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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.

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