Format

Send to

Choose Destination
Genet Med. 2019 Apr;21(4):867-876. doi: 10.1038/s41436-018-0269-0. Epub 2018 Sep 7.

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

Author information

1
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
2
Departments of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
4
Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
5
Department of Clinical Genetics and Metabolism, Children's Hospital, University of Colorado School of Medicine, Aurora, Colorado, USA.
6
Department of Pediatrics, University of California San Diego; Division of Genetics/Dysmorphology, Rady Children's Hospital, San Diego, California, USA.
7
Baylor Scott and White Hospital, Temple, Texas, USA.
8
Clinical Genetics Program, University of Vermont Medical Center, Burlington, Vermont, USA.
9
Department of Clinical Genetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
10
Department of Pediatrics, Division of Genomic Medicine, UC Davis MIND Institute, Sacramento, California, USA.
11
Department of Human Genetics, KU Leuven-University of Leuven, Leuven, Belgium.
12
Medical Genetics Unit, Bambino Gesù Children's, IRCCS, Rome, Italy.
13
Carolinas Medical Center, Charlotte, North Carolina, USA.
14
SOC Genetica Medica, AOU Meyer, Florence, Italy.
15
Department of Neurology, Division of Child Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
16
Neurofibromatosis Diagnostic & Treatment Program, St. Joseph's Children's Hospital, Paterson, New Jersey, USA.
17
Neurofibromatosis Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
18
Department of Genetics, Hospital Universitario Ramón y Cajal, Institute of Health Research (IRYCIS), Madrid, Spain.
19
Center for Biomedical Research-Network of Rare Diseases (CIBERER), Madrid, Spain.
20
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
21
Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
22
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
23
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
24
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
25
Medical Genetics Unit, G. Rummo Hospital, Benevento, Italy.
26
Department of Genetics, Yale University, New Haven, Connecticut, USA.
27
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
28
Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, North Carolina, USA.
29
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
30
Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, Minnesota, USA.
31
Department of Pediatrics, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.
32
Department of General Pediatrics, Erasmus MC-Sophia, Rotterdam, The Netherlands.
33
CHU Sainte-Justine, Mother and Child University Hospital Center, Montréal, Québec, Canada.
34
Department of Pediatrics and Ophthalmology, University of Minnesota, Minneapolis, Minnesota, USA.
35
U.O.S.C. Medical Genetics, A.O.R.N. "A. Cardarelli", Naples, Italy.
36
Division of Medical Genetics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
37
Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA.
38
Developmental Neurology Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
39
Division of Medical Genetics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, Arkansas, USA.
40
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
41
Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
42
DCH Regional Medical Center and Northport Medical Center, Northport, Alabama, USA.
43
Stead Family Department of Pediatrics, University of Iowa Hospitals & Clinics, Iowa City, Iowa, USA.
44
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
45
Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
46
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
47
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
48
IRCCS Casa Sollievo della Sofferenza, Molecular Genetics Unit, San Giovanni Rotondo, Foggia, Italy.
49
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA. lmessiaen@uabmc.edu.

Abstract

PURPOSE:

Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.

METHODS:

A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.

RESULTS:

None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.

CONCLUSION:

We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

KEYWORDS:

NF1; genotype–phenotype correlation; learning difficulties; neurofibroma; p.Met992del

PMID:
30190611
DOI:
10.1038/s41436-018-0269-0
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center