Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome

American Journal of Medical Genetics, Part A - Tập 167 Số 2 - Trang 271-281 - 2015
Karen W. Gripp1, Katherine Robbins2,3, Nara Sobreira4, P. Dane Witmer5, Lynne M. Bird6, Kristiina Avela7, Outi Mäkitie8, Daniela Alves9, Jacob S. Hogue10, Elaine H. Zackai11, Kimberly F. Doheny5, Deborah L. Stabley3, Katia Sol‐Church3
1Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, and Sidney Kimmel Medical School at T. Jefferson University, Philadelphia, Pennsylvania.
2Department of Biological Sciences, University of Delaware, Newark, Delaware
3Department of Biomedical Research, A.I. duPont Hospital for Children, Wilmington, Delaware
4Johns Hopkins University School of Medicine; Institute of Genetic Medicine; Baltimore Maryland
5Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
6University of California San Diego and Rady Children's Hospital, San Diego, California
7Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland
8Children's Hospital Helsinki University Central Hospital and University of Helsinki, and Folkhälsan Institute of Genetics Helsinki Finland
9Neurogenetics Unit Department of Medical Genetics Centro Hospitalar de São João Porto Portugal
10Madigan Army Medical Center, Tacoma, Washington
11Division of Human Genetics and Molecular Biology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Tóm tắt

Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele‐related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low‐set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high‐pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu–Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline‐glutamate‐serine‐threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain‐of‐function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu–Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL. © 2014 Wiley Periodicals, Inc.

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Thông tin xuất bản

American Journal of Medical Genetics, Part A

Tập 167 Số 2

271-281

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