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De novo loss‐of‐function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies
Author(s) -
Mullegama Sureni V.,
Klein Steven D.,
Mulatinho Milene V.,
Senaratne Tharanga Niroshini,
Singh Kathryn,
Nguyen Dzung C.,
Gallant Natalie M.,
Strom Samuel P.,
Ghahremani Shahnaz,
Rao Nagesh P.,
MartinezAgosto Julian A.
Publication year - 2017
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38207
Subject(s) - establishment of sister chromatid cohesion , cohesin , biology , genetics , microcephaly , chromatid , loss function , phenotype , microbiology and biotechnology , gene , chromosome
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.