1. Nonsense and Frameshift Mutations in ZFHX1B, Encoding Smad-Interacting Protein 1, Cause a Complex Developmental Disorder with a Great Variety of Clinical Features
- Author
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Masahiro Nagaya, Shin-ichi Sonta, Kenichiro Yamada, Rie Wakako, Hiroshi Ono, Kanefusa Kato, Nobuaki Wakamatsu, Tsutomu Yamanaka, Kiyokuni Miura, Noriko Nomura, Akiko Matsumoto, Toshiyuki Kumagai, Yasukazu Yamada, Chiemi Hayakawa, Shuji Miyazaki, and Ikuko Yoshimura
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Adult ,Male ,Microcephaly ,Adolescent ,Heart Diseases ,Mowat–Wilson syndrome ,media_common.quotation_subject ,Nonsense ,DNA Mutational Analysis ,Biology ,medicine.disease_cause ,Frameshift mutation ,Epilepsy ,Intellectual Disability ,medicine ,Genetics ,Humans ,Abnormalities, Multiple ,Genetics(clinical) ,RNA, Messenger ,Allele ,Child ,Frameshift Mutation ,Genetics (clinical) ,media_common ,Zinc Finger E-box Binding Homeobox 2 ,Homeodomain Proteins ,Mutation ,Infant ,Articles ,medicine.disease ,Developmental disorder ,Repressor Proteins ,Codon, Nonsense ,Child, Preschool ,Face ,Female ,Polymorphism, Restriction Fragment Length - 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.
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