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Pathogenic variants in CDC45 on the remaining allele in patients with a chromosome 22q11.2 deletion result in a novel autosomal recessive condition.
Unolt, Marta; Kammoun, Molka; Nowakowska, Beata; Graham, Gail E; Crowley, T Blaine; Hestand, Matthew S; Demaerel, Wolfram; Geremek, Maciej; Emanuel, Beverly S; Zackai, Elaine H; Vermeesch, Joris R; McDonald-McGinn, Donna.
  • Unolt M; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. unolt.marta@gmail.com.
  • Kammoun M; Department of Pediatrics, Sapienza University of Rome, Rome, Italy. unolt.marta@gmail.com.
  • Nowakowska B; Center for Human Genetics, KU Leuven, Leuven, Belgium.
  • Graham GE; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Crowley TB; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
  • Hestand MS; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Demaerel W; Center for Human Genetics, KU Leuven, Leuven, Belgium.
  • Geremek M; Center for Human Genetics, KU Leuven, Leuven, Belgium.
  • Emanuel BS; Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
  • Zackai EH; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Vermeesch JR; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • McDonald-McGinn D; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Genet Med ; 22(2): 326-335, 2020 02.
Article en En | MEDLINE | ID: mdl-31474763
ABSTRACT

PURPOSE:

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans, with highly variable phenotypic expression. Whereas congenital heart defects, palatal anomalies, immunodeficiency, hypoparathyroidism, and neuropsychiatric conditions are observed in over 50% of patients with 22q11DS, a subset of patients present with additional "atypical" findings such as craniosynostosis and anorectal malformations. Recently, pathogenic variants in the CDC45 (Cell Division Cycle protein 45) gene, located within the LCR22A-LCR22B region of chromosome 22q11.2, were noted to be involved in the pathogenesis of craniosynostosis.

METHODS:

We performed next-generation sequencing on DNA from 15 patients with 22q11.2DS and atypical phenotypic features such as craniosynostosis, short stature, skeletal differences, and anorectal malformations.

RESULTS:

We identified four novel rare nonsynonymous variants in CDC45 in 5/15 patients with 22q11.2DS and craniosynostosis and/or other atypical findings.

CONCLUSION:

This study supports CDC45 as a causative gene in craniosynostosis, as well as a number of other anomalies. We suggest that this association results in a condition independent of Meier-Gorlin syndrome, perhaps representing a novel condition and/or a cause of features associated with Baller-Gerold syndrome. In addition, this work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to pathogenic variants on the nondeleted chromosome.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas de Ciclo Celular / Síndrome de DiGeorge Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Child / Child, preschool / Female / Humans / Male Idioma: En Año: 2020 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas de Ciclo Celular / Síndrome de DiGeorge Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Child / Child, preschool / Female / Humans / Male Idioma: En Año: 2020 Tipo del documento: Article