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

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

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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
Pages (from-to)	704-710
Journal	American Journal of Human Genetics
Volume	99
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2016.06.025 https://doi.org/10.1016/j.ajhg.2016.08.011
Publication status	Published - 2016

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Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., Blom, N. A., de Graaff, W., Kamermans, M., Cocciadiferro, D., Malerba, N., Mandriani, B., Akdemir, Z. 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, https://doi.org/10.1016/j.ajhg.2016.08.011

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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.",

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

year = "2016",

doi = "10.1016/j.ajhg.2016.06.025",

language = "English",

volume = "99",

pages = "704--710",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

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Lodder, EM, De Nittis, P, Koopman, CD, Wiszniewski, W, Moura de Souza, CF, Lahrouchi, N, Guex, N, Napolioni, V, Tessadori, F, Beekman, L, Nannenberg, EA, Boualla, L, Blom, NA, de Graaff, W, Kamermans, M, Cocciadiferro, D, Malerba, N, Mandriani, B, Akdemir, ZHC, Fish, RJ, Eldomery, MK, Ratbi, I, Wilde, AAM, de Boer, T, Simonds, WF, Neerman-Arbez, M, Sutton, VR, Kok, F, Lupski, JR, Reymond, A, Bezzina, CR, 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, https://doi.org/10.1016/j.ajhg.2016.08.011

TY - JOUR

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

AU - Lodder, Elisabeth M

AU - De Nittis, Pasquelena

AU - Koopman, Charlotte D

AU - Wiszniewski, Wojciech

AU - Moura de Souza, Carolina Fischinger

AU - Lahrouchi, Najim

AU - Guex, Nicolas

AU - Napolioni, Valerio

AU - Tessadori, Federico

AU - Beekman, Leander

AU - Nannenberg, Eline A

AU - Boualla, Lamiae

AU - Blom, Nico A

AU - de Graaff, Wim

AU - Kamermans, M.

AU - Cocciadiferro, Dario

AU - Malerba, Natascia

AU - Mandriani, Barbara

AU - Akdemir, Zeynep Hande Coban

AU - Fish, Richard J

AU - Eldomery, Mohammad K

AU - Ratbi, Ilham

AU - Wilde, Arthur A M

AU - de Boer, Teun

AU - Simonds, William F

AU - Neerman-Arbez, Marguerite

AU - Sutton, V Reid

AU - Kok, Fernando

AU - Lupski, James R

AU - Reymond, Alexandre

AU - Bezzina, Connie R

AU - Bakkers, Jeroen

AU - Merla, Giuseppe

PY - 2016

Y1 - 2016

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.

U2 - 10.1016/j.ajhg.2016.06.025

DO - 10.1016/j.ajhg.2016.06.025

M3 - Article

C2 - 27523599

SN - 0002-9297

VL - 99

SP - 704

EP - 710

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

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

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