, H. M. J.; Kandula, T.; Macintosh, R.; Minoche, A. E.; Puttick, C.; Gayevskiy, V.; Drew, A. P.; Cowley, M. J.; Dinger, M.; Rosenfeld, J. A.; Xiao, R.; Cho, M. T.; Yakubu, S. F.; Henderson, L. B.; Guillen Sacoto, M. J.; Begtrup, A.; Hamad, M.; Shinawi, M.; Andrews, M. V.; Jones, M. C.; Lindstrom, K.; Bristol, R. E.; Kayani, S.; Snyder, M.; Villanueva, M. M.; Schteinschnaider, A.; Faivre, L.; Thauvin, C.; Vitobello, A.; Roscioli, T.; Kirk, E. P.; Bye, A.; Merzaban, J.; Jaremko, L.; Jaremko, M.; Sachdev, R. K.; Alkuraya, F. S.; Arold, S. T.
Publisher Name American Journal Of Human Genetics
Published Date 2019-03-01
Published Volume 104
Published Issue 3
Published Pages 542-552
Status Published in-print
DOI 10.1016/j.ajhg.2019.01.013
URL link to publisher's version
OpenAccess link to author's accepted manuscript version