AUTS2-related syndrome: Insights from a large European cohort

Lorenzo Loberti; Loredaria Adamo; Enrica Antolini; Giulia Casamassima; Anne Destrèe; Nicola Brunetti-Pierri; David Genevieve; Philippe Christophe; Christine Coubes; Hilde Van Esch; Theresia Herget; Fanny Kortüm; Jasmin Lisfeld; Anna Charlotte Möllring; Martin Zenker; Jonathan Levy; Laurence Perrin; Anne Claude Tabet; Anna Maruani; Arthur Sorlin; Daniel Stieber; Lucas Herissant; Karin Dahan; Lorenzo Sinibaldi; Rossella Capolino; Maria Lisa Dentici; Bruno Dallapiccola; Antonio Novelli; Livia Garavelli; Stefano Giuseppe Caraffi; Gianluca Piatelli; Irene Valenzuela; Maria Cristina Digilio; Roseline Caumes; Cordula Knopp; Karolina Chwiałkowska; Aleksandra Jezela-Stanek; Miroslaw Kwasniewski; Urszula Korotko; Ewelina Gorzałczyńska; Roberto Canitano; Salvatore Grosso; Elisa Rahikkala; Larissa Mattern; Miriam Elbracht; Orsetta Zuffardi; Valentina Caputo; Benedetta Toschi; Gea Beunders; Lisette Leeuwen; Mariet W. Elting; Liselot van der Laan; Marjoleine F. Broekema; Alexander J. Groffen; Jiddeke M. van de Kamp; Mieke M. van Haelst; Marielle Alders; Salvatore Pietro Mauro; Francesca De Razza; Dora Varvara; Johanna Kick; Harald Gaspar; Dominique Braun; Eva Lausberg; Andrea Maier; Valentin Ruault; Rita Genesio; Marco Tartaglia; Rossella Tita; Mirella Bruttini; Ilaria Longo; Margherita Baldassarri; Maria Antonietta Mencarelli; Alessandra Renieri; Anna Maria Pinto

doi:10.1016/j.gim.2025.101375

AUTS2-related syndrome: Insights from a large European cohort

Lorenzo Loberti, Loredaria Adamo, Enrica Antolini, Giulia Casamassima, Anne Destrèe, Nicola Brunetti-Pierri, David Genevieve, Philippe Christophe, Christine Coubes, Hilde Van Esch, Theresia Herget, Fanny Kortüm, Jasmin Lisfeld, Anna Charlotte Möllring, Martin Zenker, Jonathan Levy, Laurence Perrin, Anne Claude Tabet, Anna Maruani, Arthur SorlinDaniel Stieber, Lucas Herissant, Karin Dahan, Lorenzo Sinibaldi, Rossella Capolino, Maria Lisa Dentici, Bruno Dallapiccola, Antonio Novelli, Livia Garavelli, Stefano Giuseppe Caraffi, Gianluca Piatelli, Irene Valenzuela, Maria Cristina Digilio, Roseline Caumes, Cordula Knopp, Karolina Chwiałkowska, Aleksandra Jezela-Stanek, Miroslaw Kwasniewski, Urszula Korotko, Ewelina Gorzałczyńska, Roberto Canitano, Salvatore Grosso, Elisa Rahikkala, Larissa Mattern, Miriam Elbracht, Orsetta Zuffardi, Valentina Caputo, Benedetta Toschi, Gea Beunders, Lisette Leeuwen, Mariet W. Elting, Liselot van der Laan, Marjoleine F. Broekema, Alexander J. Groffen, Jiddeke M. van de Kamp, Mieke M. van Haelst, Marielle Alders, Salvatore Pietro Mauro, Francesca De Razza, Dora Varvara, Johanna Kick, Harald Gaspar, Dominique Braun, Eva Lausberg, Andrea Maier, Valentin Ruault, Rita Genesio, Marco Tartaglia, Rossella Tita, Mirella Bruttini, Ilaria Longo, Margherita Baldassarri, Maria Antonietta Mencarelli, Alessandra Renieri, Anna Maria Pinto^*

^*Corresponding author for this work

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Abstract

Purpose: AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator.

Methods: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs).

Results: Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs.

Conclusion: This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.

Original language	English
Article number	101375
Number of pages	13
Journal	Genetics in Medicine
Volume	27
Issue number	6
DOIs	https://doi.org/10.1016/j.gim.2025.101375
Publication status	Published - Jun-2025

Keywords

AUTS2
AUTS2-syndrome
Dysmorphology
Genotype-phenotype
Neurodevelopmental disorder

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AUTS2-related syndrome Insights from a large European cohortFinal publisher's version, 2.26 MBLicence: CC BY

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Loberti, L., Adamo, L., Antolini, E., Casamassima, G., Destrèe, A., Brunetti-Pierri, N., Genevieve, D., Christophe, P., Coubes, C., Van Esch, H., Herget, T., Kortüm, F., Lisfeld, J., Möllring, A. C., Zenker, M., Levy, J., Perrin, L., Tabet, A. C., Maruani, A., ... Pinto, A. M. (2025). AUTS2-related syndrome: Insights from a large European cohort. Genetics in Medicine, 27(6), Article 101375. https://doi.org/10.1016/j.gim.2025.101375

@article{7094e5c4f42c4b4dbfc7837592d880a5,

title = "AUTS2-related syndrome: Insights from a large European cohort",

abstract = "Purpose: AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator. Methods: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs). Results: Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs. Conclusion: This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.",

keywords = "AUTS2, AUTS2-syndrome, Dysmorphology, Genotype-phenotype, Neurodevelopmental disorder",

author = "Lorenzo Loberti and Loredaria Adamo and Enrica Antolini and Giulia Casamassima and Anne Destr{\`e}e and Nicola Brunetti-Pierri and David Genevieve and Philippe Christophe and Christine Coubes and \{Van Esch\}, Hilde and Theresia Herget and Fanny Kort{\"u}m and Jasmin Lisfeld and M{\"o}llring, \{Anna Charlotte\} and Martin Zenker and Jonathan Levy and Laurence Perrin and Tabet, \{Anne Claude\} and Anna Maruani and Arthur Sorlin and Daniel Stieber and Lucas Herissant and Karin Dahan and Lorenzo Sinibaldi and Rossella Capolino and Dentici, \{Maria Lisa\} and Bruno Dallapiccola and Antonio Novelli and Livia Garavelli and Caraffi, \{Stefano Giuseppe\} and Gianluca Piatelli and Irene Valenzuela and Digilio, \{Maria Cristina\} and Roseline Caumes and Cordula Knopp and Karolina Chwia{\l}kowska and Aleksandra Jezela-Stanek and Miroslaw Kwasniewski and Urszula Korotko and Ewelina Gorza{\l}czy{\'n}ska and Roberto Canitano and Salvatore Grosso and Elisa Rahikkala and Larissa Mattern and Miriam Elbracht and Orsetta Zuffardi and Valentina Caputo and Benedetta Toschi and Gea Beunders and Lisette Leeuwen and Elting, \{Mariet W.\} and \{van der Laan\}, Liselot and Broekema, \{Marjoleine F.\} and Groffen, \{Alexander J.\} and \{van de Kamp\}, \{Jiddeke M.\} and \{van Haelst\}, \{Mieke M.\} and Marielle Alders and Mauro, \{Salvatore Pietro\} and \{De Razza\}, Francesca and Dora Varvara and Johanna Kick and Harald Gaspar and Dominique Braun and Eva Lausberg and Andrea Maier and Valentin Ruault and Rita Genesio and Marco Tartaglia and Rossella Tita and Mirella Bruttini and Ilaria Longo and Margherita Baldassarri and Mencarelli, \{Maria Antonietta\} and Alessandra Renieri and Pinto, \{Anna Maria\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = jun,

doi = "10.1016/j.gim.2025.101375",

language = "English",

volume = "27",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "6",

}

Loberti, L, Adamo, L, Antolini, E, Casamassima, G, Destrèe, A, Brunetti-Pierri, N, Genevieve, D, Christophe, P, Coubes, C, Van Esch, H, Herget, T, Kortüm, F, Lisfeld, J, Möllring, AC, Zenker, M, Levy, J, Perrin, L, Tabet, AC, Maruani, A, Sorlin, A, Stieber, D, Herissant, L, Dahan, K, Sinibaldi, L, Capolino, R, Dentici, ML, Dallapiccola, B, Novelli, A, Garavelli, L, Caraffi, SG, Piatelli, G, Valenzuela, I, Digilio, MC, Caumes, R, Knopp, C, Chwiałkowska, K, Jezela-Stanek, A, Kwasniewski, M, Korotko, U, Gorzałczyńska, E, Canitano, R, Grosso, S, Rahikkala, E, Mattern, L, Elbracht, M, Zuffardi, O, Caputo, V, Toschi, B, Beunders, G, Leeuwen, L, Elting, MW, van der Laan, L, Broekema, MF, Groffen, AJ, van de Kamp, JM, van Haelst, MM, Alders, M, Mauro, SP, De Razza, F, Varvara, D, Kick, J, Gaspar, H, Braun, D, Lausberg, E, Maier, A, Ruault, V, Genesio, R, Tartaglia, M, Tita, R, Bruttini, M, Longo, I, Baldassarri, M, Mencarelli, MA, Renieri, A & Pinto, AM 2025, 'AUTS2-related syndrome: Insights from a large European cohort', Genetics in Medicine, vol. 27, no. 6, 101375. https://doi.org/10.1016/j.gim.2025.101375

TY - JOUR

T1 - AUTS2-related syndrome

T2 - Insights from a large European cohort

AU - Loberti, Lorenzo

AU - Adamo, Loredaria

AU - Antolini, Enrica

AU - Casamassima, Giulia

AU - Destrèe, Anne

AU - Brunetti-Pierri, Nicola

AU - Genevieve, David

AU - Christophe, Philippe

AU - Coubes, Christine

AU - Van Esch, Hilde

AU - Herget, Theresia

AU - Kortüm, Fanny

AU - Lisfeld, Jasmin

AU - Möllring, Anna Charlotte

AU - Zenker, Martin

AU - Levy, Jonathan

AU - Perrin, Laurence

AU - Tabet, Anne Claude

AU - Maruani, Anna

AU - Sorlin, Arthur

AU - Stieber, Daniel

AU - Herissant, Lucas

AU - Dahan, Karin

AU - Sinibaldi, Lorenzo

AU - Capolino, Rossella

AU - Dentici, Maria Lisa

AU - Dallapiccola, Bruno

AU - Novelli, Antonio

AU - Garavelli, Livia

AU - Caraffi, Stefano Giuseppe

AU - Piatelli, Gianluca

AU - Valenzuela, Irene

AU - Digilio, Maria Cristina

AU - Caumes, Roseline

AU - Knopp, Cordula

AU - Chwiałkowska, Karolina

AU - Jezela-Stanek, Aleksandra

AU - Kwasniewski, Miroslaw

AU - Korotko, Urszula

AU - Gorzałczyńska, Ewelina

AU - Canitano, Roberto

AU - Grosso, Salvatore

AU - Rahikkala, Elisa

AU - Mattern, Larissa

AU - Elbracht, Miriam

AU - Zuffardi, Orsetta

AU - Caputo, Valentina

AU - Toschi, Benedetta

AU - Beunders, Gea

AU - Leeuwen, Lisette

AU - Elting, Mariet W.

AU - van der Laan, Liselot

AU - Broekema, Marjoleine F.

AU - Groffen, Alexander J.

AU - van de Kamp, Jiddeke M.

AU - van Haelst, Mieke M.

AU - Alders, Marielle

AU - Mauro, Salvatore Pietro

AU - De Razza, Francesca

AU - Varvara, Dora

AU - Kick, Johanna

AU - Gaspar, Harald

AU - Braun, Dominique

AU - Lausberg, Eva

AU - Maier, Andrea

AU - Ruault, Valentin

AU - Genesio, Rita

AU - Tartaglia, Marco

AU - Tita, Rossella

AU - Bruttini, Mirella

AU - Longo, Ilaria

AU - Baldassarri, Margherita

AU - Mencarelli, Maria Antonietta

AU - Renieri, Alessandra

AU - Pinto, Anna Maria

PY - 2025/6

Y1 - 2025/6

N2 - Purpose: AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator. Methods: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs). Results: Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs. Conclusion: This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.

AB - Purpose: AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator. Methods: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs). Results: Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs. Conclusion: This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.

KW - AUTS2

KW - AUTS2-syndrome

KW - Dysmorphology

KW - Genotype-phenotype

KW - Neurodevelopmental disorder

UR - https://www.scopus.com/pages/publications/105002487618

U2 - 10.1016/j.gim.2025.101375

DO - 10.1016/j.gim.2025.101375

M3 - Article

C2 - 39953909

AN - SCOPUS:105002487618

SN - 1098-3600

VL - 27

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 6

M1 - 101375

ER -

AUTS2-related syndrome: Insights from a large European cohort

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