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Clinical utility gene card for: Mowat–Wilson syndrome


1.1 Name of the disease (synonyms)

  1. 1

    Mowat–Wilson.1, 2, 3, 4, 5, 6, 7

  2. 2

    Hirschsprung disease–mental retardation syndrome.1, 6, 8, 9, 10, 11

  3. 3

    Microcephaly, mental retardation and distinct facial features, with or without Hirschsprung disease.1, 6, 10, 11, 12

1.2 OMIM# of the disease


1.3 Name of the analysed genes or DNA/chromosome segments

ZEB-2; chromosome 2q21–q23.3, 6, 7, 8, 9, 13

1.4 OMIM# of the gene(s)


1.5 Mutational spectrum

  1. 1

    Large chromosome deletions, including the entire ZEB-2 gene and additional contiguous genes.2, 3, 4, 5, 6, 7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25

  2. 2

    Exon deletions. Both, complete or partial gene, deletions account for about 20% of cases.2, 3, 4, 5, 6, 7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26

  3. 3

    Loss-of-function gene mutations (truncating mutations, nonsense mutations, frameshift mutations) are detected in about 70% of cases.2, 3, 4, 5, 6, 7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27

  4. 4

    Missense variants are rare.2, 3, 4, 5, 6, 7, 14, 28, 29

  5. 5

    A small proportion of patients (about 10%), who present with a clinical phenotype, highly consistent with MWS, have a negative genetic test. Atypical mutations can be considered in these cases, and the diagnosis can be confirmed clinically.2, 3, 4, 5, 6, 7

1.6 Analytical methods

  1. 1

    Multiplex ligation-dependent probe amplification (MLPA).2, 3, 5, 7, 13

  2. 2

    Direct gene sequencing of ZEB-2 gene between amino acid positions 1 and 1214 (Gene Bank Accession Number NM_014795.2), by analysing exons and flanking intron sequences.2, 3, 5, 7, 13, 14

1.7 Analytical validation

(1) If a partial or complete gene deletion is detected by MLPA by several probes or by array-CGH, with reliably sufficient probes for the given array and analysis setting, no alternative validation is necessary. If the parents are analysed for mosaicism or balanced rearrangements by FISH, confirmation of FISH with molecular probes containing ZEB-2 should be performed in the index patient. If MLPA or array-CGH results are indicated by an unreliable number of probes, alternative validation should be performed by FISH, qPCR, further MLPA probes or by higher density array-CGH.

In cases with deletions, detectable by FISH, parents are investigated by FISH to look for a balanced chromosome insertion, encompassing ZEB-2 or a mosaic deletion.

If a single exon deletion is detected by a MLPA probe, the respective exon should be sequenced to exclude a mutation or polymorphism at the probe-binding site. If the latter was excluded, confirmation can be performed by real-time PCR on genomic DNA or by phenotypic analysis, in particular by facial features evaluation.2, 3, 5, 7, 13, 14

(2) Gene mutations are validated by (a) bidirectional direct sequencing, (b) evaluation of the expected functional impairment of the altered protein and (c) exclusion of the presumed mutation in healthy parents.

1.8 Estimated frequency of the disease

Estimated birth incidence is 1 in 50 000–100 000.2, 3, 4, 5, 6, 7

1.9 If applicable, prevalence in the ethnic group of investigated person

Unknown.2, 3, 4, 5, 6, 7

1.10 Diagnostic setting

Comment: Non-mosaic ZEB-2 mutations are fully penetrant. Parents of an affected child could be tested for a somatic mosaicism, but the detection rate is expected to be low. Healthy relatives (parents excluded) are not at risk for being mosaic for the mutation; thus, they are not eligible for the genetic test exploring a potential mosaicism. Recurrence risk in patient's siblings is about 2%, based on documented cases of gonadal mosaicism.30, 31 Accordingly, prenatal diagnosis is offered in subsequent pregnancies of the patient's parents only.


2.1 Analytical sensitivity (proportion of positive tests if the genotype is present)

In our experience, sensitivity of the genetic test is above 90%.2, 3, 4, 5, 6, 7

2.2 Analytical specificity (proportion of negative tests if the genotype is not present)

Analytical specificity in our experience is about 100%.2, 3, 4, 5, 6, 7

2.3 Clinical sensitivity

The reliability of a clinical diagnosis is dependent on the experience of the physician and diagnosis might be difficult in some patients, even for experts on the disorder. Moreover, a reliable prenatal diagnosis can only be offered if the underlying genetic mutation in the index case is known.2, 3, 4, 5, 6, 7, 25

2.4 Clinical specificity

Almost 100% of cases in which the clinical phenotype is not consistent with MWS have a negative genetic test.25

2.5 Positive clinical predictive value

Gene mutations associated with Mowat–Wilson syndrome are 100% fully penetrant with variable phenotype. For these reasons, a positive genetic test never has a predictive value.2, 3, 4, 5, 6, 7

2.6 Negative clinical predictive value

If the index case in the family had been tested with positive results, practically 100% of relatives without symptoms will not develop the disease.2, 3, 4, 5, 6, 7

If the index case in the family had not been tested, a low risk to develop the disease in presence of a negative genetic test is limited to siblings of the patient.30, 31


3.1 (Differential) diagnosis: the tested person is clinically affected

At a very early age, differential diagnosis could consider Pitt–Hopkins syndrome, or some chromosome deletion syndromes with an overlapping phenotype, although a detailed phenotype analysis is highly predictive for MW. Array-CGH is recommended if the genetic test for MWS is negative.1, 2, 3, 4, 5, 6, 7

3.1.1 Can a diagnosis be made other than through a genetic test?

3.1.2 Describe the burden of alternative diagnostic methods to the patient

The reliability of a clinical diagnosis is dependent on the experience of the physician and diagnosis might be difficult in some patients, even for experts on the disorder. Moreover, a reliable prenatal diagnosis can only be offered if the underlying genetic mutation in the index case is known.

If the genetic test for MWS is negative, alternative diagnostic methods are strongly suggested by the constellation of clinical manifestations. In considering a slightly overlapping phenotype with either Pitt–Hopkins syndrome or different microdeletion/microduplication syndromes, additional genetic tests could include:

  1. 1

    MLPA/gene sequencing of TCF4 for differential diagnosis with Pitt–Hopkins syndrome.

  2. 2

    Array-CGH for differential diagnosis with chromosome del/dup syndromes mimicking in part the MWS phenotype.2, 3, 4, 5, 6, 7

3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?

No data available.

3.1.4 Will disease management be influenced by the result of a genetic test?

There is no specific treatment for MWS, as the neurological defect and also other malformations, resulting from the mutation, occur in the early stage of embryonal development. The frequent presence of serious congenital malformations require clinical investigation with intervention of neonatologists, paediatricians and several specialists. Congenital heart disease and Hirschsprung disease require early surgery during the first days or months of life. Constipation may persist after HSCR surgery. Seizures are common and require standard therapy. Genitourinary anomalies such as hypospadias, cryptorchidism, bifid scrotum, vesicoureteral reflux and hydronephrosis might be present in the first years of life and may require surgery. Eye problems are frequent and require a specialized help. Musculoskeletal anomalies, such as pes planus, calcaneovalgus deformity and scoliosis, may occur, so orthopaedic evaluation is appropriate. Audiology is recommended, although deafness is rarely present. All advised vaccinations are recommended. A periodic follow-up for the different clinical problems should be carried out regularly. Psychomotor development is retarded in all patients, and speech is almost always severely limited (typically from 0 to 100 words). Rehabilitation, including physical therapy, psychomotor and speech therapy, should be started as soon as possible. Augmented communication (signing, picture exchange, Makaton) is recommended.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41

3.3 Genetic risk assessment in family members of a diseased person

A slight increase of the recurrence risk in family members is limited to siblings of the diseased person, caused by a potential gonadal mosaicism in one parent. Genetic prenatal diagnosis is offered in these cases.30, 31

3.3.1 Does the result of a genetic test resolve the genetic situation in that family?

If the diseased person had a positive genetic test, family members with a negative test, in particular parents and patient's siblings tested prenatally, are not at risk for being affected.

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?

With exception of the patient's parents, each healthy family member is not eligible for the genetic test.

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?


3.4 Prenatal diagnosis

Prenatal diagnosis is offered to siblings of the affected person, limited to the specific gene mutation detected in the diseased person.2, 3, 4, 5, 6, 7, 30, 31

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnostic?

Yes, limited to siblings.2, 3, 4, 5, 6, 7, 30, 31


A positive genetic test is greatly useful for family members. It restricts a low recurrence risk to subsequent siblings of the diseased person. On the contrary, each healthy family member has not an increased risk of having affected children, with the only exclusion of the healthy parents of the affected person because of a possible gonadal or somatic mosaicism.


  1. 1

    Mowat DR, Croaker GDH, Cass DT et al: Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. J Med Genet 1998; 35: 617–623.

    CAS  Article  Google Scholar 

  2. 2

    Adam MP, Bean LJH, Ranger Miller V : Mowat-Wilson syndrome. Gene Reviews

  3. 3

    Garavelli L, Cerruti-Mainardi P : Mowat-Wilson syndrome. Orphanet J Rare Dis 2007; 2: 42.

    Article  Google Scholar 

  4. 4

    Mowat DR, Wilson MJ, Goossens M : Mowat-Wilson syndrome. J Med Genet 2003; 40: 305–310.

    CAS  Article  Google Scholar 

  5. 5

    Mowat D, Wilson M : Mowat-Wilson syndrome. Chapter 35; in Cassidy SB, Allanson JE (eds): Management of Genetic Syndromes, 3rd edn. Hoboken, NJ: Wiley-Blackwel, 2010.

    Google Scholar 

  6. 6

    Electronic database information: online Mendelian inheritance in man (OMIM)

  7. 7

    Wilson M, Mowat D, Goossens M : ZEB2, Mowat-Wilson syndrome, 2007, Section III, Part C, Chapter 40; in Epstein CJ, Erickson RP, Wynshaw-Boris A (eds): Inborn Errors of Metabolism: The Molecular Basis of Clinical Disorders of Morphogenesis, 2nd edn. Oxford Press; England: Oxford University, 2007.

    Google Scholar 

  8. 8

    Cacheux V, Dastot-Le Moal F, Kääriäinen H et al: Loss-of-function mutations in SIP1 Smad interacting protein 1 results in a syndromic Hirschsprung disease. Hum Mol Genet 2001; 10: 1503–1510.

    CAS  Article  Google Scholar 

  9. 9

    Garavelli L, Donadio A, Zanacca C et al: Hirschsprung disease, mental retardation, characteristic facial features and mutation in the gene ZFHX1B (SIP1): confirmation of the Mowat-Wilson syndrome. Am J Med Genet 2003; 116A: 385–388.

    CAS  Article  Google Scholar 

  10. 10

    Kääriäinen H, Wallgren-Pettersson C, Clarke A, Pihko H, Taskinen H, Rintala R : Hirschsprung disease, mental retardation and dysmorphic facial features in five unrelated children. Clin Dysmorphol 2001; 10: 157–163.

    Article  Google Scholar 

  11. 11

    Yoneda M, Fujita T, Yamada Y et al: Late infantile Hirschsprung disease-mental retardation syndrome with a 3-bp deletion in ZFHX1B. Neurology 2002; 59: 1637–1640.

    CAS  Article  Google Scholar 

  12. 12

    Zweier C, Albrecht B, Mitulla B et al: ‘Mowat-Wilson’ syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeobox 1 B gene (ZFHX1B). Am J Med Genet 2002; 108: 177–181.

    Article  Google Scholar 

  13. 13

    Garavelli L, Zollino M, Mainardi PC et al: Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature. Am J Med Genet A 2009; 149A: 417–426. Review.

    CAS  Article  Google Scholar 

  14. 14

    Dastot-Le Moal F, Wilson M, Mowat D, Collot N, Niel F, Goosens M : ZFHX1B mutations in patients with Mowat-Wilson syndrome. Hum Mutat 2007; 0: 1–9.

    Google Scholar 

  15. 15

    Amiel J, Espinosa-Parrilla Y, Steffann J et al: Large scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures. Am J Hum Genet 2001; 69: 1370–1377.

    CAS  Article  Google Scholar 

  16. 16

    Cerruti-Mainardi P, Garavelli L, Pastore G et al: Mowat-Wilson syndrome and mutation in the zinc finger homeo box 1B gene: a new syndrome probably under-diagnosed. Italian J Pediatr 2005; 31: 116–125.

    Google Scholar 

  17. 17

    Ishihara N, Yamada K, Yamada Y et al: Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFH1B mutations and deletions at 2q22-24.1. J Med Genet 2004; 41: 387–393.

    CAS  Article  Google Scholar 

  18. 18

    Sasongko TH, Hamim A, Gunadi S, Lee MJ, Koterazawa K, Nishio H : Nonsense mutations of the ZFHX1B gene in two Japanese girgls with Mowat-Wilson syndrome Kobe. J Med Sci 2007; 53: 152–162.

    Google Scholar 

  19. 19

    Sasso A, Paucic-Kirincic E, Kamber-Makek S, Sindicic N, Brajnovic-Zaputovic S, Brajenovic-Milic B : Mowat-Wilson syndrome: the clinical report with the novel mutation in ZFHX1B (exon 8:c.2372delC;p.T791fsX816). Childs Nerv Syst 2008; 24: 615–618.

    Article  Google Scholar 

  20. 20

    Sztriha L, Espinosa-Parrilla Y, Gururaj A et al: Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome). Neuropediatrics 2003; 34: 322–335.

    CAS  Article  Google Scholar 

  21. 21

    Yamada K, Yamada Y, Nomura N et al: Nonsense and frameshift mutations in ZFHX1B, encoding Smad interacting protein 1, cause a complex developmental disorder with a great variety of clinical features. Am J Hum Genet 2001; 69: 1178–1185.

    CAS  Article  Google Scholar 

  22. 22

    Wakamatsu N, Yasukazu Y, Kenichiro Y et al: Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet 2001; 27: 369–370.

    CAS  Article  Google Scholar 

  23. 23

    Wilson M, Mowat D, Dastot-LeMood F : Further delineation of the phenotype associated with heterozygous mutation in ZFHX1B. Am J Med Genet 2003; 119A: 257–265.

    Article  Google Scholar 

  24. 24

    Zweier C, Temple IK, Beemer F et al: Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat-Wilson syndrome. J Med Genet 2003; 40: 601–605.

    CAS  Article  Google Scholar 

  25. 25

    Zweier C, Thiel CT, Dufke A et al: Clinical and mutational spectrum of Mowat-Wilson syndrome. Eur J Med Genet 2005; 48: 97–111.

    Article  Google Scholar 

  26. 26

    Zweier C, Horn D, Kraus C, Rauch A : Atypical ZFHX1B mutation associated with a mild Mowat-Wilson syndrome phenotype. Am J Med Genet 2006; 140A: 869–872.

    CAS  Article  Google Scholar 

  27. 27

    Lurie IW, Supovitz KR, Rosenblum-Vos LS, Wulfsberg EA : Phenotypic variability of del(2)(q22-q23): report of a case and review of the literature. Genet Counsel 1994; 5: 11–14.

    CAS  PubMed  Google Scholar 

  28. 28

    Gregory-Evans CY, Vieira H, Dalton R, Adams GG, Sal A, Gregory-Evans K : Ocular coloboma and high myopia with Hirschsprung disease associated a novel ZFHX1B missense mutation and trisomy 21. Am J Med Genet 2004; 131: 86–90.

    CAS  Article  Google Scholar 

  29. 29

    Heinritz W, Zweier C, Froster UG et al: A missense mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype. Am J Med Genet 2006; 140A: 1223–1227.

    CAS  Article  Google Scholar 

  30. 30

    McGaughran J, Sinnott S, Dastot-Le Moal F et al: Recurrence of Mowat-Wilson syndrome in siblings with the same proven mutation. Am J Med Genet 2005; 137A: 302–304.

    Article  Google Scholar 

  31. 31

    Ohtsuka M, Oguni H, Ito Y et al: Mowat-Wilson syndrome affecting 3 siblings. J Child Neurol 2008; 23: 274–278.

    Article  Google Scholar 

  32. 32

    Adam MP, Schelley S, Gallagher R et al: Clinical features and management issues in Mowat-Wilson syndrome. Am J Med Genet 2006; 140A: 2730–2741.

    Article  Google Scholar 

  33. 33

    Adam M, Justice AN, Bean LJH, Fernhoff PM : Mowat-Wilson syndrome with craniosynostosis. Am J Med Genet 2008; 146A: 245–246.

    Article  Google Scholar 

  34. 34

    Cerruti-Mainardi P, Pastore G, Zweier C, Rauch A : Mowat-Wilson syndrome and mutation in the zinc finger homeo box 1B gene: a well defined clinical entity. J Med Genet 2004; 41: e16 (

    CAS  Article  Google Scholar 

  35. 35

    Garavelli L, Cerruti-Mainardi P, Virdis R et al: Genitourinary anomalies are frequent in Mowat-Wilson syndrome with deletion/mutation in ZFHX1B (SIP1): report of 3 Italian cases with hypospadias and review. Horm Res 2005; 63: 187–192.

    CAS  PubMed  Google Scholar 

  36. 36

    Hoffer MJV, Hilhorst-Hofstee Y, Knijnenburg J et al: A 6 Mb deletion in band 2q22 due to a complex chromosome rearrangement associated with severe psychomotor retardation, microcephaly and distinctive dysmorphic facial features. Eur J Med Genet 2007; 50: 149–154.

    CAS  Article  Google Scholar 

  37. 37

    Horn D, Weschke B, Zweier C, Rauch A : Facial phenotype allows diagnosis of Mowat-Wilson syndrome in the absence of Hirschsprung disease. Am J Med Genet 2004; 124A: 102–104.

    Article  Google Scholar 

  38. 38

    Nagaya M, Kato J, Niimi N : Clinical features of a form of Hirschsprung's disease caused by a novel genetic abnormality. J Pediatr Surg 2002; 37: 1117–1122.

    Article  Google Scholar 

  39. 39

    Silengo M, Ferrero GB, Cortese MG, Canavese F, D’Alonzo G, Papalia F : Pachygyria and cerebellar hypoplasia in Goldberg-Shprintzen syndrome. Am J Med Genet 2003; 118A: 388–390.

    Article  Google Scholar 

  40. 40

    Silengo M, Ferrero GB, Wakamatsu N : Pachygyria and cerebellar hypoplasia in a patient with a 2q22-q23 deletion that includes the ZFHX1B gene. Am J Med Genet 2004; 127A: 109.

    Article  Google Scholar 

  41. 41

    Strenge S, Heinritz W, Zweier C et al: Pulmonary artery sling and congenital tracheal stenosis in another patient with Mowat-Wilson syndrome. Am J Med Genet 2007; 143: 1528–1530.

    Article  Google Scholar 

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This work was supported by the EuroGentest, an EU-FP6 supported NoE, contract number 512148 (EuroGentest Unit 3: ‘Clinical genetics, community genetics and public health’, Workpackage 3.2).

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Correspondence to Marcella Zollino.

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The authors declare no conflict of interest.

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Zollino, M., Garavelli, L. & Rauch, A. Clinical utility gene card for: Mowat–Wilson syndrome. Eur J Hum Genet 19, 4 (2011).

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