GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Elisabeth M M. Lodder; Pasquelena De Nittis; Charlotte D D. Koopman; Wojciech Wiszniewski; Carolina Fischinger F. Moura de Souza; Najim Lahrouchi; Nicolas Guex; Valerio Napolioni; Federico Tessadori; Leander Beekman; Eline A A. Nannenberg; Lamiae Boualla; Nico A A. Blom; Wim de Graaff; Maarten Kamermans; Dario Cocciadiferro; Natascia Malerba; Barbara Mandriani; Zeynep Hande Coban H.C. Akdemir; Richard J J. Fish; Mohammad K K. Eldomery; Ilham Ratbi; Arthur A A.M. Wilde; Teun de Boer; William F F. Simonds; Marguerite Neerman-Arbez; V. Reid Sutton; Fernando Kok; James R R. Lupski; Alexandre Reymond; Connie R R. Bezzina; Jeroen Bakkers; Giuseppe Merla

doi:10.1016/j.ajhg.2016.06.025

GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Elisabeth M M. Lodder, Pasquelena De Nittis, Charlotte D D. Koopman, Wojciech Wiszniewski, Carolina Fischinger F. Moura de Souza, Najim Lahrouchi, Nicolas Guex, Valerio Napolioni, Federico Tessadori, Leander Beekman, Eline A A. Nannenberg, Lamiae Boualla, Nico A A. Blom, Wim de Graaff, Maarten Kamermans, Dario Cocciadiferro, Natascia Malerba, Barbara Mandriani, Zeynep Hande Coban H.C. Akdemir, Richard J J. FishMohammad K K. Eldomery, Ilham Ratbi, Arthur A A.M. Wilde, Teun de Boer, William F F. Simonds, Marguerite Neerman-Arbez, V. Reid Sutton, Fernando Kok, James R R. Lupski, Alexandre Reymond, Connie R R. Bezzina, Jeroen Bakkers, Giuseppe Merla

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

46 Scopus citations

Abstract

GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.

Original language	English (US)
Pages (from-to)	704-710
Number of pages	7
Journal	American Journal of Human Genetics
Volume	99
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2016.06.025
State	Published - Sep 1 2016
Externally published	Yes

Keywords

G-protein signaling
heart rate
hypotonia
intellectual disability
parasympathetic system
whole-exome sequencing

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2016.06.025

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Lodder, EM. M., De Nittis, P., Koopman, CD. D., Wiszniewski, W., Moura de Souza, CF. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, EA. A., Boualla, L., Blom, NA. A., de Graaff, W., Kamermans, M., Cocciadiferro, D., Malerba, N., Mandriani, B., Akdemir, ZHC. H. C., ... Merla, G. (2016). GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability. American Journal of Human Genetics, 99(3), 704-710. https://doi.org/10.1016/j.ajhg.2016.06.025

Lodder, EMM, De Nittis, P, Koopman, CDD, Wiszniewski, W, Moura de Souza, CFF, Lahrouchi, N, Guex, N, Napolioni, V, Tessadori, F, Beekman, L, Nannenberg, EAA, Boualla, L, Blom, NAA, de Graaff, W, Kamermans, M, Cocciadiferro, D, Malerba, N, Mandriani, B, Akdemir, ZHCHC, Fish, RJJ, Eldomery, MKK, Ratbi, I, Wilde, AAAM, de Boer, T, Simonds, WFF, Neerman-Arbez, M, Sutton, VR, Kok, F, Lupski, JRR, Reymond, A, Bezzina, CRR, Bakkers, J & Merla, G 2016, 'GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability', American Journal of Human Genetics, vol. 99, no. 3, pp. 704-710. https://doi.org/10.1016/j.ajhg.2016.06.025

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title = "GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability",

abstract = "GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.",

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author = "Lodder, {Elisabeth M M.} and Pasquelena De Nittis and Koopman, {Charlotte D D.} and Wojciech Wiszniewski and Moura de Souza, {Carolina Fischinger F.} and Najim Lahrouchi and Nicolas Guex and Valerio Napolioni and Federico Tessadori and Leander Beekman and Nannenberg, {Eline A A.} and Lamiae Boualla and Blom, {Nico A A.} and Wim de Graaff and Maarten Kamermans and Dario Cocciadiferro and Natascia Malerba and Barbara Mandriani and Akdemir, {Zeynep Hande Coban H.C.} and Fish, {Richard J J.} and Eldomery, {Mohammad K K.} and Ilham Ratbi and Wilde, {Arthur A A.M.} and Teun de Boer and Simonds, {William F F.} and Marguerite Neerman-Arbez and Sutton, {V. Reid} and Fernando Kok and Lupski, {James R R.} and Alexandre Reymond and Bezzina, {Connie R R.} and Jeroen Bakkers and Giuseppe Merla",

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T1 - GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

AU - Lodder, Elisabeth M M.

AU - De Nittis, Pasquelena

AU - Koopman, Charlotte D D.

AU - Wiszniewski, Wojciech

AU - Moura de Souza, Carolina Fischinger F.

AU - Lahrouchi, Najim

AU - Guex, Nicolas

AU - Napolioni, Valerio

AU - Tessadori, Federico

AU - Beekman, Leander

AU - Nannenberg, Eline A A.

AU - Boualla, Lamiae

AU - Blom, Nico A A.

AU - de Graaff, Wim

AU - Kamermans, Maarten

AU - Cocciadiferro, Dario

AU - Malerba, Natascia

AU - Mandriani, Barbara

AU - Akdemir, Zeynep Hande Coban H.C.

AU - Fish, Richard J J.

AU - Eldomery, Mohammad K K.

AU - Ratbi, Ilham

AU - Wilde, Arthur A A.M.

AU - de Boer, Teun

AU - Simonds, William F F.

AU - Neerman-Arbez, Marguerite

AU - Sutton, V. Reid

AU - Kok, Fernando

AU - Lupski, James R R.

AU - Reymond, Alexandre

AU - Bezzina, Connie R R.

AU - Bakkers, Jeroen

AU - Merla, Giuseppe

PY - 2016/9/1

Y1 - 2016/9/1

N2 - GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.

AB - GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.

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KW - hypotonia

KW - intellectual disability

KW - parasympathetic system

KW - whole-exome sequencing

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JF - American Journal of Human Genetics

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ER -

GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

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