Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

Alison M Muir; Jennifer F Gardner; Richard H van Jaarsveld; Iris M de Lange; Jasper J van der Smagt; Golder N Wilson; Holly Dubbs; Ethan M Goldberg; Lia Zitano; Caleb Bupp; Jose Martinez; Myriam Srour; Andrea Accogli; Afnan Alhakeem; Meira Meltzer; Andrea Gropman; Carole Brewer; Richard C Caswell; Tara Montgomery; Caoimhe McKenna; Shane McKee; Corinna Powell; Pradeep C Vasudevan; Angela F Brady; Shelagh Joss; Carolyn Tysoe; Grace Noh; Mark Tarnopolsky; Lauren Brady; Muhammad Zafar; Samantha A Schrier Vergano; Brianna Murray; Lindsey Sawyer; Bryan E Hainline; Katherine Sapp; Danielle DeMarzo; Darcy J Huismann; Ingrid M Wentzensen; Rhonda E Schnur; Kristin G Monaghan; Jane Juusola; Lindsay Rhodes; William B Dobyns; Francois Lecoquierre; Alice Goldenberg; Tilman Polster; Susanne Axer-Schaefer; Konrad Platzer; Chiara Klöckner; Trevor L Hoffman; Daniel G MacArthur; Melanie C O'Leary; Grace E VanNoy; Eleina England; Vinod C Varghese; Heather C Mefford

doi:10.1038/s41436-020-01076-8

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

Alison M Muir
, Jennifer F Gardner
, Richard H van Jaarsveld
, Iris M de Lange
, Jasper J van der Smagt
, Golder N Wilson
, Holly Dubbs
, Ethan M Goldberg
, Lia Zitano
, Caleb Bupp
, Jose Martinez
, Myriam Srour
, Andrea Accogli
, Afnan Alhakeem
, Meira Meltzer
, Andrea Gropman
, Carole Brewer
, Richard C Caswell
, Tara Montgomery
, Caoimhe McKenna

Shane McKee, Corinna Powell, Pradeep C Vasudevan, Angela F Brady, Shelagh Joss, Carolyn Tysoe, Grace Noh, Mark Tarnopolsky, Lauren Brady, Muhammad Zafar, Samantha A Schrier Vergano, Brianna Murray, Lindsey Sawyer, Bryan E Hainline, Katherine Sapp, Danielle DeMarzo, Darcy J Huismann, Ingrid M Wentzensen, Rhonda E Schnur, Kristin G Monaghan, Jane Juusola, Lindsay Rhodes, William B Dobyns, Francois Lecoquierre, Alice Goldenberg, Tilman Polster, Susanne Axer-Schaefer, Konrad Platzer, Chiara Klöckner, Trevor L Hoffman, Daniel G MacArthur, Melanie C O'Leary, Grace E VanNoy, Eleina England, Vinod C Varghese, Heather C Mefford^*

^*Corresponding author for this work

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

Abstract

PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.

METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.

RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.

CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

Original language	English
Pages (from-to)	881-887
Number of pages	7
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Volume	23
Issue number	5
DOIs	https://doi.org/10.1038/s41436-020-01076-8
Publication status	Published - May 2021

Keywords

Child
Developmental Disabilities/genetics
Exome Sequencing
Humans
Intellectual Disability/diagnosis
Muscle Hypotonia/diagnosis
Neurodevelopmental Disorders/diagnosis
Seizures/genetics

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10.1038/s41436-020-01076-8

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Muir, A. M., Gardner, J. F., van Jaarsveld, R. H., de Lange, I. M., van der Smagt, J. J., Wilson, G. N., Dubbs, H., Goldberg, E. M., Zitano, L., Bupp, C., Martinez, J., Srour, M., Accogli, A., Alhakeem, A., Meltzer, M., Gropman, A., Brewer, C., Caswell, R. C., Montgomery, T., ... Mefford, H. C. (2021). Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia. Genetics in medicine : official journal of the American College of Medical Genetics, 23(5), 881-887. https://doi.org/10.1038/s41436-020-01076-8

@article{2d1c1b6be0fe421993af85790ed7de43,

title = "Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia",

abstract = "PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.",

keywords = "Child, Developmental Disabilities/genetics, Exome Sequencing, Humans, Intellectual Disability/diagnosis, Muscle Hypotonia/diagnosis, Neurodevelopmental Disorders/diagnosis, Seizures/genetics",

author = "Muir, \{Alison M\} and Gardner, \{Jennifer F\} and \{van Jaarsveld\}, \{Richard H\} and \{de Lange\}, \{Iris M\} and \{van der Smagt\}, \{Jasper J\} and Wilson, \{Golder N\} and Holly Dubbs and Goldberg, \{Ethan M\} and Lia Zitano and Caleb Bupp and Jose Martinez and Myriam Srour and Andrea Accogli and Afnan Alhakeem and Meira Meltzer and Andrea Gropman and Carole Brewer and Caswell, \{Richard C\} and Tara Montgomery and Caoimhe McKenna and Shane McKee and Corinna Powell and Vasudevan, \{Pradeep C\} and Brady, \{Angela F\} and Shelagh Joss and Carolyn Tysoe and Grace Noh and Mark Tarnopolsky and Lauren Brady and Muhammad Zafar and \{Schrier Vergano\}, \{Samantha A\} and Brianna Murray and Lindsey Sawyer and Hainline, \{Bryan E\} and Katherine Sapp and Danielle DeMarzo and Huismann, \{Darcy J\} and Wentzensen, \{Ingrid M\} and Schnur, \{Rhonda E\} and Monaghan, \{Kristin G\} and Jane Juusola and Lindsay Rhodes and Dobyns, \{William B\} and Francois Lecoquierre and Alice Goldenberg and Tilman Polster and Susanne Axer-Schaefer and Konrad Platzer and Chiara Kl{\"o}ckner and Hoffman, \{Trevor L\} and MacArthur, \{Daniel G\} and O'Leary, \{Melanie C\} and VanNoy, \{Grace E\} and Eleina England and Varghese, \{Vinod C\} and Mefford, \{Heather C\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.",

year = "2021",

month = may,

doi = "10.1038/s41436-020-01076-8",

language = "English",

volume = "23",

pages = "881--887",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

publisher = "Elsevier",

number = "5",

}

Muir, AM, Gardner, JF, van Jaarsveld, RH, de Lange, IM, van der Smagt, JJ, Wilson, GN, Dubbs, H, Goldberg, EM, Zitano, L, Bupp, C, Martinez, J, Srour, M, Accogli, A, Alhakeem, A, Meltzer, M, Gropman, A, Brewer, C, Caswell, RC, Montgomery, T, McKenna, C, McKee, S, Powell, C, Vasudevan, PC, Brady, AF, Joss, S, Tysoe, C, Noh, G, Tarnopolsky, M, Brady, L, Zafar, M, Schrier Vergano, SA, Murray, B, Sawyer, L, Hainline, BE, Sapp, K, DeMarzo, D, Huismann, DJ, Wentzensen, IM, Schnur, RE, Monaghan, KG, Juusola, J, Rhodes, L, Dobyns, WB, Lecoquierre, F, Goldenberg, A, Polster, T, Axer-Schaefer, S, Platzer, K, Klöckner, C, Hoffman, TL, MacArthur, DG, O'Leary, MC, VanNoy, GE, England, E, Varghese, VC & Mefford, HC 2021, 'Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia', Genetics in medicine : official journal of the American College of Medical Genetics, vol. 23, no. 5, pp. 881-887. https://doi.org/10.1038/s41436-020-01076-8

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia. / Muir, Alison M; Gardner, Jennifer F; van Jaarsveld, Richard H et al.
In: Genetics in medicine : official journal of the American College of Medical Genetics, Vol. 23, No. 5, 05.2021, p. 881-887.

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

TY - JOUR

T1 - Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

AU - Muir, Alison M

AU - Gardner, Jennifer F

AU - van Jaarsveld, Richard H

AU - de Lange, Iris M

AU - van der Smagt, Jasper J

AU - Wilson, Golder N

AU - Dubbs, Holly

AU - Goldberg, Ethan M

AU - Zitano, Lia

AU - Bupp, Caleb

AU - Martinez, Jose

AU - Srour, Myriam

AU - Accogli, Andrea

AU - Alhakeem, Afnan

AU - Meltzer, Meira

AU - Gropman, Andrea

AU - Brewer, Carole

AU - Caswell, Richard C

AU - Montgomery, Tara

AU - McKenna, Caoimhe

AU - McKee, Shane

AU - Powell, Corinna

AU - Vasudevan, Pradeep C

AU - Brady, Angela F

AU - Joss, Shelagh

AU - Tysoe, Carolyn

AU - Noh, Grace

AU - Tarnopolsky, Mark

AU - Brady, Lauren

AU - Zafar, Muhammad

AU - Schrier Vergano, Samantha A

AU - Murray, Brianna

AU - Sawyer, Lindsey

AU - Hainline, Bryan E

AU - Sapp, Katherine

AU - DeMarzo, Danielle

AU - Huismann, Darcy J

AU - Wentzensen, Ingrid M

AU - Schnur, Rhonda E

AU - Monaghan, Kristin G

AU - Juusola, Jane

AU - Rhodes, Lindsay

AU - Dobyns, William B

AU - Lecoquierre, Francois

AU - Goldenberg, Alice

AU - Polster, Tilman

AU - Axer-Schaefer, Susanne

AU - Platzer, Konrad

AU - Klöckner, Chiara

AU - Hoffman, Trevor L

AU - MacArthur, Daniel G

AU - O'Leary, Melanie C

AU - VanNoy, Grace E

AU - England, Eleina

AU - Varghese, Vinod C

AU - Mefford, Heather C

PY - 2021/5

Y1 - 2021/5

N2 - PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

AB - PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

KW - Child

KW - Developmental Disabilities/genetics

KW - Exome Sequencing

KW - Humans

KW - Intellectual Disability/diagnosis

KW - Muscle Hypotonia/diagnosis

KW - Neurodevelopmental Disorders/diagnosis

KW - Seizures/genetics

UR - https://www.scopus.com/pages/publications/85099532198

U2 - 10.1038/s41436-020-01076-8

DO - 10.1038/s41436-020-01076-8

M3 - Article

C2 - 33473207

SN - 1098-3600

VL - 23

SP - 881

EP - 887

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 5

ER -

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

Abstract

Keywords

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