Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1

Ishihara, Naoko; Yamada, Kenichiro; Yamada, Yasukazu; Miura, Kiyokuni; Kato, Junji; Kuwabara, Naoko; Hara, Yuichiro; Kobayashi, Yasuhiko; Hoshino, Kyoko; Nomura, Yasuo; Mimaki, Masakazu; Ohya, Kazuhiro; Matsushima, Masaki; Nitta, H.; Tanaka, Keita; Segawa, Masaya; Ohki, Takashi; Ezoe, Takanori; Kumagai, Toshiyuki; Ônuma, Akira; Kuroda, Takeshi; Yoneda, Makoto; Yamanaka, Tsutomu; Saeki, Masami; Saji, Tsutomu; Nagaya, Masahiro; Wakamatsu, Nobuaki

doi:10.1136/jmg.2003.016154

Cited by 79 publications

(99 citation statements)

References 27 publications

(33 reference statements)

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“…Besides several structural anomalies, distinct facial dysmorphisms, ID/DD, ACC or hypogenesis of corpus callosum are among the core phenotypic features of MOWS. In accordance, previous reports (Ishihara et al, 2004;Park et al, 2013) describe patients with ACC and deletions of chromosomal region 2q22.3 containing ZEB2. In addition two entries in DECIPHER database January 2015 describe two patients (patient 251811; patient 2566) with ZEB2 comprising deletions, each displaying hypoplasia of the corpus callosum.…”

Section: Discussionsupporting

confidence: 92%

Array‐based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions

Krutzke

Engels

Hofmann

et al. 2015

Birth Defects Research

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BACKGROUND: For the majority of congenital brain malformations, the underlying cause remains unknown. Recent studies have implicated rare copy number variations (CNVs) in their etiology. METHODS: Here, we used array-based molecular karyotyping to search for causative CNVs in 33 fetuses of terminated pregnancies with prenatally detected brain malformations and additional extracerebral anomalies. RESULTS: In 11 fetuses, we identified 15 CNVs (0.08 Mb to 29.59 Mb), comprising four duplications and eleven deletions. All larger CNVs (> 5 Mb) had also been detected by prenatal conventional karyotyping. None of these CNVs was present in our 1307 healthy in-house controls (frequency < 0.0008). Among these CNVs, we prioritized six chromosomal regions (1q25.1, 5q35.1, 6q25.3-qter, 11p14.3, 15q11.2-q13.1, 18q21.1) due to their previous association with human brain malformations or owing to the presence of a single gene expressed in human brain. Prioritized genes within these regions were UBTD2, SKA1, SVIP, and, most convincingly, GPR52. However, re-sequencing of GPR52 in 100 samples from fetuses with brain malformations or patients with intellectual disability and brain malformations revealed no disease-causing mutation. CONCLUSION: Our study suggests chromosomal regions 1q25.1, 5q35.1, 6q25.3-qter, 11p14.3, 15q11.2-q13.1, and 18q21.1 to be involved in human brain development. Within three of these regions, we suggest UBTD2, GPR52, and SKA1 as possible candidate genes. Because the overall detection rate of array-based molecular karyotyping was slightly higher (23%) than that of conventional prenatal karyotyping (20%), we suggest it's use for prenatal diagnostic testing in fetuses with nonisolated brain malformations.

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Section: Discussionsupporting

confidence: 92%

Array‐based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions

Krutzke

Engels

Hofmann

et al. 2015

Birth Defects Research

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“…3,4 In 2002 Zweier et al 5 further delineated the phenotype of MWS with or without HSCR, invariably characterized by ZEB2 gene defects, and proposed that the condition be named Mowat-Wilson syndrome. More than 300 patients have been reported so far [6][7][8][9][10][11][12][13][14][15][16][17] (additional reviewed articles are listed in Supplementary File S1 online).…”

Section: Mowat-wilson Syndrome (Mws) (Omim # 235730) Ismentioning

confidence: 99%

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Ivanovski

Djurić

Caraffi

et al. 2018

Genetics in Medicine

131

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ORIGINAL RESEARCH ARTICLEPurpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. Methods:In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. Conclusion:Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

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“…This condition, now designated Mowat-Wilson (MWS) syndrome, was subsequently shown to be caused by heterozygous mutations in the ZFHX1B gene [Cacheux et al, 2001;Wakamatsu et al, 2001]. A series of subsequent publications have further delineated the phenotype [Zweier et al, 2002;Mowat et al, 2003;Wilson et al, 2003;Ishihara et al, 2004]. Other common features described in these patients include agenesis of the corpus callosum, congenital heart malformations, and genital and urinary tract anomalies.…”

Section: Introductionmentioning

confidence: 99%

Recurrence of Mowat–Wilson syndrome in siblings with the same proven mutation

McGaughran

Sinnott

Moal

et al. 2005

American J of Med Genetics Pt A

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Mowat–Wilson syndrome (MWS) is a mental retardation syndrome associated with distinctive facial features, microcephaly, epilepsy, and a variable spectrum of congenital anomalies, including Hirschsprung disease (HSCR), agenesis of the corpus callosum, genitourinary abnormalities, and congenital heart disease. Heterozygous mutations or deletions involving the gene ZFHX1B (previously SIP1) [OMIM 605802] have recently been found to cause MWS. There have previously been no reports of a sibling recurrence of this syndrome. A brother and sister are described with clinical features of MWS, where both have the same truncating mutation in exon 8 of ZFHX1B. As their parents are phenotypically normal and do not have the mutation in lymphocyte‐derived DNA, the most likely explanation is germ‐line mosaicism. © 2005 Wiley‐Liss, Inc.

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Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1

Cited by 79 publications

References 27 publications

Array‐based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions

Array‐based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions

Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Recurrence of Mowat–Wilson syndrome in siblings with the same proven mutation

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