3′ UTR Deletion of FBXO28 in a Patient with Brain Abnormalities and Developmental Delay

Constitutional deletions of chromosome 1q42 region are rare. The phenotype spectrum associated with this copy number change is variable, including developmental delay, intellectual disability, seizures, and dysmorphology. This study describes a patient with developmental delays and brain abnormalities. G-banded karyotype, FISH, SNP oligonucleotide microarray analysis (SOMA), and whole exome sequencing analysis were performed. Postnatal reanalysis of prenatal SOMA and follow-up parental testing revealed a paternally inherited 63 kb deletion at 1q42.11 in the patient. We characterized the clinical features of this patient, providing insight into the clinical phenotype associated with deletions of the 1q42.11 sub-band. Our study provides new evidence supporting the potential functional importance of the FBXO28 3′ UTR region and the hypothesis that FBXO28 is a critical gene in the pathogenesis of chromosome 1q41q42 microdeletion syndrome. It also highlights the different goals and reporting criteria between prenatal and postnatal microarray tests.

[1]  Brian K. Lee,et al.  Random capillary glucose levels throughout pregnancy, obstetric and neonatal outcomes, and long-term neurodevelopmental conditions in children: a group-based trajectory analysis , 2023, BMC Medicine.

[2]  A. Murray,et al.  Maternal metabolic syndrome in pregnancy and child development at age 5: exploring mediating mechanisms using cord blood markers , 2023, BMC Medicine.

[3]  Brian K. Lee,et al.  Rates of maternal weight gain over the course of pregnancy and offspring risk of neurodevelopmental disorders , 2023, BMC Medicine.

[4]  L. Muglia,et al.  Maternal factors during pregnancy influencing maternal, fetal, and childhood outcomes , 2022, BMC Medicine.

[5]  C. Wright,et al.  Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts , 2022, Frontiers in Genetics.

[6]  A. McNeill Comment on: Bi-allelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2 , 2021, European Journal of Human Genetics.

[7]  A. Newson,et al.  To offer or request? Disclosing variants of uncertain significance in prenatal testing , 2021, Bioethics.

[8]  M. Hosur,et al.  Identification of 3’-UTR single nucleotide variants and prediction of select protein imbalance in mesial temporal lobe epilepsy patients , 2021, PloS one.

[9]  I. Scheffer,et al.  FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability , 2020, Epilepsia.

[10]  D. Goudie,et al.  SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect. , 2020, Brain : a journal of neurology.

[11]  S. South,et al.  Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) , 2019, Genetics in Medicine.

[12]  James E. Cox,et al.  Targeting a ceramide double bond improves insulin resistance and hepatic steatosis , 2019, Science.

[13]  Kiely N. James,et al.  Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy , 2019, The Journal of clinical investigation.

[14]  C. Mayr What Are 3' UTRs Doing? , 2018, Cold Spring Harbor perspectives in biology.

[15]  S. Szelinger,et al.  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 , 2018, American journal of medical genetics. Part A.

[16]  A. Fischer,et al.  Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons , 2018, Proceedings of the National Academy of Sciences.

[17]  S. Vernes,et al.  Understanding Neurodevelopmental Disorders: The Promise of Regulatory Variation in the 3′UTRome , 2017, Biological Psychiatry.

[18]  E. Gennaro,et al.  The crucial role of FBXO28 in the pathogenesis of the 1q41q42 microdeletion syndrome , 2016, American Journal of Medical Genetics. Part A.

[19]  M. Clementi,et al.  FBXO28 is a critical gene of the 1q41q42 microdeletion syndrome , 2015, American journal of medical genetics. Part A.

[20]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[21]  J. Parboosingh,et al.  Refinement of the critical region of 1q41q42 microdeletion syndrome identifies FBXO28 as a candidate causative gene for intellectual disability and seizures , 2014, American journal of medical genetics. Part A.

[22]  C. Tyler-Smith,et al.  Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease , 2013, Human Genetics.

[23]  M. Hurles,et al.  Copy number variation in human health, disease, and evolution. , 2009, Annual review of genomics and human genetics.

[24]  Murat Gunel,et al.  Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome , 2005, Science.