Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature

C4RCD Research Group, DDD study

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype–phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype–phenotype correlations.

Original languageEnglish
Pages (from-to)2259-2275
Number of pages17
JournalAmerican Journal of Medical Genetics, Part A
Volume176
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

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Phenotype
Mutation
Cutaneous Mastocytosis
Mosaicism
Dystonia
Germ-Line Mutation
Exons
Growth

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@article{c90d95aabd234360a4e8218093dda805,
title = "Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature",
abstract = "De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28{\%} of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype–phenotype correlation. In the new cohort of 18 patients, 50{\%} of males had genitourinary anomalies and 61{\%} of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype–phenotype correlations.",
keywords = "developmental disabilities, GNB1, hypotonia, mastocytosis, seizures, whole exome sequencing",
author = "{C4RCD Research Group} and {DDD study} and Parisa Hemati and Anya Revah-Politi and Haim Bassan and Slav{\'e} Petrovski and Bilancia, {Colleen G.} and Keri Ramsey and Griffin, {Nicole G.} and Louise Bier and Cho, {Megan T.} and Monica Rosello and Lynch, {Sally Ann} and Sophie Colombo and Astrid Weber and Marte Haug and Heinzen, {Erin L.} and Sands, {Tristan T.} and Vinodh Narayanan and Michelle Primiano and Aggarwal, {Vimla S.} and Francisca Millan and Sattler-Holtrop, {Shannon G.} and Alfonso Caro-Llopis and Nir Pillar and Janice Baker and Rebecca Freedman and Kroes, {Hester Y.} and Stephanie Sacharow and Nick Stong and Pablo Lapunzina and Schneider, {Michael C.} and Mendelsohn, {Nancy J.} and Amanda Singleton and {Loik Ramey}, Valerie and Karen Wou and Alla Kuzminsky and Sandra Monfort and Monica Weiss and Samantha Doyle and Alejandro Iglesias and Francisco Martinez and Fiona Mckenzie and Carmen Orellana and {van Gassen}, {Koen L.I.} and Maria Palomares and Lily Bazak and Andy Lee and Ana Bircher and Lina Basel-Vanagaite and Maria Hafstr{\"o}m and Gunnar Houge and Goldstein, {David B.} and Kwame Anyane-Yeboa",
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Refining the phenotype associated with GNB1 mutations : Clinical data on 18 newly identified patients and review of the literature. / C4RCD Research Group; DDD study.

In: American Journal of Medical Genetics, Part A, Vol. 176, No. 11, 01.11.2018, p. 2259-2275.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Refining the phenotype associated with GNB1 mutations

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AU - C4RCD Research Group

AU - DDD study

AU - Hemati, Parisa

AU - Revah-Politi, Anya

AU - Bassan, Haim

AU - Petrovski, Slavé

AU - Bilancia, Colleen G.

AU - Ramsey, Keri

AU - Griffin, Nicole G.

AU - Bier, Louise

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AU - Colombo, Sophie

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AU - Millan, Francisca

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AU - Caro-Llopis, Alfonso

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AU - Baker, Janice

AU - Freedman, Rebecca

AU - Kroes, Hester Y.

AU - Sacharow, Stephanie

AU - Stong, Nick

AU - Lapunzina, Pablo

AU - Schneider, Michael C.

AU - Mendelsohn, Nancy J.

AU - Singleton, Amanda

AU - Loik Ramey, Valerie

AU - Wou, Karen

AU - Kuzminsky, Alla

AU - Monfort, Sandra

AU - Weiss, Monica

AU - Doyle, Samantha

AU - Iglesias, Alejandro

AU - Martinez, Francisco

AU - Mckenzie, Fiona

AU - Orellana, Carmen

AU - van Gassen, Koen L.I.

AU - Palomares, Maria

AU - Bazak, Lily

AU - Lee, Andy

AU - Bircher, Ana

AU - Basel-Vanagaite, Lina

AU - Hafström, Maria

AU - Houge, Gunnar

AU - Goldstein, David B.

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N2 - De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype–phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype–phenotype correlations.

AB - De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype–phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype–phenotype correlations.

KW - developmental disabilities

KW - GNB1

KW - hypotonia

KW - mastocytosis

KW - seizures

KW - whole exome sequencing

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DO - 10.1002/ajmg.a.40472

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