title: A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome.
abstract: We present an 18-year-old boy with cerebral palsy, intellectual disability, speech delay, and seizures. He carries a likely pathogenic 1.3 Mb de novo heterozygous deletion in the 4q21.22 microdeletion syndrome region. He also carries a 436 kb maternally-inherited duplication impacting the first three exons of CHRNA7. The majority of previously published cases with 4q21.22 syndrome shared common features including growth restriction, muscular hypotonia, and absent or severely delayed speech. Using copy number variation (CNV) data available for other subjects, we defined a minimal critical region of 170.8 kb within the syndromic region, encompassing HNRNPD. We also identified a larger 2 Mb critical region encompassing ten protein-coding genes, of which six (PRKG2, RASGEF1B, HNRNPDL, HNRNPD, LIN54, COPS4) have a significantly low number of truncating loss-of-function mutations. Long-range chromatin interaction data suggest that this deletion may alter chromatin interactions at the 4q21.22 microdeletion region. We suggest that the deletion or misregulation of these genes is likely to contribute to the neurodevelopmental and neuromuscular abnormalities in 4q21.22 syndrome.
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Zarrei
authors.affiliation: Deep Genomics Inc., Toronto, Ontario, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kellam
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Worrawat
authors.initials: W
authors.lastname: Engchuan
authors.affiliation: Royal University Hospital, Saskatoon, Saskatchewan, Canada.
authors.forename: Tara
authors.initials: T
authors.lastname: Scriver
authors.affiliation: Yorkton Regional Health Center, Yorkton, Saskatchewan, Canada.
authors.forename: Rikash
authors.initials: R
authors.lastname: Jokhan
authors.affiliation: Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wilson
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Parr
authors.affiliation: Department of Pediatrics, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Edmond G
authors.initials: EG
authors.lastname: Lemire
authors.affiliation: Department of Pediatric Laboratory Medicine, Cytogenetics Laboratory, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.identifier: http://orcid.org/0000-0002-8326-1999
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000293:Adolescent; D002547:Cerebral Palsy / Q000235:genetics* / Q000503:physiopathology; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005091:Exons / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D007805:Language Development Disorders / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics
chemical_list: C579167:Chrna7 protein, human; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords:  intellectual disability; 4q21.22 microdeletion syndrome; HNRNPD; cerebral palsy; copy number variation; delayed speech