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

Am J Med Genet A 2018 11 8;176(11):2259-2275. Epub 2018 Sep 8.

Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center (CUMC), New York, New York.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.40472DOI Listing
November 2018
30 Reads

Publication Analysis

Top Keywords

patients
10
patients carrying
8
gnb1
6
residue encoded
4
additional patients
4
pile80 residue
4
substitution pile80
4
observed substitution
4
patients providing
4
encoded exon
4
exon 28%
4
residue dystonia
4
observed three
4
variant residue
4
carrying variant
4
nonverbal observed
4
28% patients
4
three additional
4
non-ambulatory nonverbal
4
gnb1 will
4

References

(Supplied by CrossRef)
Acute lymphoblastic leukemia in a child with a de novo germline gnb1 mutation
Brett et al.
American Journal of Medical Genetics. Part A 2017
Epidemiology of systemic mastocytosis in Denmark
Cohen et al.
British Journal of Haematology 2014
Mutations in GNAL cause primary torsion dystonia
Fuchs et al.
Nature Genetics 2013
The incidence of congenital heart disease
Hoffman et al.
Journal of the American College of Cardiology 2002
Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans
Lohmann et al.
Human Molecular Genetics 2017

Similar Publications