title: De novo loss-of-function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies.
abstract: The cohesin complex is an evolutionarily conserved multi-subunit protein complex which regulates sister chromatid cohesion during mitosis and meiosis. Additionally, the cohesin complex regulates DNA replication, DNA repair, and transcription. The core of the complex consists of four subunits: SMC1A, SMC3, RAD21, and STAG1/2. Loss-of-function mutations in many of these proteins have been implicated in human developmental disorders collectively termed "cohesinopathies." Through clinical exome sequencing (CES) of an 8-year-old girl with a clinical history of global developmental delay, microcephaly, microtia with hearing loss, language delay, ADHD, and dysmorphic features, we describe a heterozygous de novo variant (c.205C>T; p.(Arg69*)) in the integral cohesin structural protein, STAG2. This variant is associated with decreased STAG2 protein expression. The analyses of metaphase spreads did not exhibit premature sister chromatid separation; however, delayed sister chromatid cohesion was observed. To further support the pathogenicity of STAG2 variants, we identified two additional female cases from the DECIPHER research database with mutations in STAG2 and phenotypes similar to our patient. Interestingly, the clinical features of these three cases are remarkably similar to those observed in other well-established cohesinopathies. Herein, we suggest that STAG2 is a dosage-sensitive gene and that heterozygous loss-of-function variants lead to a cohesinopathy.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.|UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Sureni V
authors.initials: SV
authors.lastname: Mullegama
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Klein
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Milene V
authors.initials: MV
authors.lastname: Mulatinho
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Tharanga Niroshini
authors.initials: TN
authors.lastname: Senaratne
authors.affiliation: Division of Genetic and Genomic Medicine, University of California, Irvine, California.|Miller Children's and Women's Hospital Long Beach, Long Beach, California.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Singh
authors.affiliation: UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Dzung C
authors.initials: DC
authors.lastname: Nguyen
authors.affiliation: Division of Genetic and Genomic Medicine, University of California, Irvine, California.|Miller Children's and Women's Hospital Long Beach, Long Beach, California.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Gallant
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.|UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Samuel P
authors.initials: SP
authors.lastname: Strom
authors.affiliation: Department of Radiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Ghahremani
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Nagesh P
authors.initials: NP
authors.lastname: Rao
authors.affiliation: UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, California.|Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California.|Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California.
authors.forename: Julian A
authors.identifier: http://orcid.org/0000-0001-6776-6949
authors.initials: JA
authors.lastname: Martinez-Agosto
mesh_terms: D034961:Antigens, Nuclear / Q000096:biosynthesis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D000013:Congenital Abnormalities / Q000235:genetics* / Q000503:physiopathology; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000097722:Cohesins; C508565:STAG2 protein, human
keywords:  cohesin complex; STAG2; X-linked; cohesin-associated genes; cohesinopathy; gene dosage