Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May;23(5):881-887.
doi: 10.1038/s41436-020-01076-8. Epub 2021 Jan 20.

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

Alison M Muir #  1 , Jennifer F Gardner #  2 , Richard H van Jaarsveld  3 , Iris M de Lange  3 , Jasper J van der Smagt  3 , Golder N Wilson  4 , Holly Dubbs  5 , Ethan M Goldberg  5 , Lia Zitano  6 , Caleb Bupp  6 , Jose Martinez  7 , Myriam Srour  8 , Andrea Accogli  8 , Afnan Alhakeem  8 , Meira Meltzer  9 , Andrea Gropman  9 , Carole Brewer  10 , Richard C Caswell  11   12 , Tara Montgomery  13 , Caoimhe McKenna  14 , Shane McKee  14 , Corinna Powell  15 , Pradeep C Vasudevan  15 , Angela F Brady  16 , Shelagh Joss  17 , Carolyn Tysoe  18 , Grace Noh  19 , Mark Tarnopolsky  20 , Lauren Brady  20 , Muhammad Zafar  21 , Samantha A Schrier Vergano  22 , Brianna Murray  22 , Lindsey Sawyer  22 , Bryan E Hainline  23 , Katherine Sapp  23 , Danielle DeMarzo  24 , Darcy J Huismann  24 , Ingrid M Wentzensen  25 , Rhonda E Schnur  25 , Kristin G Monaghan  25 , Jane Juusola  25 , Lindsay Rhodes  25 , William B Dobyns  1   26 , Francois Lecoquierre  27 , Alice Goldenberg  27 , Tilman Polster  28 , Susanne Axer-Schaefer  28 , Konrad Platzer  29 , Chiara Klöckner  29 , Trevor L Hoffman  19 , Daniel G MacArthur  30   31   32 , Melanie C O'Leary  30 , Grace E VanNoy  30 , Eleina England  30 , Vinod C Varghese  2 , Heather C Mefford  33
Affiliations

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

Alison M Muir et al. Genet Med. 2021 May.

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

IMW, RES, KGM, JJ, and LR are employees of GeneDx, Inc. The other authors declare no conflicts of interest.

Figures

Figure 1:
Figure 1:. Distribution of disease-causing variants across GNAI1.
A) Schematic showing the pathogenic and likely pathogenic variants identified in GNAI1, including one previously reported variant (*) (Kaplanis et al. 2020). Variants cluster within the first guanine nucleotide-binding domain (green box). Missense variants are represented as brown diamonds, coding deletion variants as blue circles, and the truncating frameshift variant as a yellow star. Each symbol represents one individual. B) 3D structure of GNAi1. The left figure shows the structure of GNAi1 as part of the trimeric G-protein complex (PDB accession 6crk); GNAi1 is shown as a cyan ribbon, except for positions of novel variants which are coloured as follows: missense, magenta; in-frame deletions, yellow; frameshifting insertion at Ile278, light green; bound GDP is shown as space-filling spheres, coloured by atom type (white, carbon; blue, nitrogen; red, oxygen; orange, phosphorus); the molecular surface is shown for the βγ dimer, with the β1 and γ2 chains coloured dark green and orange respectively. The right figure shows GNAi1 only, rotated around the vertical axis; Gly45 is obscured by the GDP ligand in this view. In both parts, labelling in bold font indicates residues making direct contact with GDP (Gly45, Thr48, Lys270, Ala326).
Figure 1:
Figure 1:. Distribution of disease-causing variants across GNAI1.
A) Schematic showing the pathogenic and likely pathogenic variants identified in GNAI1, including one previously reported variant (*) (Kaplanis et al. 2020). Variants cluster within the first guanine nucleotide-binding domain (green box). Missense variants are represented as brown diamonds, coding deletion variants as blue circles, and the truncating frameshift variant as a yellow star. Each symbol represents one individual. B) 3D structure of GNAi1. The left figure shows the structure of GNAi1 as part of the trimeric G-protein complex (PDB accession 6crk); GNAi1 is shown as a cyan ribbon, except for positions of novel variants which are coloured as follows: missense, magenta; in-frame deletions, yellow; frameshifting insertion at Ile278, light green; bound GDP is shown as space-filling spheres, coloured by atom type (white, carbon; blue, nitrogen; red, oxygen; orange, phosphorus); the molecular surface is shown for the βγ dimer, with the β1 and γ2 chains coloured dark green and orange respectively. The right figure shows GNAi1 only, rotated around the vertical axis; Gly45 is obscured by the GDP ligand in this view. In both parts, labelling in bold font indicates residues making direct contact with GDP (Gly45, Thr48, Lys270, Ala326).
Figure 2:
Figure 2:. Photographs of affected individuals.
A) individual 2; B) individual 10; C) individuals 11; D) individual 16; E) individual 18; F, individual 19; G) individual 20; H) individual 22; I) individual 23; J) individual 24. Affected individuals have variable minor dysmorphic features and tend to have tapering fingers.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Deciphering Developmental Disorders S. Large-scale discovery of novel genetic causes of developmental disorders Nature. 2015. March 12;519:223–228. - PMC - PubMed
    1. Kaplanis J, Samocha KE, Wiel L, Zhang Z, Arvai KJ, Eberhardt RY, et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data Nature. 2020. October;586:757–762. - PMC - PubMed
    1. Nakamura K, Kodera H, Akita T, Shiina M, Kato M, Hoshino H, et al. De Novo mutations in GNAO1, encoding a Galphao subunit of heterotrimeric G proteins, cause epileptic encephalopathy American journal of human genetics. 2013. September 5;93:496–505. - PMC - PubMed
    1. Petrovski S, Kury S, Myers CT, Anyane-Yeboa K, Cogne B, Bialer M, et al. Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures American journal of human genetics. 2016. May 5;98:1001–1010. - PMC - PubMed
    1. McCudden CR, Hains MD, Kimple RJ, Siderovski DP, Willard FS. G-protein signaling: back to the future Cellular and molecular life sciences : CMLS. 2005. March;62:551–577. - PMC - PubMed

Publication types

MeSH terms