Introduction: Mowat-Wilson syndrome (MWS) is an autosomal-dominant complex developmental disorder characterized by distinctive facial appearance, intellectual disability, epilepsy, and various clinically heterogeneous abnormalities reminiscent of neurocristopathies. MWS is caused by haploinsufficiency of ZEB2 due to heterozygous point mutations and copy number variations. Case Presentation: We report on two unrelated affected individuals with novel ZEB2indel mutations, molecularly confirming the diagnosis of MWS. Quantitative real-time polymerase chain reaction (PCR) for the comparison of total transcript levels and allele-specific quantitative real-time PCR were also performed and demonstrated that the truncating mutations did not lead to nonsense-mediated decay as expected. Conclusion:ZEB2 encodes a multifunctional pleiotropic protein. Novel mutations in ZEB2 should be reported in order that genotype-phenotype correlations might be established in this clinically heterogeneous syndrome. Further cDNA and protein studies may help elucidate the underlying pathogenetic mechanisms of MWS since nonsense-mediated RNA decay was found to be absent in only a few studies including this study.

Established Facts

  • Mowat-Wilson syndrome is a complex developmental single gene disorder with diverse allelic and clinical heterogeneity reminiscent of neurocristopathies.

Novel Insights

  • Allele-specific quantitative real-time polymerase chain reaction demonstrated that the truncating mutations did not lead to nonsense-mediated decay as expected.

  • Further cDNA and protein studies may help elucidate the underlying pathogenetic mechanisms of Mowat-Wilson syndrome.

Mowat-Wilson syndrome (MWS) (OMIM #235730) is a multiple congenital anomaly syndrome characterized by distinctive facial appearance, varying degrees of intellectual disability, and epilepsy. Typical facial appearance becomes evident with advancing age and consists of prominent and medially flared eyebrows, deep-set eyes, uplifted earlobes with a central depression, a prominent columella, an open mouth with an M-shaped upper lip, frequent smiling, and a prominent pointed chin. Multiple congenital anomalies, including congenital heart disease, structural central nervous system anomalies, Hirschsprung disease, and genital anomalies, may be seen accompanying this syndrome. MWS was first described in 1998 by Mowat and Wilson in several patients presenting with Hirschsprung disease, microcephaly, intellectual disability, and characteristic facial features [Mowat et al., 1998]. Later in 2001, de novo heterozygous ZEB2 mutations were identified as causative for MWS by two independent groups of researchers [Cacheux et al., 2001; Wakamatsu et al., 2001; Zweier et al., 2002].

The prevalence of MWS has been estimated to be at least 1 in 70,000 live births [Mowat and Wilson, 2021]. However, even though MWS is a clinically well-delineated syndrome, the diagnosis is possibly underestimated because of the phenotypic variability, and especially at younger ages, it may be difficult to differentiate MWS from other syndromes characterized by intellectual disability including Goldberg-Shprintzen syndrome, Pitt Hopkins syndrome, and Angelman syndrome [Kilic et al., 2016; Adam et al., 2019]. To date, there are more than 300 patients reported in the literature [Ivanovski et al., 2018].

Cellular processes deranged by heterozygous ZEB2 mutations are yet unknown. ZEB2 (zinc-finger E-box binding homeobox 2, MIM #605802) is located on chromosome 2q22 and is a member of the two-handed zinc-finger/homeodomain transcription factors. ZEB2 is expressed in various tissues during embryonic development including the central nervous system, peripheral nervous system, enteric system, and craniofacial skeleton [Epifanova et al., 2019]. Additionally, ZEB2 acts mostly as a transcriptional repressor for many downstream target genes that regulate morphogenesis of the neural crest-derived craniofacial mesenchyme and parasympathetic ganglia [Epifanova et al., 2019]. We report on two unrelated affected individuals with two novel frameshift ZEB2 mutations, in whom we aimed to demonstrate whether truncating mutations lead to nonsense-mediated decay (NMD) or not.

Affected individual 1 was the first child of healthy, nonconsanguineous parents with an unremarkable prenatal history. He was born via normal spontaneous vaginal delivery at term with a birth weight of 3,610 g (50th–75th centiles). Birth length and head circumference were not noted. He was hospitalized in the neonatal intensive care unit because of feeding difficulty. He was pale and had hypotonia, decreased neonatal reflexes, and abdominal distention. He was diagnosed with Hirschsprung disease, and colostomy was performed. Colostomy reversal was done later, at the age of 3 months. During his hospitalization, at the age of 3 months, hypospadias was diagnosed as well.

He was referred to the genetics department at the age of 311/12 years for evaluation of congenital megacolon, ataxic gait, intellectual disability, stereotypic movements, and dysmorphic facial features. His weight was 20 kg (90th–97th centiles), height was 112 cm (50th centile), and head circumference was 47 cm (−3.8 SD). Physical examination revealed hypotonia, a prominent forehead, deep-set eyes, upslanted palpebral fissures, posteriorly rotated ears, a broad nasal bridge, a prominent philtrum, a thin upper lip, retrognathia, single palmar crease on the right and Sydney crease on the left, and hypospadias. He could sit without support after the age of 1, and he could speak with only three to four words at the age of 311/12 years. He still had an unsteady gait. The Denver Developmental Screening Test revealed delays in all domains. He was usually calm and quiet, with occasional spontaneous laughter. He had stereotypies including hand biting when nervous and hand flapping when cheerful. Echocardiography revealed a patent foramen ovale during infancy, which underwent spontaneous occlusion later. Brain magnetic resonance imaging showed agenesis of the corpus callosum. Ophthalmologic and audiometric evaluations were normal. An abdominal ultrasound revealed cholelithiasis. He had been receiving antibiotic prophylaxis for vesicoureteral reflux.

Affected individual 2 was born at term as the 3rd child of the family, following an unremarkable prenatal history. Birth weight, birth length, and head circumference were not noted. She had her first febrile seizure at the age of 11 months and once every 3 to 4 months later on. Her last recorded seizure occurred at the age of 6 years. She was referred to our clinic at the age of 77/12 years because of her past seizure history, intellectual disability, and dysmorphic facial features. On physical examination, her weight was 27 kg (75th centile), height was 131 cm (75th–90th centiles), and head circumference was 49 cm (−2.7 SD). Physical examination revealed a narrow forehead with hypertrichosis, a low anterior hairline, bushy eyebrows, hypertelorism, upslanted palpebral fissures, a long triangular face, overfolded helices, a prominent columella and chin, a high-arched palate, prominent upper central incisors, long and slender fingers, bilateral partial cutaneous syndactyly of all fingers, prominent fingertip pads, and a sandal gap. She was reevaluated during the follow-up at the age of 102/12 years. Her anthropometric measurements revealed body weight 53.5 kg (97th centile), height 151 cm (97th centile), and head circumference 52 cm (25th–50th centiles). Dysmorphic facial features became more evident as she got older.

Gross motor development was always delayed. At the age of 7.5 years, she could not walk independently and could speak only a few words, unable to form sentences. Psychometric evaluation using the Wechsler Intelligence Scale revealed a severe degree of intellectual disability (IQ score of 20–35). She needed continuous supervision and attended special education.

Echocardiography revealed bicuspid aortic valve, aortic valve stenosis, and supravalvular pulmonary stenosis. Cranial magnetic resonance imaging demonstrated a craniofacial ratio in favor of the cranium, cavum septum pellucidum, and focal asymmetric increased cerebrospinal fluid width adjacent to the left occipital pole. Abdominal ultrasound was normal. Ophthalmologic and audiometric evaluations were not performed. She had been treated with levetiracetam (initially started at 11.3 mg/kg/d, then decreased to 7.5 mg/kg/d) for 3 years and did not experience any clinical seizures during the treatment. Nevertheless, recent sleep EEG monitoring demonstrated asynchronous discharges of high voltage spikes originating from bilateral posterior areas in a multifocal manner. In addition, she was evaluated for pubarche, and a gonadotropin-releasing hormone (GnRH) stimulation test revealed an LH value of ≥5 IU/L at 40 min. Decapeptyl® treatment was commenced due to the diagnosis of precocious puberty. Karyotype analysis was normal.

This study was performed after obtaining written informed consent from the parents of the affected individuals. Genomic DNA was extracted by standard salting out method from peripheral blood of index cases. All coding exons of the ZEB2 were amplified by the use of primers designed with Primer 3 program (http://primer3.wi.mit.edu). Primer sequences and detailed polymerase chain reaction (PCR) protocols are available on request. The PCR fragments were then sequenced via Sanger sequencing on an ABI Prism 3500 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA).

In order to analyze ZEB2 mRNA expression and NMD, RNA isolation was also performed from the collected peripheral blood samples of affected individuals. Lymphocytes were extracted by Ficoll-Paque (Amersham Bioscience, Chalfont St. Giles, UK) density gradient centrifugation method, and total RNA was obtained by Trizol reagent (Invitrogen, Paisley, UK) according to manufacturer’s recommendations. cDNA was generated by reverse transcription using the High-Capacity cDNA Reverse Transcription Kit with random primer mix (Thermo Fisher Scientific, CA, USA). Quantitative real-time PCR (qRT-PCR) was performed with SYBR Green I Master (Roche Diagnostics, Mannheim, Germany) by using the LightCycler 480 System (Roche Diagnostics). qRT-PCR was performed using a single primer set that amplifies both wild-type and mutated transcripts to compare the total expression level of ZEB2 normalized to ACTB. Moreover, allele-specific qRT-PCR was performed using a total of three primers for each affected individual: one forward primer for the wild-type transcript (Fwt), one forward primer for the mutated transcript (Fmt), and one common reverse primer (R). Primers Fwt and R can specifically detect the wild-type transcripts of ZEB2, while the mutated allele can be detected by primers Fmt and R. Primers proximal to identified indel variants and allele-specific primers were designed based on wild-type or mutant genomic sequences obtained from Sanger sequencing of the ZEB2 locus. The designed primer sequences for qRT-PCR studies were analyzed for hairpin structure formation, self-dimerization, and heterodimerization using oligo analysis software (e.g., Oligo Analyzer 3.1). For allele-specific studies, four different qRT-PCR reactions were performed using a gender-matched healthy control sample for each affected individual, with primers separately designed for wild-type and mutant transcripts. Allele-specific qRT-PCR products were then sequenced using respective reverse primers to confirm allelic discrimination.

In addition, conventional PCR was conducted for the co-amplification of both wild-type and mutated sequences using a single set of primers for each affected individual (online suppl. Table; see www.karger.com/doi/10.1159/000528769 for all online suppl. material). Conventional PCR products were then sequenced bidirectionally on an ABI Prism 3500 Genetic Analyzer (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA). Relative ratio of tandem overlapping electropherogram peaks was calculated by repurposing a known web tool, the Inference of CRISPR Edits (ICE) CRISPR Analysis Tool available from Synthego (Redwood City, CA, USA) (https:/ice.synthego.com/number/, accessed on June 23, 2022). The nucleotide sequences and genomic locations of primers used in cDNA studies are presented in online supplementary Table.

The frequency of the clinical features of MWS patients reported so far are shown in Table 1 along with the findings of the two affected individuals in this report. Sanger sequencing revealed two novel heterozygous truncation variants: c.1249_1256delAATGGTGG; (p.Asn417Alaf­s*36) in exon 8 in affected individual 1 and c.122_125delinsGGAAG; (p.Glu41Glyfs*8) in exon 3 of ZEB2 (NM_0014795) in affected individual 2, respectively (shown in Fig. 1). The variants were not found in GnomAD and G1000 databases. Various in silico analysis programs including MutationTaster predicted these two variants as disease-causing variants. Although full segregation analysis could not be performed, these two novel frameshift mutations possibly leading to truncated protein products were evaluated as likely pathogenic (PM2, PM4, PP3, PP4) according to the variant interpretation guidelines of the ACMG [Richards et al., 2015].

Table 1.

The incidence of the clinical features of previously reported MWS patients with clinical comparison of the individuals in this report

 The incidence of the clinical features of previously reported MWS patients with clinical comparison of the individuals in this report
 The incidence of the clinical features of previously reported MWS patients with clinical comparison of the individuals in this report
Fig. 1.

a ZEB2gene and protein structure. Mutations identified in this report are illustrated with color red. Electropherograms demonstrate overlapping peaks confirming the presence of intact mutated transcript along with the wild-type transcript in affected individual 2 (b) and affected individual 1 (c). Nucleotide sequences of wild-type transcripts post-qRT-PCR in affected individual 2 (d) and affected individual 1 (e). Nucleotide sequences of mutant transcripts post-qRT-PCR in affected individual 2 (f) and affected individual 1 (g).

Fig. 1.

a ZEB2gene and protein structure. Mutations identified in this report are illustrated with color red. Electropherograms demonstrate overlapping peaks confirming the presence of intact mutated transcript along with the wild-type transcript in affected individual 2 (b) and affected individual 1 (c). Nucleotide sequences of wild-type transcripts post-qRT-PCR in affected individual 2 (d) and affected individual 1 (e). Nucleotide sequences of mutant transcripts post-qRT-PCR in affected individual 2 (f) and affected individual 1 (g).

Close modal

Relative quantification of the qRT-PCR data demonstrated that there was no decrease in total ZEB2 transcript levels in cDNA samples from peripheral blood of affected individuals (online suppl. Fig. 1, 2). To further assess the allelic expression of the mutated transcripts in affected individuals, allele-specific expression study was performed. No expression of the mutated transcript was observed in the gender-matched healthy control samples, whereas, interestingly, both alleles were present in similar amounts to the normal allele in the ZEB2 mRNA from both affected individuals, revealing that the mutated transcripts were not subject to NMD (online suppl. Fig. 3). Sanger sequencing of qRT-PCR products also validated the successful allelic discrimination (Fig. 1). In addition, conventional PCR was performed for each affected individual to co-amplify both wild-type and mutated transcripts, which were then sequenced. Electropherograms revealed overlapping peaks, confirming the presence of intact mutated transcript along with the wild-type transcript in both affected individuals (Fig. 1). Electropherograms containing tandem overlapping peaks (n > 100) were uploaded to the ICE CRISPR Analysis Tool and comparable percentages were calculated for the wild-type and mutated sequences in both affected individuals (online suppl. Fig. 4).

In this study, we report two novel heterozygous frameshift mutations in ZEB2 and the absence of NMD of the mutated transcripts in two non-related patients. To date, more than 180 distinct de novo ZEB2 mutations including nonsense and missense point mutations, deletions, duplications, and large chromosomal rearrangements have been reported [Baxter et al., 2017]. The majority of these mutations are single point mutations that account for 70–80% of the genetic etiology of MWS. 2q22 deletions, which range in size from solely ZEB2 exons to multiple contiguous genes, represent another 15–20% of the genetic etiology of this syndrome. Moreover, in rare cases, large chromosomal rearrangements and ZEB2 duplications have also been observed [Baxter et al., 2017].

Advanced paternal age is suspected to result in an increased risk of neurodevelopmental disorders due to de novo mutations [Girard et al., 2016; Janecka et al., 2017]. However, paternal ages of both individuals were younger than 35 years at the time of conception. Recurrence in siblings has also been rarely reported in the literature, which suggests a possibility of germline mosaicism [Zweier et al., 2002; McGaughran et al., 2005; Cecconi et al., 2008]. Recently, Ivanovski et al. [2018] evaluated the clinical and molecular findings of 87 MWS patients, which represent the most comprehensive MWS cohort analyzed in the literature to date. This recent research by Ivanovski et al. [2018] showed that the majority of mutations in their cohort were small insertions/deletions/indels (46%), similar to the mutations detected in the present study.

ZEB2 is a key protein that interacts with SMAD proteins and has a transcriptional repressor function throughout the TGF-B signaling network [Grabitz and Duncan, 2012]. ZEB2 primarily consists of a homeodomain, a SMAD binding domain, a CtBP interaction domain, a NuRD complex interaction motif (NIM), and two N- and C-terminal zinc fingers (NZF, CZF). ZEB2 regulates the downstream genes via an interaction between these two terminal zinc-finger sequences and target gene promoter E-box element sequences [Epifanova et al., 2019]. One of the well-defined downstream target genes is E-cadherin, and ZEB2 acts as a transcriptional repressor through binding the promoter region of E-cadherin and blocking other transcription factors.

The two mutations detected in this study are not localized to any of the known functional domains of ZEB2. Since both affected individuals harbored frameshift mutations, it can be assumed that transcripts probably underwent NMD, resulting in haploinsufficiency. There is not much information about experimental NMD data available regarding the previously reported mutations, except for the studies by Saunders et al. [2009] and Zweier et al. [2002]. In their studies, Saunders et al. [2009] showed that the mutated transcripts from 4 patients harboring nonsense and frameshift mutations were detectable, while Zweier et al. [2002] demonstrated that the truncating mutation in exon 5 harbored by one of the patients did not lead to NMD [Saunders et al., 2009].

Similarly, allele-specific expression performed in affected individuals in this study demonstrated comparable expression from both mutant and wild-type transcripts. Both the total gene and allelic expression results indicate that the mutant mRNA transcripts are not subject to nonsense-mediated mRNA decay, which is of particular interest for the very early stop codon mutation located in the N terminus of ZEB2 in affected individual 2. Even though the data presented are limited to peripheral blood studies that may not reflect other tissues, and protein studies have not been performed, mutations identified in both individuals are possibly expected to result in a truncated ZEB2 which has lost most of its functional domains including the CZF domain, as seen in Figure 1. As integrity of both ZF clusters is important for the proper binding of ZEB2 to DNA, lack of CZF domain in both truncated proteins presumably destroys direct binding of ZEB2 to target genes [Remacle et al., 1999]. It might be speculated that the truncated protein expected in affected individual 2 contains only NIM, whereas truncated protein expected to be translated in affected individual 1 retains both binding (NZF) and protein-protein interaction (NIM) domains, which are accepted as toxic protein domains when overexpressed in experimental setup [Boyer et al., 2004].

Thus, the mutations identified in affected individuals most likely lead to haploinsufficiency as a result of lacking most of the functional domains of ZEB2 or a speculative dominant negative effect due to the result of accumulated truncated proteins that may repress wild-type ZEB2 activity as suggested by Garavelli et al. [2017].

The diverse clinical findings including aganglionic megacolon, intellectual disability, typical craniofacial characteristics, structural CNS anomalies, cardiac anomalies and epilepsy observed in the present study indicate that ZEB2 functions as a pleiotropic gene in relation to multiple developmental pathways. In fact, ZEB2 expression is known to be critical for the embryological development of various tissues including the central nervous system, craniofacial skeleton, and main arteries of the aortic arch. First, ZEB2 is a key molecule involved in neural crest cell migration, which regulates epithelial to mesenchymal transition via the repression of E-cadherin activity. ZEB2 also has roles in axonal branching, corticogenesis, CNS myelination, hippocampus formation, interneuronal neuron migration, and development of the corpus callosum and corticospinal tract [Epifanova et al., 2019]. Therefore, the GABAergic interneuronal defects are thought to cause epilepsy in MWS patients.

Furthermore, ZEB2 also interacts with SOX10, an important protein for the development of the enteric nervous system, which demonstrates the molecular pathophysiology of Hirschsprung disease in MWS patients [Stanchina et al., 2010]. In addition, to ensure proper aortic arch development, E-cadherin signaling is required to be repressed by ZEB2 expression. This may represent the underlying pathophysiology of the cardiac anomalies commonly seen in MWS patients such as pulmonary artery sling and bicuspid aortic valve, which were also observed in affected individual 2 in the present study [Cano Sierra et al., 2018]. Considering all the anomalies involving the craniofacial skeleton, enteric ganglia, central nervous system, and aortic arches, it appears that MWS results from developmental defects of the neural crest cells and, therefore, is considered a neurocristopathy.

Anthropometric measurements such as the birth weight and length are typically within the normal range in patients with this syndrome. Short stature is present in 50% of patients studied, and initiatives have been started to generate a growth chart for evaluating MWS patients [Ivanovski et al., 2018].

Short stature was not observed in affected individuals in the present study as it was in a prior study involving a cohort of Turkish MWS patients [Kiliç et al., 2016]. In fact, height percentiles were over the 50th centile in both affected individuals in this study. Additionally, head circumference at birth is important, as patients with a head circumference below 50th centile usually develop microcephaly as they grow. Unfortunately, this could not be assessed in the present study because head circumference measurements at birth were missing. Yet, individual 2 demonstrated microcephaly at the age of 7 years, whereas physical examination at the age of 10 years revealed a normal head circumference.

Pubertal development in MWS patients has been rarely addressed. While most MWS patients undergo typical pubertal development, delayed or precocious puberty was observed in a few cases in previous reports, as in affected individual 2 [Wannes et al., 2018; Adam et al., 2019; D. Mowat, personal communication]. If there is an association between MWS and precocious puberty, as in several other genetic syndromes, additional studies on further MWS patients are needed to demonstrate this causality [Winter et al., 2019].

MWS is a genetically homogenous disease, which means that no further testing or genome-wide investigation needs to be performed other than searching for a causal ZEB2 variant. The molecular diagnosis algorithm begins with Sanger sequencing and continues to include FISH as well as karyotype, MLPA, or microarray analyses for large ZEB2 deletions, chromosomal rearrangements, or intermediate-sized deletions, respectively [Kilic et al., 2016; Adam et al., 2019]. In contrast, exome sequencing with adequate bioinformatic tools for detecting point mutations and small or large-size deletions has also been suggested as a first-tier test for diagnosis of MWS [Gosso et al., 2018]. Yet, as most of the reported mutations are located in exon 8, Saunders et al. [2009] suggested sequencing exon 8 first for hot spot mutations. The molecular genetic analysis of affected individual 1 in this study was performed using this approach.

MWS is a single gene disorder with diverse allelic and clinical heterogeneity. A few studies, including ours, have revealed that NMD does not occur in some of the mutated transcripts. Prior studies have suggested that deletions usually cause more severe phenotypes than missense or in-frame mutations [Garavelli et al., 2017]. Although this latter information suggests that haploinsufficiency, rather than a speculative dominant negative effect, underlies this neurocristopathy, the findings of the present study, together with those of Garavelli et al. [2017] and Zou et al. [2020], may suggest that some manifestations might be related due to the NMD-escaped mutated transcripts. Novel mutations in this gene encoding a multifunctional pleiotropic protein are worth reporting since genotype-phenotype correlations in this clinically heterogeneous syndrome might later be established based on the fate of the transcripts translated by protein expression studies.

We thank the patients and the families for their participation in the study. We thank Ersan Kalay for providing the cDNA sample of affected individual 1.

This work was conducted ethically in accordance with the World Medical Association Declaration of Helsinki Principles. Written informed consent for genetic testing was obtained from all patients’ parents. All patients’ parents involved in this study have given their written informed consent for publication. Ethical approval was not required for this study in accordance with national guidelines, as individuals’ identifiable attributes were anonymized.

The authors have no conflicts of interest to declare.

This study did not receive any funding.

G.E. Utine and P.Ö. Şimşek-Kiper constructed the idea for research and the manuscript. G.E. Utine, Z.E. Taskiran, and N. Güleray-Lafcı designed the study. G.E. Utine, P.Ö. Şimşek-Kiper, and Z.E. Taskiran supervised the course of the project, provided support, and revised the manuscript and finalized it. N. Güleray-Lafcı and B. Karaosmanoglu collected data. N. Güleray-Lafcı, B. Karaosmanoglu, and Z.E. Taskiran carried out experiments and interpreted the results. G.E. Utine and N. Güleray-Lafcı were responsible for the literature review and took the lead in writing the manuscript.

Further inquiries about the data generated or analyzed during this study can be directed to the corresponding author.

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