A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41‐q42 deletion phenotype
- 16 July 2018
- journal article
- research article
- Published by Wiley in American Journal of Medical Genetics Part A
- Vol. 176 (7), 1549-1558
- https://doi.org/10.1002/ajmg.a.38712
Abstract
Chromosome 1q41‐q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41‐q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41‐q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3‐year‐old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41‐q42 MDS. Through a familial whole‐exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41‐q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41‐q42 gene deletion syndrome.Keywords
Funding Information
- Wellcome Trust
This publication has 51 references indexed in Scilit:
- CDK‐mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancerEMBO Molecular Medicine, 2013
- SIFT web server: predicting effects of amino acid substitutions on proteinsNucleic Acids Research, 2012
- Mutations in SRCAP, Encoding SNF2-Related CREBBP Activator Protein, Cause Floating-Harbor SyndromeAmerican Journal of Human Genetics, 2012
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- Single-nucleotide evolutionary constraint scores highlight disease-causing mutationsNature Methods, 2010
- Fast and accurate long-read alignment with Burrows–Wheeler transformBioinformatics, 2010
- DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl ResourcesAmerican Journal of Human Genetics, 2009
- Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humansHuman Genetics, 2009
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007
- Mapping of Deletion and Translocation Breakpoints in 1q44 Implicates the Serine/Threonine Kinase AKT3 in Postnatal Microcephaly and Agenesis of the Corpus CallosumAmerican Journal of Human Genetics, 2007