Dataset Information

Physical, language, neurodevelopment and phenotype-genotype correlation of Chinese patients with Mowat-Wilson syndrome.

ABSTRACT: Background: To report detailed knowledge about the clinical manifestations, genetic spectrum as well as physical, language, neurodevelopment features and genotype-phenotype correlations of Chinese patients with Mowat-Wilson syndrome (MWS). Methods: We retrospectively collected and analyzed clinical data for twenty-two patients with molecularly confirmed diagnoses. We used Gesell Developmental Schedules (GDS) to assess their neurodevelopment and the Diagnostic Receptive and Expressive Assessment of Mandarin-Infant & Toddler (DREAM-IT) to evaluate their language ability and compared the data with the two types of underlying pathogenic variations. Results: The height and weight of all patients were below the 75th percentile, and microcephaly was observed in 16 of 22 patients (72.7%). Four patients carrying chromosome deletions encompassing the ZEB2 gene were more severely affected. All MWS patients exhibited better performance in cognitive play and social communication than in receptive and expressive language. In the receptive language area, the types of words that children with MWS understood most were nouns, followed by adjectives and verbs. Conclusion: This study delineated the phenotypic spectrum of the largest MWS cohort in China and provided comprehensive profiling of their physical, language, neurodevelopment features and genotype-phenotype correlations.

SUBMITTER: Wu L

PROVIDER: S-EPMC9669270 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Physical, language, neurodevelopment and phenotype-genotype correlation of Chinese patients with Mowat-Wilson syndrome.

Wu Lihua L Wang Jianhong J Wang Lei L Xu Qi Q Zhou Bo B Zhang Zhen Z Li Qi Q Wang Hui H Han Lu L Jiang Qian Q Wang Lin L

Frontiers in genetics 20221103

<b>Background:</b> To report detailed knowledge about the clinical manifestations, genetic spectrum as well as physical, language, neurodevelopment features and genotype-phenotype correlations of Chinese patients with Mowat-Wilson syndrome (MWS). <b>Methods:</b> We retrospectively collected and analyzed clinical data for twenty-two patients with molecularly confirmed diagnoses. We used Gesell Developmental Schedules (GDS) to assess their neurodevelopment and the Diagnostic Receptive and Expressi ...[more]

PMID: 36406119

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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.

Project description:AimTo determine the mutational characterization of P-type ATP7B gene and to explore the correlation of ATP7B genotype to phenotype in Chinese patients with Wilson disease (WD).MethodsSeventy-five patients with WD from 72 no-kinship families, 44 males and 31 females, were enrolled in this study. The age of onset ranged from 4 to 39 years, <=18 years in 72 patients. Some exons of ATP7B gene mutations were analyzed in patients with WD by using biochemical methods, polymerase chain reaction-single strand configuration polymorphism (PCR-SSCP) and DNA sequence analysis. A total of 778 coding regions were identified with restriction enzyme Msp I. The activity of Cu-ATPase was assessed by measuring inorganic phosphorus.ResultsSixty-six of 75 patients (88%) had with hepatic manifestations, 39 of them had only hepatic manifestations, 27 patients had hepatic and neurological manifestations or other symptoms at the same time (16 patients had associated neurological manifestation, 3 patients had osteopathy, 8 patients had other symptoms). Eight of the 75 patients (10.7%) had only neurological symptoms, one patient (5 years old) had no symptom. Twelve changing patterns were detected in ATP7B gene by DNA sequencing, including seven mutations (R778L, C656X, G943D, V1140A, V1106I V1216M and 1384del17), six polymorphisms (IVS4-5t/c, A2495G, C2310G, IVS18+6c/t and IVS20+5a/g). R778L occurred in 49/66 patients (74%) with hepatic manifestations, homozygosis of R778L in 16 patients, heterozygosity of R778L in 33 patients. V1106I mutation of ATP7B gene occurred in 2 patients with delaying onset of clinical symptoms. Cu-ATPase activity of three patients with known mutations (R778L/V1106I/A2495G, R778L/V1216M and R778L/R778L) were determined, and the activity of Cu-ATPase was decreased by 44.55%, 88.23% and 69.49% respectively.Conclusion1384del17bp is a novel mutation found in WD patients. R778L is the most common mutation of ATP7B gene. There is a correlation between R778L and hepatic manifestations in WD patient.

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.

Dataset Information

Physical, language, neurodevelopment and phenotype-genotype correlation of Chinese patients with Mowat-Wilson syndrome.

Publications

Physical, language, neurodevelopment and phenotype-genotype correlation of Chinese patients with Mowat-Wilson syndrome.

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