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

  • Am J Med Genet A. 2018 Jul;176(7):1549-1558. doi: 10.1002/ajmg.a.38712.
Chris Balak  1 ,  Newell Belnap  1 ,  Keri Ramsey  1 ,  Shelagh Joss  2 ,  Koen Devriendt  3 ,  Marcus Naymik  1 ,  Wayne Jepsen  1 ,  Ashley L Siniard  1 ,  Szabolcs Szelinger  1  4 ,  Mary E Parker  5  6 ,  Ryan Richholt  1 ,  Tyler Izatt  1 ,  Madison LaFleur  1 ,  Panieh Terraf  1 ,  Lorida Llaci  1 ,  Matt De Both  1 ,  Ignazio S Piras  1 ,  Sampathkumar Rangasamy  1 ,  Isabelle Schrauwen  1  7 ,  David W Craig  1  8 ,  Matt Huentelman  1 ,  Vinodh Narayanan  1
Affiliations
  • 1. Neurogenomics Division, Center for Rare Childhood Disorders (C4RCD), Translational Genomics Research Institute, Phoenix, Arizona.
  • 2. West of Scotland Genetics Service, Queen Elizabeth University Hospital, Glasgow, United Kingdom.
  • 3. Center for Human Genetics (Centrum Menselijke Erfelijkheid), University of Leuven, Leuven, Belgium.
  • 4. UCLA Pathology & Laboratory Medicine, UCLA Center for the Health Sciences, Los Angeles, California.
  • 5. Department of Physical Therapy, Texas State University, San Marcos, Texas.
  • 6. U.R. Our Hope, , Undiagnosed and Rare Disorder Organization, Austin, Texas.
  • 7. Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, Texas.
  • 8. Department of Translational Genomics, Keck School of Medicine of USC, Los Angeles, California.
PMID: 30160831 DOI: 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
1q41q42; F-Box protein 28; FBXO28; SCF complex; WDR26; chromosome 1q41-q42 deletion syndrome; dominant negative; intellectual disability; seizures.