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.

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

“…Earlier chromosome studies identified several recurrent deletions in patients with CDH, including, e.g., 1q41-42, 8p23.1, and 15q26. Recently, efforts at identifying other genetic causes using large cohorts of patients with CDH have been made [34,35] and several critical CDH genes have been identified such as ZFPM2, GATA4, GATA6 [36,37] and rare variants in other genes, e.g., STAG2 which is implicated in a syndromic form of XLID with microcephaly and a behavioral phenotype [38][39][40]. Complex disorders including CDH with associated LH (and pulmonary hypertension) include Donnai-Barrow syndrome (LRP2), CHARGE syndrome (CHD7), Matthew-Wood syndrome (STRA6), Simpson-Golabi-Behmel syndrome (GPC3), Cornelia de Lange syndrome (NIPBL), and autosomal recessive Fryns Syndrome (PIGN) [32].…”

Mutations in STAG2 cause an X‐linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphia: Expanding the phenotype in males

“…The variant was initially classified as a variant of unknown clinical significance based on the American College of Medical Genetics and Genomics variant assessment (Richards et al, ) (Supporting Information Table ). Since then, STAG2 variants have been recently been associated with a new clinical entity (Mullegama et al, ; Soardi et al, ). Based on the effects of the missense variant on the protein structure (Figure c), this variant, p.Lys1009Asn, was reclassified as likely pathogenic.…”

“…The first reports of STAG2 copy number variants were identified in 33 males with chromosome Xq25 duplications, involving STAG2, with intellectual disability, behavioral problems, seizures, malar flatness, and prognathism (Bonnet et al, ; Kumar et al, ; Leroy et al, ; Philippe et al, ; Yingjun et al, ). Shortly after, we described three cases of de novo heterozygous STAG2 variants in females associated with a distinct phenotype that affects growth, nervous system development, hearing, and limb formation (Table ) (Mullegama et al, ). Subsequently, a familial STAG2 missense mutation was identified in one family with five affected males.…”

“…The majority of these genes have been reported in human disease (Ball, Chen, & Yokomori, 2014;Barbero, 2013;Gerkes, Kevie-Kersemaekers, Yakin, Smeets, & Ravenswaaij-Arts, 2010;McNairn & Gerton, 2008;Musio & Krantz, 2010;Skibbens et al, 2013). Recently, we described the first reported de novo heterozygous loss-of-function variants in the X-linked Stromal Antigen 2 (STAG2, OMIM: 300826) gene, in three females with common phenotypes including microcephaly, microtia, hearing loss, developmental delay, dysmorphic features, language delay, congenital heart defect, and clinodactyly of the 5th finger (Mullegama et al, 2017). Subsequently, a familial STAG2 germline hemizygous missense mutation in five males was recently identified that exhibited an overlapping yet milder phenotype than our published female STAG2 cases.…”

“…Soardi et al (2017).b Mullegama et al (2017).c Bonnet et al (2009), DiBenedetto et al (2013),Leroy et al (2016),Philippe et al (2013) andYingjun et al (2015). d Polydactyly, syndactyly and 5th finger clinodactyly.…”