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Open Access Case report

De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies

Darrell L Dinwiddie1234567*, Sarah E Soden124, Carol J Saunders1234, Neil A Miller12, Emily G Farrow124, Laurie D Smith124 and Stephen F Kingsmore1234

Author Affiliations

1 Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO 64108, USA

2 Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO 64108, USA

3 Department of Pathology, Children’s Mercy Hospital, Kansas City, MO 64108, USA

4 School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA

5 Department of Pediatrics, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA

6 Clinical Translational Science Center, University of New Mexico, Albuquerque, NM 87131, USA

7 University of New Mexico, MSC08 4635, Albuquerque, NM 87131-0001, USA

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BMC Medical Genomics 2013, 6:32  doi:10.1186/1755-8794-6-32

Published: 17 September 2013

Abstract

Background

Currently, diagnosis of affected individuals with rare genetic disorders can be lengthy and costly, resulting in a diagnostic odyssey and in many patients a definitive molecular diagnosis is never achieved despite extensive clinical investigation. The recent advent and use of genomic medicine has resulted in a paradigm shift in the clinical molecular genetics of rare diseases and has provided insight into the causes of numerous rare genetic conditions. In particular, whole exome and genome sequencing of families has been particularly useful in discovering de novo germline mutations as the cause of both rare diseases and complex disorders.

Case presentation

We present a six year old, nonverbal African American female with microcephaly, autism, global developmental delay, and metopic craniosynostosis. Exome sequencing of the patient and her two parents revealed a heterozygous two base pair de novo deletion, c.1897_1898delCA, p.Gln633ValfsX13 in ASXL3, predicted to result in a frameshift at codon 633 with substitution of a valine for a glutamine and introduction of a premature stop codon.

Conclusions

We provide additional evidence that, truncating and frameshifting mutations in the ASXL3 gene are the cause of a newly recognized disorder characterized by severe global developmental delay, short stature, microcephaly, and craniofacial anomalies. Furthermore, we expand the knowledge about disease causing mutations and the genotype-phenotype relationships in ASXL3 and provide evidence that rare, nonsynonymous, damaging mutations are not associated with developmental delay or microcephaly.

Keywords:
ASXL3; Bohring-Opitz syndrome; Global developmental delay; Microcephaly; Craniofacial anomalies; de novo frameshift; Exome sequencing