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

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; Łukas Jaremko; Mariusz Jaremko; Rani K. Sachdev; Fowzan S. Alkuraya; Stefan T. Arold

doi:10.1016/j.ajhg.2019.01.013

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

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 SacotoAmber 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, Łukas Jaremko, Mariusz Jaremko, Rani K. Sachdev, Fowzan S. Alkuraya, Stefan T. Arold

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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.

Original language	English (US)
Pages (from-to)	542-552
Number of pages	11
Journal	American Journal of Human Genetics
Volume	104
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2019.01.013
State	Published - Mar 7 2019

Keywords

HX repeat
allelic disorders
developmental delay
dysmorphic
intellectual disability

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Access to Document

10.1016/j.ajhg.2019.01.013

Cite this

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., ... Arold, S. T. (2019). De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome. American Journal of Human Genetics, 104(3), 542-552. https://doi.org/10.1016/j.ajhg.2019.01.013

Palmer, EE, Hong, S, Al Zahrani, F, Hashem, MO, Aleisa, FA, Ahmed, HMJ, Kandula, T, Macintosh, R, Minoche, AE, Puttick, C, Gayevskiy, V, Drew, AP, Cowley, MJ, Dinger, M, Rosenfeld, JA, Xiao, R, Cho, MT, Yakubu, SF, Henderson, LB, Guillen Sacoto, MJ, Begtrup, A, Hamad, M, Shinawi, M, Andrews, MV, Jones, MC, Lindstrom, K, Bristol, RE, Kayani, S, Snyder, M, Villanueva, MM, Schteinschnaider, A, Faivre, L, Thauvin, C, Vitobello, A, Roscioli, T, Kirk, EP, Bye, A, Merzaban, J, Jaremko, Ł, Jaremko, M, Sachdev, RK, Alkuraya, FS & Arold, ST 2019, 'De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome', American Journal of Human Genetics, vol. 104, no. 3, pp. 542-552. https://doi.org/10.1016/j.ajhg.2019.01.013

@article{50a0b59915b54f96a3da0c6254aba96f,

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

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.",

keywords = "HX repeat, allelic disorders, developmental delay, dysmorphic, intellectual disability",

author = "Palmer, {Elizabeth E.} and Seungbeom Hong and {Al Zahrani}, Fatema and Hashem, {Mais O.} and Aleisa, {Fajr A.} and Ahmed, {Heba M.Jalal} and Tejaswi Kandula and Rebecca Macintosh and Minoche, {Andre E.} and Clare Puttick and Velimir Gayevskiy and Drew, {Alexander P.} and Cowley, {Mark J.} and Marcel Dinger and Rosenfeld, {Jill A.} and Rui Xiao and Cho, {Megan T.} and Yakubu, {Suliat F.} and Henderson, {Lindsay B.} and {Guillen Sacoto}, {Maria J.} and Amber Begtrup and Muddathir Hamad and Marwan Shinawi and Andrews, {Marisa V.} and Jones, {Marilyn C.} and Kristin Lindstrom and Bristol, {Ruth E.} and Saima Kayani and Molly Snyder and Villanueva, {Mar{\'i}a Mercedes} and Angeles Schteinschnaider and Laurence Faivre and Christel Thauvin and Antonio Vitobello and Tony Roscioli and Kirk, {Edwin P.} and Ann Bye and Jasmeen Merzaban and {\L}ukas Jaremko and Mariusz Jaremko and Sachdev, {Rani K.} and Alkuraya, {Fowzan S.} and Arold, {Stefan T.}",

note = "Publisher Copyright: {\textcopyright} 2019 American Society of Human Genetics",

year = "2019",

month = mar,

day = "7",

doi = "10.1016/j.ajhg.2019.01.013",

language = "English (US)",

volume = "104",

pages = "542--552",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome

AU - Palmer, Elizabeth E.

AU - Hong, Seungbeom

AU - Al Zahrani, Fatema

AU - Hashem, Mais O.

AU - Aleisa, Fajr A.

AU - Ahmed, Heba M.Jalal

AU - Kandula, Tejaswi

AU - Macintosh, Rebecca

AU - Minoche, Andre E.

AU - Puttick, Clare

AU - Gayevskiy, Velimir

AU - Drew, Alexander P.

AU - Cowley, Mark J.

AU - Dinger, Marcel

AU - Rosenfeld, Jill A.

AU - Xiao, Rui

AU - Cho, Megan T.

AU - Yakubu, Suliat F.

AU - Henderson, Lindsay B.

AU - Guillen Sacoto, Maria J.

AU - Begtrup, Amber

AU - Hamad, Muddathir

AU - Shinawi, Marwan

AU - Andrews, Marisa V.

AU - Jones, Marilyn C.

AU - Lindstrom, Kristin

AU - Bristol, Ruth E.

AU - Kayani, Saima

AU - Snyder, Molly

AU - Villanueva, María Mercedes

AU - Schteinschnaider, Angeles

AU - Faivre, Laurence

AU - Thauvin, Christel

AU - Vitobello, Antonio

AU - Roscioli, Tony

AU - Kirk, Edwin P.

AU - Bye, Ann

AU - Merzaban, Jasmeen

AU - Jaremko, Łukas

AU - Jaremko, Mariusz

AU - Sachdev, Rani K.

AU - Alkuraya, Fowzan S.

AU - Arold, Stefan T.

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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.

AB - 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.

KW - HX repeat

KW - allelic disorders

KW - developmental delay

KW - dysmorphic

KW - intellectual disability

UR - http://www.scopus.com/inward/record.url?scp=85062276538&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062276538&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2019.01.013

DO - 10.1016/j.ajhg.2019.01.013

M3 - Article

C2 - 30827498

AN - SCOPUS:85062276538

SN - 0002-9297

VL - 104

SP - 542

EP - 552

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this