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

TitleTruncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
Publication TypeJournal Article
Year of Publication2015
AuthorsGripp, KW, Robbins, KM, Sobreira, NL, P Witmer, D, Bird, LM, Avela, K, Mäkitie, O, Alves, D, Hogue, JS, Zackai, EH, Doheny, KF, Stabley, DL, Sol-Church, K
JournalAm J Med Genet A
Date Published2015 Feb
KeywordsAbnormalities, Multiple, Child, Child, Preschool, DNA Mutational Analysis, Exome, Exons, Facies, High-Throughput Nucleotide Sequencing, Humans, Magnetic Resonance Imaging, Male, Meningocele, Mutation, Phenotype, Receptor, Notch3, Receptors, Notch, Young Adult

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.

Alternate JournalAm. J. Med. Genet. A
PubMed ID25394726
PubMed Central IDPMC5589071
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
P20 GM103464 / GM / NIGMS NIH HHS / United States
P20GM103446 / GM / NIGMS NIH HHS / United States
T32 GM007471 / GM / NIGMS NIH HHS / United States
1U54HG006542 / HG / NHGRI NIH HHS / United States
P20 GM103446 / GM / NIGMS NIH HHS / United States
P20GM103464 / GM / NIGMS NIH HHS / United States