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.
KAUST Repository Item: Exported on 2021-02-16
Acknowledged KAUST grant number(s): FCC1/1976-25
Acknowledgements: The authors thank the affected individuals and their families for their participation in this study and also thank the clinical neurology, general pediatric, and clinical genetics teams involved with their clinical care and support. We thank Toby Baldwin, Toni Saville, and Michael Buckley at SEALS genetics laboratory for their technical assistance. The research was supported by the National Health and Medical Research Council (GNT11149630 to E.E.P.; GNT0512123 to T.R.), Office of Health and Medical Research, NSW Health (to E.E.P.), King Abdulaziz City for Science and Technology (13-BIO1113-20 and 15-BIO3688-20 to F.S.A.), King Salman Center for Disability Research (F.S.A.), Saudi Human Genome Program (F.S.A.), and the King Abdullah University of Science and Technology through baseline funds (S.T.A., S.H., J.M., H.A., F.A., L.J., M.J.) and the Award No. FCC1/1976-25 from the Office of Sponsored Research (S.T.A.). The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing done at Baylor Genetics Laboratory.