1. De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome
- Author
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Tejaswi Kandula, Maria J. Guillen Sacoto, Mais Hashem, Saima Kayani, André E. Minoche, Edwin P. Kirk, Łukasz Jaremko, Heba M. Jalal Ahmed, Marwan Shinawi, Elizabeth E. Palmer, Christel Thauvin, Molly Snyder, Mark J. Cowley, Muddathir H Hamad, Maria Mercedes Villanueva, Seungbeom Hong, Fatema Al Zahrani, Laurence Faivre, Suliat F. Yakubu, Ann M. E. Bye, Velimir Gayevskiy, Megan T. Cho, Jasmeen S. Merzaban, Marisa V. Andrews, Alexander P. Drew, Ruth E. Bristol, Jill A. Rosenfeld, Stefan T. Arold, Lindsay B. Henderson, Antonio Vitobello, Tony Roscioli, Clare Puttick, Mariusz Jaremko, Rui Xiao, Fajr A. Aleisa, Amber Begtrup, Marilyn C. Jones, Fowzan S. Alkuraya, Rebecca Macintosh, Marcel E. Dinger, Kristin Lindstrom, Rani Sachdev, and Angeles Schteinschnaider
- Subjects
0301 basic medicine ,Male ,allelic disorders ,Amino Acid Motifs ,Neurodegenerative ,Medical and Health Sciences ,Repetitive Sequences ,Epilepsy ,Motif (narrative) ,0302 clinical medicine ,Missense mutation ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Genetics (clinical) ,Genetics ,Pediatric ,Genetics & Heredity ,Neurodegeneration ,Syndrome ,Biological Sciences ,Prognosis ,Phenotype ,Hypotonia ,developmental delay ,intellectual disability ,Child, Preschool ,symbols ,Female ,dysmorphic ,medicine.symptom ,Neurocognitive Disorders ,Nerve Tissue Proteins ,Biology ,03 medical and health sciences ,symbols.namesake ,Atrophy ,Rare Diseases ,Report ,medicine ,Humans ,Preschool ,Repetitive Sequences, Nucleic Acid ,Nucleic Acid ,business.industry ,Neurosciences ,Correction ,Infant ,Genetic Variation ,medicine.disease ,Human genetics ,HX repeat ,Brain Disorders ,030104 developmental biology ,Mendelian inheritance ,Human genome ,business ,Neurocognitive ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2019