GNB5-Related Neurodevelopmental Disorder

Review

GNB5-Related Neurodevelopmental Disorder

Gemma Poke¹, Lynette Grant Sadleir¹, Giuseppe Merla^{2

3}, Guillem de Valles-Ibáñez¹, Jonathan Robert Skinner^{4

5}

Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Anne Amemiya

, editors.

In: GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.

2021 Aug 26 [updated 2021 Sep 9].

Affiliations

¹ University of Otago, Wellington, New Zealand
² Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
³ Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
⁴ Department of Paediatrics, Child and Youth Health, University of Auckland, Auckland, New Zealand
⁵ Heart Centre for Children, Sydney Children's Hospitals Network, Sydney, Australia

PMID: 34436834
Bookshelf ID: NBK573218

Free Books & Documents

Review

GNB5-Related Neurodevelopmental Disorder

Gemma Poke et al.

Free Books & Documents

In: GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.

2021 Aug 26 [updated 2021 Sep 9].

Authors

Gemma Poke¹, Lynette Grant Sadleir¹, Giuseppe Merla^{2

3}, Guillem de Valles-Ibáñez¹, Jonathan Robert Skinner^{4

5}

Book Editors

Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Anne Amemiya

Affiliations

¹ University of Otago, Wellington, New Zealand
² Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
³ Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
⁴ Department of Paediatrics, Child and Youth Health, University of Auckland, Auckland, New Zealand
⁵ Heart Centre for Children, Sydney Children's Hospitals Network, Sydney, Australia

PMID: 34436834
Bookshelf ID: NBK573218

Excerpt

Clinical characteristics: GNB5-related neurodevelopmental disorder (GNB5-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of GNB5-NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased.

Diagnosis/testing: The diagnosis of GNB5-NDD is established in a proband with suggestive clinical findings and biallelic pathogenic variants in GNB5 identified by molecular genetic testing.

Management: Treatment of manifestations: Management by multidisciplinary specialists including a general pediatrician, developmental pediatrician, pediatric neurologist, speech-language pathologist, orthopedist, physical medicine and rehabilitation specialist, physical therapist, occupational therapist, pediatric ophthalmologist, and pediatric cardiologist is recommended.

Surveillance: Routine follow up by multidisciplinary care providers based on individual needs and circumstances.

Agents/circumstances to avoid: Use parasympathomimetics with extreme caution because of the potential to cause asystole. It is best to avoid other drugs that can potentiate bradycardia, particularly beta blockers.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of at-risk neonates (if prenatal testing was not performed) in order to identify as early as possible those who warrant developmental assessment (and monitoring) and evaluation by a pediatric cardiologist.

Genetic counseling: GNB5-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GNB5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the GNB5 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

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1. De Nittis P, Efthymiou S, Sarre A, Guex N, Chrast J, Putoux A, Sultan T, Raza Alvi J, Ur Rahman Z, Zafar F, Rana N, Rahman F, Anwar N, Maqbool S, Zaki MS, Gleeson JG, Murphy D, Galehdari H, Shariati G, Mazaheri N, Sedaghat A, Lesca G, Chatron N, Salpietro V, Christoforou M, Houlden H, Simonds WF, Pedrazzini T, Maroofian R, Reymond A, et al. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome. J Med Genet. 2021;58:815–31. - PMC - PubMed
1. Jones PG, Lombardi SJ, Cockett MI. Cloning and tissue distribution of the human G protein β5 cDNA. Biochim Biophys Acta. 1998;1402:288–91. - PubMed
1. Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. - PubMed
1. 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. GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability. Am J Hum Genet. 2016;99:704–10. - PMC - PubMed
1. Mai JH, Ou ZH, Chen L, Duan J, Liao JX, Han CX. Intellectual developmental disorder with cardiac arrhythmia syndrome in a family caused by GNB5 variation and literature review. Zhonghua Er Ke Za Zhi. 2020;58:833–7. - PubMed

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[1] De Nittis P, Efthymiou S, Sarre A, Guex N, Chrast J, Putoux A, Sultan T, Raza Alvi J, Ur Rahman Z, Zafar F, Rana N, Rahman F, Anwar N, Maqbool S, Zaki MS, Gleeson JG, Murphy D, Galehdari H, Shariati G, Mazaheri N, Sedaghat A, Lesca G, Chatron N, Salpietro V, Christoforou M, Houlden H, Simonds WF, Pedrazzini T, Maroofian R, Reymond A, et al. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome. J Med Genet. 2021;58:815–31. - PMC - PubMed

[2] De Nittis P, Efthymiou S, Sarre A, Guex N, Chrast J, Putoux A, Sultan T, Raza Alvi J, Ur Rahman Z, Zafar F, Rana N, Rahman F, Anwar N, Maqbool S, Zaki MS, Gleeson JG, Murphy D, Galehdari H, Shariati G, Mazaheri N, Sedaghat A, Lesca G, Chatron N, Salpietro V, Christoforou M, Houlden H, Simonds WF, Pedrazzini T, Maroofian R, Reymond A, et al. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome. J Med Genet. 2021;58:815–31. - PMC - PubMed

[3] Jones PG, Lombardi SJ, Cockett MI. Cloning and tissue distribution of the human G protein β5 cDNA. Biochim Biophys Acta. 1998;1402:288–91. - PubMed

[4] Jones PG, Lombardi SJ, Cockett MI. Cloning and tissue distribution of the human G protein β5 cDNA. Biochim Biophys Acta. 1998;1402:288–91. - PubMed

[5] Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. - PubMed

[6] Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. - PubMed

[7] 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. GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability. Am J Hum Genet. 2016;99:704–10. - PMC - PubMed

[8] 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. GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability. Am J Hum Genet. 2016;99:704–10. - PMC - PubMed

[9] Mai JH, Ou ZH, Chen L, Duan J, Liao JX, Han CX. Intellectual developmental disorder with cardiac arrhythmia syndrome in a family caused by GNB5 variation and literature review. Zhonghua Er Ke Za Zhi. 2020;58:833–7. - PubMed

[10] Mai JH, Ou ZH, Chen L, Duan J, Liao JX, Han CX. Intellectual developmental disorder with cardiac arrhythmia syndrome in a family caused by GNB5 variation and literature review. Zhonghua Er Ke Za Zhi. 2020;58:833–7. - PubMed

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GNB5-Related Neurodevelopmental Disorder

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