Exome-first approach identified novel INDELs and gene deletions in Mowat-Wilson Syndrome patients.
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ABSTRACT:
SUBMITTER: Gosso MF
PROVIDER: S-EPMC6070557 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Exome-first approach identified novel INDELs and gene deletions in Mowat-Wilson Syndrome patients.
Gosso Maria Florencia MF Rohr Cristian C Brun Bianca B Mejico Guadalupe G Madeira Fernanda F Fay Fabian F Klurfan Melina M Vazquez Martin M
Human genome variation 20180801
Mowat-Wilson syndrome (MWS) is characterized by severe intellectual disability, absent or impaired speech and microcephaly, with a gradual post-natal onset. The syndrome is often confused with other Angelman-like syndromes (ALS) during infancy, but in older children and adults, the characteristic facial gestalt of Mowat-Wilson syndrome allows it to be distinguished easily from ALS. We report two cases in which an exome-first approach of patients with MWS identified two novel deletions in the ZEB ...[more]
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Project description:Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies. The prevalence of MWS is currently unknown, but 171 patients have been reported so far. It seems probable that MWS is under-diagnosed, particularly in patients without HSCR. MWS is caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). To date, over 100 deletions/mutations have been reported in patients with a typical phenotype; they are frequently whole gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism. Studies of genotype-phenotype analysis show that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, unusual mutations can lead to an atypical phenotype. The facial phenotype is particularly important for the initial clinical diagnosis and provides the hallmark warranting ZEB2 mutational analysis, even in the absence of HSCR. The majority of MWS cases reported so far were sporadic, therefore the recurrence risk is low. Nevertheless, rare cases of sibling recurrence have been observed. Congenital malformations and seizures require precocious clinical investigation with intervention of several specialists (including neonatologists and pediatricians). Psychomotor development is delayed in all patients, therefore rehabilitation (physical therapy, psychomotor and speech therapy) should be started as soon as possible.
| S-EPMC2174447 | biostudies-literature
Project description:BackgroundMowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16?years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children.ResultsIn newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7?years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7?years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build.ConclusionsThese charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.
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Project description:Mowat-Wilson Syndrome (MWS) (OMIM # 235730) is a rare disorder due to ZEB2 gene defects (heterozygous mutation or deletion). The ZEB2 gene is a widely expressed regulatory gene, extremely important for the proper prenatal development. MWS is characterized by a specific facial gestalt and multiple musculoskeletal, cardiac, gastrointestinal, and urogenital anomalies. The nervous system involvement is extensive and constitutes one of the main features in MWS, heavily affecting prognosis and life quality of affected individuals. This review aims to comprehensively organize and discuss the neurological and neurodevelopmental phenotype of MWS. First, we will describe the role of ZEB2 in the formation and development of the nervous system by reviewing the preclinical studies in this regard. ZEB2 regulates the neural crest cell differentiation and migration, as well as in the modulation of GABAergic transmission. This leads to different degrees of structural and functional impairment that have been explored and deepened by various authors over the years. Subsequently, the different neurological aspects of MWS (head and brain malformations, epilepsy, sleep disorders, and enteric and peripheral nervous system involvement, as well as developmental, cognitive, and behavioral features) will be faced one at a time and extensively examined from both a clinical and etiopathogenetic point of view, linking them to the ZEB2 related pathways.
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Project description:Lowe syndrome (LS) is an X-linked disorder affecting the eyes, nervous system and kidneys, typically caused by missense or nonsense/frameshift OCRL mutations. We report a 6-month-old male clinically suspected to have LS, but without the Fanconi-type renal dysfunction. Using a targeted-exome sequencing-first approach, LS was diagnosed by the identification of a deletion involving 1.7?Mb at Xq25-q26.1, encompassing the entire OCRL gene and neighboring loci.
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Project description:Mowat-Wilson syndrome (OMIM 235730) is a genetic condition characterized by moderate-to-severe intellectual disability, a recognizable facial phenotype, and multiple congenital anomalies. The striking facial phenotype in addition to other features such as severely impaired speech, hypotonia, microcephaly, short stature, seizures, corpus callosum agenesis, congenital heart defects, hypospadias, and Hirschsprung disease are particularly important clues for the initial clinical diagnosis. All molecularly confirmed cases with typical MWS have a heterozygous loss-of-function mutation in the zinc finger E-box protein 2 (ZEB2) gene, also called SIP1 (Smad-interacting protein 1) and ZFHX1B, suggesting that haploinsufficiency is the main pathological mechanism. Approximately 80% of mutations are nonsense and frameshift mutations (small insertions or deletions). About half of these mutations are located in exon eight. Here, we report the first Indonesian patient with Mowat-Wilson syndrome confirmed by molecular analysis.
| S-EPMC3517822 | biostudies-literature
Project description:Mowat-Wilson syndrome is a mental retardation-multiple congenital anomaly syndrome characterized by a typical facies, developmental delay, epilepsy, and variable congenital malformations, including Hirschsprung disease, urogenital anomalies, congenital heart disease, and agenesis of the corpus callosum. This disorder is sporadic and is caused by heterozygous mutations or deletions of the ZFHX1B gene located in the 2q22 region. We report here the first Moroccan patient, born to consanguineous parents, with Mowat-Wilson syndrome, due to a de novo, unreported mutation of the ZFHX1B gene.
| S-EPMC3168139 | biostudies-literature
Project description:After its publication in 1999 as a DNA-binding and SMAD-binding transcription factor (TF) that co-determines cell fate in amphibian embryos, ZEB2 was from 2003 studied by embryologists mainly by documenting the consequences of conditional, cell-type specific Zeb2 knockout (cKO) in mice. In between, it was further identified as causal gene causing Mowat-Wilson Syndrome (MOWS) and novel regulator of epithelial-mesenchymal transition (EMT). ZEB2's functions and action mechanisms in mouse embryos were first addressed in its main sites of expression, with focus on those that helped to explain neurodevelopmental and neural crest defects seen in MOWS patients. By doing so, ZEB2 was identified in the forebrain as the first TF that determined timing of neuro-/gliogenesis, and thereby also the extent of different layers of the cortex, in a cell non-autonomous fashion, i.e., by its cell-intrinsic control within neurons of neuron-to-progenitor paracrine signaling. Transcriptomics-based phenotyping of Zeb2 mutant mouse cells have identified large sets of intact-ZEB2 dependent genes, and the cKO approaches also moved to post-natal brain development and diverse other systems in adult mice, including hematopoiesis and various cell types of the immune system. These new studies start to highlight the important adult roles of ZEB2 in cell-cell communication, including after challenge, e.g., in the infarcted heart and fibrotic liver. Such studies may further evolve towards those documenting the roles of ZEB2 in cell-based repair of injured tissue and organs, downstream of actions of diverse growth factors, which recapitulate developmental signaling principles in the injured sites. Evident questions are about ZEB2's direct target genes, its various partners, and ZEB2 as a candidate modifier gene, e.g., in other (neuro)developmental disorders, but also the accurate transcriptional and epigenetic regulation of its mRNA expression sites and levels. Other questions start to address ZEB2's function as a niche-controlling regulatory TF of also other cell types, in part by its modulation of growth factor responses (e.g., TGFβ/BMP, Wnt, Notch). Furthermore, growing numbers of mapped missense as well as protein non-coding mutations in MOWS patients are becoming available and inspire the design of new animal model and pluripotent stem cell-based systems. This review attempts to summarize in detail, albeit without discussing ZEB2's role in cancer, hematopoiesis, and its emerging roles in the immune system, how intense ZEB2 research has arrived at this exciting intersection.
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Project description:Insertion and deletion (INDEL) mutations, the most common type of structural variance, are associated with several human diseases. The detection of INDELs through next-generation sequencing (NGS) is becoming more common due to the decrease in costs, the increase in efficiency, and sensitivity improvements demonstrated by the various sequencing platforms and analytical tools. However, there are still many errors associated with INDEL variant calling, and distinguishing INDELs from errors in NGS remains challenging. To evaluate INDEL calling from whole-exome sequencing (WES) data, we performed Sanger sequencing for all INDELs called from the several calling algorithm. We compared the performance of the four algorithms (i.e. GATK, SAMtools, Dindel, and Freebayes) for INDEL detection from the same sample. We examined the sensitivity and PPV of GATK (90.2 and 89.5%, respectively), SAMtools (75.3 and 94.4%, respectively), Dindel (90.1 and 88.6%, respectively), and Freebayes (80.1 and 94.4%, respectively). GATK had the highest sensitivity. Furthermore, we identified INDELs with high PPV (4 algorithms intersection: 98.7%, 3 algorithms intersection: 97.6%, and GATK and SAMtools intersection INDELs: 97.6%). We presented two key sources of difficulties in accurate INDEL detection: 1) the presence of repeat, and 2) heterozygous INDELs. Herein we could suggest the accessible algorithms that selectively reduce error rates and thereby facilitate INDEL detection. Our study may also serve as a basis for understanding the accuracy and completeness of INDEL detection.
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Project description:Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and characterized by typical clinical features. The congenital malformations typical of this syndrome call for early diagnostic and surgical procedures requiring general anesthesia, but few information about the anesthesiology management of such patients is available. We enrolled 11 families of patients with Mowat-Wilson syndrome who had undergone surgical or diagnostic procedures requiring general anesthesia, and sent them a retrospective questionnaire including 16 open questions about the procedures. They were further contacted by phone for a semistructured interview. A total of 37 procedures requiring general anesthesia was reported in 11 patients. Only two patients reported anesthesia-related complications during the procedure. No true additional anesthesiarelated risk was present for the patients with MW syndrome, besides difficult intubation, weaning and lower respiratory tract infection. Perception of risk, however, is derived by non-medical observation on the part of the parents.
| S-EPMC5907729 | biostudies-literature
Project description:Mowat-Wilson syndrome is a rare genetic condition characterized by intellectual disability, structural anomalies, and dysmorphic features. It is caused by haploinsufficiency of the ZEB2 gene in chromosome 2q22.3. Over 180 distinct mutations in ZEB2 have been reported, including nonsense and missense point mutations, deletions, and large chromosomal rearrangements. We report on a 14-year-old female with a clinical diagnosis of Mowat-Wilson syndrome. Chromosomal microarray identified a novel de novo 69-kb duplication containing exons 1 and 2 of the ZEB2 gene. Sequence analysis identified no other variants in this gene. This is the first report of a partial duplication of the ZEB2 gene resulting in Mowat-Wilson syndrome.
| S-EPMC5498959 | biostudies-literature