title: Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features.
abstract: Mutations in ZFHX1B, encoding Smad-interacting protein 1 (SIP1), have been recently reported to cause a form of Hirschsprung disease (HSCR). Patients with ZFHX1B deficiency typically show mental retardation, delayed motor development, epilepsy, microcephaly, distinct facial features, and/or congenital heart disease, in addition to the cardinal form of HSCR. To investigate the breadth of clinical variation, we studied DNA samples from six patients with clinical profiles quite similar to those described elsewhere for ZFHX1B deficiency, except that they did not have HSCR. The results showed the previously reported R695X mutation to be present in three cases, with three novel mutations-a 2-bp insertion (760insCA resulting in 254fs262X), a single-base deletion (270delG resulting in 91fs107X), and a 2-bp deletion (2178delTT resulting in 727fs754X)-newly identified in the other three. All mutations occurred in one allele and were de novo events. These results demonstrate that ZFHX1B deficiency is an autosomal dominant complex developmental disorder and that individuals with functional null mutations present with mental retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels.
authors.affiliation: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: N
authors.initials: N
authors.lastname: Nomura
authors.forename: K
authors.initials: K
authors.lastname: Miura
authors.forename: R
authors.initials: R
authors.lastname: Wakako
authors.forename: C
authors.initials: C
authors.lastname: Hayakawa
authors.forename: A
authors.initials: A
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: Kumagai
authors.forename: I
authors.initials: I
authors.lastname: Yoshimura
authors.forename: S
authors.initials: S
authors.lastname: Miyazaki
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Sonta
authors.forename: H
authors.initials: H
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Yamanaka
authors.forename: M
authors.initials: M
authors.lastname: Nagaya
authors.forename: N
authors.initials: N
authors.lastname: Wakamatsu
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D006331:Heart Diseases / Q000151:congenital; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018389:Codon, Nonsense; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2