title: Gonadal mosaicism of a novel IQSEC2 variant causing female limited intellectual disability and epilepsy.
abstract: We report a family with four girls with moderate to severe intellectual disability and epilepsy. Two girls showed regression in adolescence and died of presumed sudden unexpected death in epilepsy at 16 and 22 years. Whole exome sequencing identified a truncating pathogenic variant in IQSEC2 at NM_001111125.2: c.2679_2680insA, p.(D894fs*10), a recently identified cause of epileptic encephalopathy in females (MIM 300522). The IQSEC2 variant was identified in both surviving affected sisters but in neither parent. We describe the phenotypic spectrum associated with IQSEC2 variants, highlighting how IQSEC2 is adding to a growing list of X-linked genes that have a female-specific phenotype typically associated with de novo mutations. This report illustrates the need for careful review of all whole exome data, incorporating all possible modes of inheritance including that suggested by the family history.
authors.affiliation: St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.|Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Ewans
authors.affiliation: The Genetics of Learning Disability Service, Waratah, New South Wales, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.affiliation: The Genetics of Learning Disability Service, Waratah, New South Wales, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: The Genetics of Learning Disability Service, Waratah, New South Wales, Australia.
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.affiliation: The Genetics of Learning Disability Service, Waratah, New South Wales, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Leffler
authors.affiliation: St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.|Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Dinger
authors.affiliation: St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.|Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: SEALS Molecular and Cytogenetics Laboratories, Randwick Hospitals Campus, Sydney, New South Wales, Australia.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Buckley
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne Austin Health, Melbourne, Victoria, Australia.|Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Matilda R
authors.initials: MR
authors.lastname: Jackson
authors.affiliation: St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.|Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.|Sydney Children's Hospital, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.affiliation: Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
mesh_terms: D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D018095:Germ-Line Mutation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D009030:Mosaicism; D010375:Pedigree; D013577:Syndrome
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C550083:IQSEC2 protein, human