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Early diagnosis of lateral meningocele syndrome in an infant without neurological symptoms based on genomic analysis

March 2022
Child's Nervous System 38(3):1-5

March 2022
38(3):1-5

DOI:10.1007/s00381-021-05232-6

Authors:

Takeshi Arimitsu

Keio University

Show all 5 authorsHide

Lateral meningocele syndrome is characterized by multiple lateral meningoceles with a distinctive craniofacial appearance, hyperextensibility of the skin, and hypermobility of the joints. The syndrome is caused by heterozygous truncating variants in the last exon, exon 33, of the NOTCH3 gene. Here, we present a 2-year-old girl for whom an early genomic analysis allowed us to recognize the presence of lateral meningoceles and to begin early monitoring of her condition for possible neurological complications. She had a characteristic facial appearance, hyperextensibility of the skin and mobility of the joints, and developmental delays. Given that lateral meningocele syndrome is a rare syndrome, the existence of lateral meningoceles is suspected only when the causative gene is detected by genetic testing. MRI scans are unlikely to be performed in infancy in the absence of neurological symptoms suggestive of meningoceles. No formal guidelines have been established for the neurosurgical indications for lateral meningocele syndrome. Given the features of hyperextensibility of the skin and hypermobility of the joints, lateral meningocele syndrome can be categorized as a connective tissue disease and may be progressive, as with the dural ectasia in Marfan syndrome and Loeys-Dietz syndrome. Watchful monitoring of dural ectasia may be warranted in patients with lateral meningocele syndrome.

Facial features of the patient at the age of 2 years. Characteristic features included proptosis, ptosis, upslanting palpebral fissures, hypertelorism, micrognathia, arched eyebrows, sagging cheeks, long philtrum, open mouth, and angulated ears

…

Spinal neuroimaging findings of the patient at the age of 22 months. T2-weighted MR imaging of the spine showed multiple lateral meningoceles and expansion of the spinal canal. a The coronal plane at the level of the L1-3; b the axial plane at the level of the L2; c the sagittal plane at the level of the Th5-S4 (particularly from L1to L3)

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https://doi.org/10.1007/s00381-021-05232-6

CASE REPORT

Early diagnosis oflateral meningocele syndrome inaninfant

withoutneurological symptoms based ongenomic analysis

MamikoYamada1 · TakeshiArimitsu2 · HisatoSuzuki1 · TomoruMiwa3 · KenjiroKosaki1

Received: 20 May 2021 / Accepted: 26 May 2021

Abstract

Lateral meningocele syndrome is characterized by multiple lateral meningoceles with a distinctive craniofacial appearance,

hyperextensibility of the skin, and hypermobility of the joints. The syndrome is caused by heterozygous truncating variants in

the last exon, exon 33, of the NOTCH3 gene. Here, we present a 2-year-old girl for whom an early genomic analysis allowed

us to recognize the presence of lateral meningoceles and to begin early monitoring of her condition for possible neurologi-

cal complications. She had a characteristic facial appearance, hyperextensibility of the skin and mobility of the joints, and

developmental delays. Given that lateral meningocele syndrome is a rare syndrome, the existence of lateral meningoceles

is suspected only when the causative gene is detected by genetic testing. MRI scans are unlikely to be performed in infancy

in the absence of neurological symptoms suggestive of meningoceles. No formal guidelines have been established for the

neurosurgical indications for lateral meningocele syndrome. Given the features of hyperextensibility of the skin and hyper-

mobility of the joints, lateral meningocele syndrome can be categorized as a connective tissue disease and may be progres-

sive, as with the dural ectasia in Marfan syndrome and Loeys-Dietz syndrome. Watchful monitoring of dural ectasia may be

warranted in patients with lateral meningocele syndrome.

Keywords NOTCH3· Lateral meningocele syndrome· Dural ectasia· Exome analysis

Introduction

Lateral meningoceles represents a severe and anatomically

extended form of dural ectasia and can be associated with

neurological complications such as bladder dysfunction and

neuropathy arising from the protrusion of the arachnoid and

dura mater through the spinal foramina [1]. Lateral menin-

gocele syndrome (LMNS; OMIM 130720) is a newly rec-

ognized syndrome characterized by multiple lateral menin-

goceles and distinctive craniofacial appearances [2]. Other

syndromes, including Marfan syndrome, Loeys-Dietz syn-

drome, Nevo syndrome, Ehlers-Danlos syndrome, and neu-

roﬁbromatosis type 1, can sometimes lead to dural ectasia

but not commonly to the degree observed with LMNS [3].

The genetic cause of LMNS was delineated in 2015 [1];

all nine patients with LMNS who have undergone genetic

testing so far had heterozygous truncating variants in the

last exon, exon 33, of the NOTCH3 gene [1, 2, 4–9]. It is

well established that heterozygous loss-of-function muta-

tions in NOTCH3 lead to cerebral autosomal dominant arte-

riopathy with subcortical infarcts and leukoencephalopathy

(CADASIL; OMIM 125310), which is characterized by

symmetrical white matter lesions with microbleeds and lacu-

nar ischemic infarcts as well as dilated perivascular spaces

but not by lateral meningoceles [10]. The clinical features

of LMNS that are distinctive from those of CADASIL can

be attributed to the peculiar nature of the mutations that

* Kenjiro Kosaki

kkosaki@z3.keio.jp

Mamiko Yamada

mamiko318@keio.jp

Takeshi Arimitsu

arimitsu@z8.keio.jp

Hisato Suzuki

hsuzuki-tuk@umin.ac.jp

Tomoru Miwa

tenmiwa@keio.jp

1 Center forMedical Genetics, Keio University School

ofMedicine, Tokyo, Japan

2 Department ofPediatrics, Keio University School

ofMedicine, Tokyo, Japan

3 Department ofNeurosurgery, Keio University School

ofMedicine, Tokyo, Japan

/ Published online: 13 June 2021

Child’s Nervous System (2022) 38:659–663

Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Management of lateral meningocele syndrome in a child without neurological symptoms and literature review

Article

Full-text available

May 2022
CHILD NERV SYST

Purpose Lateral meningocele syndrome (LMS) is a rare genetic connective tissue disorder which is associated with meningocele-related neurologic dysfunction. Several patients with LMS have been reported. But, guidelines for screening and treatment of LMS have not been established. Method and results We review the current knowledge of LMS in the article. Then, we describe a boy for whom a genomic analysis which allowed us to make a diagnosis of LMS and to begin monitoring of his condition for possible neurological complications. Conclusion It would be difficult to make a diagnosis of LMS on the basis of clinical manifestations alone. The natural history of dural ectasia in patients with LMS needs to be better defined to establish surgical indications. Based upon the current literature, ventriculoperitoneal shunting (V-Ps) has been recommended as the first-line surgical treatment option for patients with symptomatic thoracolumbar meningoceles.

A Case of Lateral Meningocele Syndrome without Lateral Meningoceles

Article

Mar 2024

b> Introduction: Lateral meningocele syndrome (LMS), also known as Lehman syndrome, is caused by pathogenic variants in exon 33 of NOTCH3 . Variants in this final exon of NOTCH3 interrupt the regulatory PEST domain, leading to enhanced NOTCH3 signaling due to prolonged cellular half-life. Individuals with LMS are expected to have multiple lateral meningoceles, developmental delay, neonatal hypotonia, dysmorphic facial features, and feeding difficulties. Case Presentation: We report an 8-year-old male with a history of autism, feeding difficulties, developmental delay, severe intellectual disability, and self-injurious behavior. Genetic testing revealed a NOTCH3 c.6663C>G (p.Y2221*) pathogenic variant in exon 33, consistent with a diagnosis of LMS. A follow-up spine MRI showed a ventral sacral extradural arachnoid cyst but no lateral meningoceles. This individual’s most recent exam noted multiple dysmorphic features including prominent metopic ridging, broad forehead, downslanting palpebral fissures, high-arched palate, long narrow philtrum, mild pectus excavatum, and wide-based gait. Discussion/Conclusion: This individual shares the dysmorphic facial features, ongoing G-tube dependence, failure to thrive, and developmental delay seen in other individuals with LMS. His lack of lateral meningoceles expands the phenotype for this condition, as all previously reported individuals with molecularly confirmed LMS had multiple lateral meningoceles before age 8 years with an average age of identification at 4 years.

CADASIL: a NOTCH3-associated cerebral small vessel disease

Article

Jan 2024

Novel Cysteine-Sparing Hypomorphic NOTCH3 A1604T Mutation Observed in a Family With Migraine and White Matter Lesions

Article

Full-text available

Apr 2021

Objective: To conduct a clinical study of a family with neurologic symptoms and findings carrying a novel NOTCH3 mutation and to analyze the molecular consequences of the mutation. Methods: We analyzed a family with complex neurologic symptoms by MRI and neurologic examinations. Exome sequencing of the NOTCH3 locus was conducted, and whole-genome sequencing was performed to identify COL4A1, COL4A2, and HTRA1 mutations. Cell lines expressing the normal or NOTCH3A1604T receptors were analyzed to assess proteolytic processing, cell morphology, receptor routing, and receptor signaling. Results: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease (SVD) and caused by mutations in the NOTCH3 gene. Most CADASIL mutations alter the number of cysteine residues in the extracellular domain of the NOTCH3 receptor, but in this article, we describe a family in which some members carry a novel cysteine-sparing NOTCH3 mutation (c.4810 G>A, p.Ala1604Thr). Two of 3 siblings heterozygous for the NOTCH3A1604T mutation presented with migraine and white matter lesions (WMLs), the latter of a type related to but distinct from what is normally observed in CADASIL. Two other members instead carried a novel COL4A1 missense mutation (c.4795 G>A; p.(Ala1599Thr)). The NOTCH3A1604T receptor was aberrantly processed, showed reduced presence at the cell surface, and less efficiently activated Notch downstream target genes. Conclusions: We identify a family with migraine and WML in which some members carry a cysteine-sparing hypomorphic NOTCH3 mutation. Although a causal relationship is not established, we believe that the observations contribute to the discussion on dysregulated Notch signaling in cerebral SVDs.

Expansion of the phenotype of lateral meningocele syndrome

Article

Full-text available

Mar 2020

Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left‐convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss‐of‐function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra‐ and extra‐dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi‐cystic kidney disease.

Neurosurgical Management of Lateral Meningocele Syndrome: A Clinical Update for the Pediatric Neurosurgeon

Article

Full-text available

Dec 2019
PEDIATR NEUROSURG

Background: Lateral meningocele syndrome (LMS) is an exceedingly rare connective tissue disease with phenotypic anomalies similar to those seen in Marfan syndrome, Ehler-Danlos syndrome, and Loeys-Dietz syndrome. However, this syndrome is invariably associated with the presence of multiple lateral thoracolumbar spinal meningoceles: a distinct point of phenotypic divergence from other connective tissue disorders. The etiopathogenesis of this syndrome has recently been linked to truncating mutations within exon 33 of NOTCH3. Despite numerous reports, neurosurgical management of multiple spinal meningoceles remains poorly defined in the literature. We conducted a literature review to provide insight into the nosology, clinical significance, and neurosurgical management strategies of this distinct connective tissue disorder. Summary: Our literature search revealed 11 articles (16 cases) of LMS, which included 9 males and 7 females, belonging to 14 different families. Half of these cases underwent genetic screening: all of which were discovered to exhibit a truncating mutation within exon 33 of NOTCH3. All patients exhibited multiple lateral thoracolumbar spinal meningoceles with craniofacial dysmorphisms. Other clinical characteristics included pathologic changes in spine morphology, Chiari I malformation, syringomyelia, hydrocephalus, and tethered cord. Operative management of multiple spinal meningoceles in LMS is complicated by the presence of such coexisting structural neurologic pathologies, which may alter cerebrospinal fluid flow dynamics and, ultimately, impact operative intervention. Key Messages: LMS is an exceedingly rare connective tissue disorder with severe spinal dural involvement. Neurosurgical management of multiple spinal meningoceles is complex, which is further complicated by the presence of coexisting neuropathology, such as pathologic transformation of spine morphology and Chiari I malformation. Patients with a connective tissue disorder phenotype found to have multiple spinal meningoceles on imaging studies may benefit from evaluation by a medical geneticist and a pediatric neurosurgeon.

Dural ectasia in Marfan syndrome and other hereditary connective tissue disorders A 10-year follow-up study

Article

Full-text available

Apr 2019
SPINE J

Background context: Dural ectasia is widening of the dural sac often seen in patients with Marfan syndrome and other hereditary connective tissue disorders. Dural ectasia can cause specific symptoms and is associated with surgical complications. The knowledge on how and at which age dural ectasia develops is incomplete. There is no established gold standard for diagnosing dural ectasia, making it difficult to compare results from different studies. Purpose: Our primary aim was to explore whether the radiological findings of dural ectasia changed after 10 years in an adult cohort with suspected Marfan syndrome. Our secondary aim was to re-evaluate the radiological criteria of dural ectasia. Study design: Prospective cohort study. Patient sample: Sixty-two persons from a cross-sectional study of 105 persons with suspected Marfan syndrome were included in a 10-year follow-up of dural ectasia. Forty-six were diagnosed with Marfan syndrome, 7 with Loeys-Dietz syndrome, and 5 with other hereditary connective tissue disorders. For comparison 64 matched hospital controls were evaluated. Outcome measures: Previously used radiological criteria for dural ectasia based on quantitative measurements of the lumbosacral spine. Methods: MRI of the lumbosacral spine was performed if not contraindicated, and if so then CT was performed. Differences in the study group between baseline and follow-up were assessed with paired Student t test, Wilcoxon rank signed test, and McNemar test. Receiver operating characteristic curves were constructed to assess the ability of radiological measurement to differentiate between the study and control group. Results: Fifty-two of 58 patients with hereditary connective tissue disorders and 11 controls had dural ectasia at follow-up. Forty-five Marfan patients had dural ectasia at follow-up vs. 41 at baseline. Five Loeys-Dietz patients had dural ectasia at follow-up vs. four at baseline. Twenty-four Marfan and 2 Loeys-Dietz patients had anterior sacral meningocele at follow-up, compared with 21 and 1, respectively, at baseline. Three Marfan patients developed herniation of a nerve root sleeve during follow-up. This was not seen in other individuals. The dural sac ended significantly lower at follow-up, and the dural sac ratio at level L5 was significantly increased from baseline in the Marfan patients. Conclusions: In Marfan and Loeys-Dietz syndrome, dural ectasia may present or worsen during adulthood. The cut-off value of dural sac ratio at level S1 is suggested elevated to 0.64. The results from the present study may help as guidance for appropriate follow-up of patients with dural ectasia.

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Article

Full-text available

Mar 2015
GENET MED

Disclaimer: These ACMG Standards and Guidelines were developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient’s record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.¹ In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes, and epigenetic assays for genetic disorders. By virtue of increased complexity, this shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context the ACMG convened a workgroup in 2013 comprising representatives from the ACMG, the Association for Molecular Pathology (AMP), and the College of American Pathologists to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP, and College of American Pathologists stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. This report recommends the use of specific standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified in genes that cause Mendelian disorders. Moreover, this recommendation describes a process for classifying variants into these five categories based on criteria using typical types of variant evidence (e.g., population data, computational data, functional data, segregation data). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent. Genet Med17 5, 405–423.

Role of chimeric transcript formation in the pathogenesis of birth defects

Article

Nov 2020

Chimeric transcripts are formed by chromosomal aberrations. Little is known about the role of chimeric transcripts in the pathogenesis of birth defects. We reanalyzed RNA‐seq data in alignment map files from the peripheral blood of 56 patients in whom the diagnoses could not be confirmed by standard exome analysis and transcriptome analysis to screen for chimeric transcripts using a dedicated software, ChimPipe. Chimeric analysis led to a diagnosis in two of the 56 patients: (a) the first patient had a chimeric transcript spanning the causative gene ZEB2 and the GTDC1 gene in its neighboring locus. RNA‐seq revealed reads spanning exon 5 of ZEB2 and exon 7 of GTDC1. Whole genome sequencing revealed a 436‐kb deletion spanning intron 4 of ZEB2 and intron 7 of GTDC1 and the diagnosis of Mowat‐Wilson syndrome was made. (b) The second patient had a chimeric transcript spanning the causative gene KCNK9 and the TRAPPC9 gene in its neighboring locus. RNA‐seq revealed reads spanning exon 21 of TRAPPC9 and exon 1 of KCNK9. Whole genome sequencing revealed a 186‐kb deletion spanning intron 20 of TRAPPC9 and intron 1 of KCNK9 in this patient. KCNK9 gene is a maternally expressed imprinted gene. The diagnosis of Birk‐Barel syndrome was made. Thus, both patients had chimeric transcripts that were directly involved in the pathogenesis of the birth defects. The approach reported herein, of detecting chimeric transcripts from RNA‐seq data, is unique in that the approach does not rely on any prior information on the presence of genomic deletion.

Increase in dural ectasia size in scoliosis patients with Marfan syndrome

Article

Jul 2020
J PEDIATR ORTHOP B

Increased dural ectasia and vertebral thinning in the lumbosacral spine are common in Marfan syndrome. Dural ectasia is unchanged in middle-aged patients, who have stopped growing. Therefore, evaluation from childhood to adulthood is mandatory. Sixteen patients [four men and 12 women; mean age:17.7 (8.6-33.5) years] with dural ectasia at final follow-up [mean follow-up: 10.4 (5.0-16.7) years] were enrolled. Dural sac diameter (DD)/vertebral diameter (VD) were measured on MRI or CT images of midline sagittal slices at the level of dural ectasia between L5 and S3. The widest part of the dural sac was evaluated with Fattori grading: grade 0, normal; 1, mild; 2, moderate; and 3, severe dural ectasia. At final follow-up, dural ectasia was observed at L5 in 3, S1 in 9, S2 in 14, and S3 in 11 patients. Respective changes in DD/VD from primary to final follow-up were L5: 21.7-24.2 mm/29.1-27.9 mm; S1: 17.0-18.6 mm/21.0-19.5 mm; S2: 15.5-19.6 mm (P < 0.01)/9.6-7.5 mm; and S3: 15.6-17.9 mm (P < 0.05)/6.2-3.3 mm (P < 0.05). Four patients had grade 0 dural ectasia, seven had grade 1, two had grade 2, and three had grade 3. Grade was increased in nine patients with juvenile to young adult patients but did not with adults. During follow-up, dural ectasia size changed in the juvenile to young adult patients with Marfan syndrome, particularly at the S2-S3 level in our series.

Neurosurgical management in lateral meningocele syndrome: case report

Article

Dec 2016

Lateral meningocele syndrome (LMS) is a rare genetic connective tissue disorder. It is associated with morphological changes similar to those of other connective tissue disorders, with the unique distinction of multiple, often bilateral and large, lateral meningoceles herniating through the spinal foramina. In some cases, these lateral meningoceles can cause pain and discomfort due to their presence within retroperitoneal tissues or cause direct compression of the spinal nerve root exiting the foramen; in some cases compression may also involve motor weakness. The presence of lateral meningoceles imposes unique challenges related to CSF flow dynamics, especially with concurrent Chiari malformation, which also occurs with increased frequency in individuals with LMS. The authors present the case of a 6-month-old female with LMS with multiple lateral meningoceles throughout the thoracic and lumbar spine. The infant experienced a focal neurological abnormality due to enlargement of her lateral meningoceles following decompression of a symptomatic Chiari malformation and endoscopic third ventriculostomy. The finding was reversed through implantation of a ventriculoperitoneal shunt, which reduced the burden of CSF upon the lateral meningoceles. Such a case compels consideration that CSF flow dynamics in addition to altered connective tissue play a role in the presence of lateral meningoceles in patients within this and similar patient populations.

Lateral meningocele (Lehman) syndrome: A child with a novel NOTCH3 mutation

Article

Jan 2016
AM J MED GENET A

Lateral meningocele syndrome (LMS), or Lehman syndrome, is a rare disorder characterized by multiple lateral spinal meningoceles, distinctive facial features, joint hypermobility and hypotonia, along with skeletal, cardiac, and urogenital anomalies. Heterozygous NOTCH3 mutations affecting the terminal exon 33 were recently reported as causative in six families with LMS. We report a boy with LMS, the fourteenth reported case, with a de novo 80 base pair deletion in exon 33 of NOTCH3. Our patient's prenatal findings, complex cardiac anomalies, and severe feeding difficulties further expand our understanding of this rare condition.

PEST Domain Mutations in Notch Receptors Comprise an Oncogenic Driver Segment in Triple Negative Breast Cancer Sensitive to a -Secretase Inhibitor

Article

Jan 2015

Purpose: To identify and characterize novel, activating mutations in Notch receptors in breast cancer and to determine response to the gamma secretase inhibitor (GSI) PF-03084014. Experimental Design: We used several computational approaches, including novel algorithms, to analyze next generation sequencing data and related omic data sets from The Cancer Genome Atlas (TCGA) breast cancer cohort. Patient-derived xenograft (PDX) models were sequenced and Notch mutant models were treated with PF-03084014. Gene expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by PF-03084014. Results: We identified mutations within and upstream of the PEST domains of NOTCH1, NOTCH2 and NOTCH3 in the TCGA data set. Mutations occurred via several genetic mechanisms and compromised the function of the PEST domain, a negative regulatory domain commonly mutated in other cancers. Focal amplifications of NOTCH2 and NOTCH3 were also observed as were heterodimerization or extracellular domain mutations at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes and functional mutations were significantly enriched in the triple negative breast cancer subtype (TNBC) subtype. PDX models were also identified that harbored PEST domain mutations and these models were highly sensitive to PF-03084014. Conclusions: This work suggests Notch altered breast cancer constitutes a bona fide oncogenic driver segment with the most common alteration being PEST domain mutations present in multiple Notch receptors. Importantly, functional studies suggest this newly identified class can be targeted with Notch inhibitors including GSIs. Copyright © 2015, American Association for Cancer Research.

Early diagnosis of lateral meningocele syndrome in an infant without neurological symptoms based on genomic analysis

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