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1.
Ann Neurol. 2017 Sep;82(3):466-478. doi: 10.1002/ana.25032.

GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy.

Author information

1
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
2
Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
3
Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
4
Department of Pediatrics, Department of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Republic of Korea.
5
Department of Rehabilitation Medicine, Pusan National University College of Medicine, Pusan, Republic of Korea.
6
Department of Physiology, Chosun University School of Medicine, Kwangju, Republic of Korea.
7
Department of Science in Korean Medicine, Cancer Preventive Material Developmental Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
8
Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
9
Albany Medical Center, Albany, NY.
10
UH Cleveland Medical Center, Center for Human Genetics, Cleveland, OH.
11
GeneDx, 207 Perry Parkway, Gaithersburg, MD.
12
Yale Center for Genome Analysis, West Haven, CT.
13
Department of Genetics, Yale University School of Medicine, New Haven, CT.
14
Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea.
15
Department of Biological Sciences, Seoul National University College of Natural Sciences, Seoul, Republic of Korea.

Abstract

OBJECTIVE:

Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions.

METHODS:

We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole-exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models.

RESULTS:

We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model.

INTERPRETATION:

GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.

PMID:
28856709
DOI:
10.1002/ana.25032
[Indexed for MEDLINE]
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2.
Am J Med Genet A. 2017 Aug;173(8):2108-2125. doi: 10.1002/ajmg.a.38279. Epub 2017 May 26.

Phenotypes and genotypes in individuals with SMC1A variants.

Author information

1
Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
2
Prinsenstichting Institute, Purmerend, the Netherlands.
3
Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands.
4
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
5
Division of Clinical Genetics, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
6
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
7
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
8
Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy.
9
División Genetica, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina.
10
Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
11
Department of Medical Genetics, Reference Center for Skeletal Dysplasia, INSERM UMR 1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes-Sorbonne Paris Cité University, AP-HP, Institut Imagine, and Hôpital Universitaire Necker-Enfants Malades, Paris, France.
12
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
13
Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
14
MRC Human Genetics Unit, IGMM, Western General Hospital, Edinburgh, United Kingdom.
15
Department of Health Sciences, Medical Genetics, University of Milan, Milan, Italy.
16
Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.
17
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
18
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
19
Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
20
Institut für Medizinische Genetik und Humangenetik, Berlin, Germany.
21
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
22
Section for Functional Genetics, Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
23
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
24
Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Birmingham, United Kingdom.
25
Institute of Cognitive Neuroscience, University College London, London, United Kingdom.
26
Laboratorio de Genética Clínica y Genómica Funcional, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain.
27
Unidad de Genética Clínica, Servicio de Pediatría, Hospital Clínico Universitario "Lozano Blesa" CIBERER-GCV02 and Departamento de Pediatría, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain.
28
Division of Human Genetics, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
29
Molecular Biology Laboratory, Istituto Auxologico Italiano, Milan, Italy.
30
UOC Pediatria, ASST Lariana, Como, Italy.
31
Severinus Institute, Veldhoven, the Netherlands.
32
Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, Washington.
33
Departments of Pediatrics, Hematology, Oncology and Department of General Nursery, Medical University of Gdansk, Gdansk, Poland.

Abstract

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

KEYWORDS:

Brachmann-De Lange syndrome; Cornelia de Lange syndrome; NIPBL; Rett syndrome; SMC1A; behavior; self-injurious behavior; severity score; syndrome delineation

PMID:
28548707
DOI:
10.1002/ajmg.a.38279
[Indexed for MEDLINE]
Icon for Wiley

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