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Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22–q24.1
  1. N Ishihara1,2,
  2. K Yamada1,
  3. Y Yamada1,
  4. K Miura3,
  5. J Kato4,
  6. N Kuwabara5,
  7. Y Hara6,
  8. Y Kobayashi7,
  9. K Hoshino8,
  10. Y Nomura8,
  11. M Mimaki9,
  12. K Ohya10,
  13. M Matsushima11,
  14. H Nitta12,
  15. K Tanaka13,
  16. M Segawa8,
  17. T Ohki3,
  18. T Ezoe15,
  19. T Kumagai3,
  20. A Onuma7,
  21. T Kuroda16,
  22. M Yoneda17,
  23. T Yamanaka3,
  24. M Saeki16,
  25. M Segawa14,
  26. T Saji14,
  27. M Nagaya4,
  28. N Wakamatsu1
  1. 1Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan
  2. 2Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  3. 3Department of Pediatric Neurology, Central Hospital, Aichi Human Service Center, Kasugai, Aichi, Japan
  4. 4Department of Pediatric Surgery, Central Hospital, Aichi Human Service Center, Kasugai, Aichi, Japan
  5. 5Department of Pediatric Cardiology, Gifu Prefectural Hospital, Gifu, Japan
  6. 6Department of Pediatrics, Obama Public Hospital, Obama, Fukui, Japan
  7. 7Division of Pediatric Neurology, Takutoh Rehabilitation Center for Children, Sendai, Miyagi, Japan
  8. 8Segawa Neurological Clinic for Children, Tokyo, Japan
  9. 9Department of Pediatrics, Chigasaki Municipal Hospital, Chigasaki, Kanagawa, Japan
  10. 10Department of Pediatrics, Aomori Central Hospital, Aomori, Japan
  11. 11Department of Pediatric Cardiology, Social Insurance Chukyo Hospital, Nagoya, Japan
  12. 12Department of Pediatrics, Hamagumi Medical and Educational Center for Handicapped Children, Niigata, Japan
  13. 13Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
  14. 14Division of Pediatric Cardiology, Department of 1st Pediatrics, Toho University, Tokyo, Japan
  15. 15Department of Pediatric Neurology, Tokyo Metropolitan Higashiyamato Medical Center for the Handicapped, Higashiyamato, Tokyo, Japan
  16. 16Department of Surgery, National Center for Child Health and Development, Tokyo, Japan
  17. 17Second Department of Internal Medicine, Fukui Medical University, Fukui, Japan
  1. Correspondence to:
 Dr N Wakamatsu
 Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya-cho, Kasugai, Aichi 480-0392, Japan; nwakainst-hsc.jp

https://doi.org/10.1136/jmg.2003.016154

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    Hirschsprung disease (HSCR), a clinically complex syndrome often associated with a combination of mental retardation, microcephaly, and characteristic facial features, is genetically heterogeneous.1–10 Recently, mutations in ZFHX1B, which encodes Smad-interacting protein 1 (SIP1), were identified by our group11 and Cacheux et al12 in patients with t(2;13)(q22;q22) and t(2;11)(q22.2;q21), respectively. These patients had clinical profiles consistent with a dominant form of the disease (Mowat-Wilson syndrome: MIM 235730).9,13 These and subsequent articles have demonstrated a link between patients with nonsense and frameshift mutations of the gene and the presence in these patients of the following clinical findings: profound mental retardation, delayed motor development, and specific facial features, including hypertelorism, a broad nasal bridge, strabismus, a pointed chin, prognathism, a nose with a prominent columella, and posteriorly rotated ears. Often associated with these features were microcephaly, epilepsy, congenital heart disease, HSCR, and midline defects such as agenesis or hypoplasia of the corpus callosum and hypospadias.13–19 This variety of clinical features is observed not only in patients with nonsense and frameshift mutations but also in patients harbouring deletions involving ZFHX1B at 2q22,9,11,15,20 including a previously reported isolated case.6 Thus, ZFHX1B clearly plays a critical role in the manifestation of clinical features of Mowat-Wilson syndrome. However, several points remain to be elucidated: (1) How broad are the clinical features in patients with ZFHX1B mutations and deletions? (2) What are the underlying molecular mechanisms by which the deletion of ZFHX1B at 2q22 affects the clinical phenotype? (3) What kind of clinical features might appear if the deletions were extended to include 2q23–q24.1? To address these questions, we have characterized the clinical features and underlying molecular basis of 27 cases with mutations or deletions in ZFHX1B, including 12 previously reported cases comprising …

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    Footnotes

    • This study was supported by a grant from Research on Psychiatric and Neurological Diseases and Mental Health, the Ministry of Health, Labor, and Welfare, Japan (to NW).

    • Conflicts of interest: none declared.