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Am J Med Genet A. 2018 Nov;176(11):2259-2275. doi: 10.1002/ajmg.a.40472. Epub 2018 Sep 8.

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

Author information

1
Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
2
Pediatric Neurology & Development Center, Assaf Harofe Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
3
Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.
4
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
5
Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona.
6
GeneDx, Gaithersburg, Maryland.
7
Unidad de Genetica, Hospital Universitario y Politecnico La Fe, Valencia, Spain.
8
Temple Street Children's University Hospital, Dublin, Ireland.
9
Department of Clinical Genetics, Liverpool Women's Hospital, Liverpool, United Kingdom.
10
Department of Medical Genetics, St. Olav's University Hospital, Trondheim, Norway.
11
Department of Pediatrics, Children's Hospital of New York-Presbyterian, New York, New York.
12
Carle Physician Group, Urbana, Illinois.
13
Department of Genetics, Le Bonheur Children's Hospital, Memphis, Tennessee.
14
Genomics Medicine Program, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.
15
Genetic Services of Western Australia, Department of Health, Government of Western Australia, Perth, Western Australia, Australia.
16
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
17
Department of Genetics, University Medical Center Utrecht, The Netherlands.
18
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
19
INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
20
Centro de Investigación Biomédica en Red de Enfermedades Raras, CIBERER, ISCIII, Madrid, Spain.
21
Biochemical Genetics, Neurology Division, St Christopher's Hospital for Children, Philadelphia, Pennsylvania.
22
Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center (CUMC), New York, New York.
23
Child development Center, Clalit Health Service, Netanya, Israel.
24
Brentwood Children's Clinic, Brentwood, Tennessee.
25
Inner Vision Women's Ultrasound & Genetics, Nashville, Tennessee.
26
Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
27
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
28
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
29
Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.
30
Department of Pediatrics, St Olav's Hospital, Trondheim, Norway.
31
Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
32
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
33
DDD Study, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

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:

GNB1; developmental disabilities; hypotonia; mastocytosis; seizures; whole exome sequencing

PMID:
30194818
DOI:
10.1002/ajmg.a.40472

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