Abstract
De novo sequence variants, including truncating and splicing variants, in the additional sex-combs like 3 gene (ASXL3) have been described as the cause of Bainbridge-Ropers syndrome (BRS). This pathology is characterized by delayed psychomotor development, severe intellectual disability, growth delay, hypotonia and facial dimorphism. The present study reports a case of a girl (born in 2013) with severe global developmental delay, central hypotonia, microcephaly and poor speech. The proband was examined using a multi-step molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, with negative results. Therefore, the proband and her unaffected parents were enrolled for a pilot study using targeted next-generation sequencing technology (NGS) with gene panel ClearSeq Inherited DiseaseXT and subsequent validation by Sanger sequencing. A novel de novo heterozygous frameshift variant in the ASXL3 gene (c.3006delT, p.R1004Efs*21), predicted to result in a premature termination codon, was identified. In conclusion, the present study demonstrated that targeted NGS using a suitable, gene-rich panel may provide a conclusive molecular genetics diagnosis in children with severe global developmental delays.
Highlights
The advent of the ‐generation sequencing (NGS) technology has revolutionized the current approaches in molecularKey words: developmental delay, Bainbridge‐Ropers syndrome, array‐comparative genomic hybridization (CGH), ‐generation sequencing, additional sex‐combs like 3 gene diagnostics of individuals with severe intellectual disabilities (ID), developmental delay (DD), autism spectrum disorders (ASD) and multiple congenital abnormalities (MCA)
Bainbridge‐Ropers syndrome (BRS; Online Mendelian Inheritance in Man (OMIM) #615485) is a rare congenital disorder characterized by delayed neuronal, motor and growth development, severe ID accompanied by absent or poor speech, muscular hypotonia, feeding difficulties and facial dimorphism [4]
It was first described by Bainbridge et al [5], who identified rare de novo truncating sequence variants in the additional sex‐combs like 3 (ASXL3) gene in a group of 4 unrelated affected children presenting similar phenotypic features
Summary
The advent of the ‐generation sequencing (NGS) technology has revolutionized the current approaches in molecular. Bainbridge‐Ropers syndrome (BRS; OMIM #615485) is a rare congenital disorder characterized by delayed neuronal, motor and growth development, severe ID accompanied by absent or poor speech, muscular hypotonia, feeding difficulties and facial dimorphism [4] It was first described by Bainbridge et al [5], who identified rare de novo truncating sequence variants in the additional sex‐combs like 3 (ASXL3) gene in a group of 4 unrelated affected children presenting similar phenotypic features. The patient and her healthy parents took part in a pilot study using targeted NGS with a commercially available gene‐rich panel This panel contained 2,742 genes catalogued in the Online Mendelian Inheritance in Man (OMIM) database whose pathogenic sequence variants are associated with human inherited diseases. WAYHELOVA et al: de novo FRAMESHIFT VARIANT IN ASXL3 IN A CHILD WITH DEVELOPMENTAL DELAY
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