Research Papers

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

by Elizabeth E Palmer, Seungbeom Hong, Fatema Al Zahrani, Mais O Hashem, Fajr A Aleisa, Heba M Jalal Ahmed, Tejaswi Kandula, Rebecca Macintosh, Andre E Minoche, Clare Puttick, Velimir Gayevskiy, Alexander P Drew, Mark J Cowley, Marcel Dinger, Jill A Rosenfeld, Rui Xiao, Megan T Cho, Suliat F Yakubu, Lindsay B Henderson, Maria J Guillen Sacoto, Amber Begtrup, Muddathir Hamad, Marwan Shinawi, Marisa V Andrews, Marilyn C Jones, Kristin Lindstrom, Ruth E Bristol, Saima Kayani, Molly Snyder, María Mercedes Villanueva, Angeles Schteinschnaider, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Tony Roscioli, Edwin P Kirk, Ann Bye, Jasmeen Merzaban, Łukasz Jaremko, Mariusz Jaremko, Rani K Sachdev, Fowzan S Alkuraya, Stefan T Arold
American Journal of Human Genetics Year: 2019 DOI: 10.1016/j.ajhg.2019.01.013

Extra Information



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.



allelic disorders HX repeat intellectual disability developmental delay dysmorphic