Stromal Antigen 1 (STAG1, OMIM 604358) is a core protein of the cohesin complex (Sumara, Toth, Carramolino) that regulates chromatid separation in mitosis, gene transcription, DNA repair and DNA replication (Peters). Pathogenic variants in components of the cohesin complex are rare and referred to as cohesinopathies. A published cohort of 17 patients with STAG1 pathogenic variants (7 deletions, 8 missense and 2 frameshift) notes a neurodevelopmental phenotype (Lehalle). De novo changes were noted in 76% of the cohort, while 12% were maternally inherited and 12% were unknown. All STAG1 patients had intellectual disability/developmental delay (100%). Additional findings included IUGR (18%), neonatal feeding difficulties (53%), hypotonia (29%), facial dysmorphisms (82%), epilepsy (41%), scoliosis (12%) and abnormal brain imaging (18%) (Lehalle). The authors conclude that the pathogenic STAG1 variant most likely resulted in haploinsufficiency of the gene product and in turn disrupted gene regulation resulting in the observed phenotypes. To add to the limited knowledge regarding STAG-1 cohesinopathies, we present a patient with a novel, missense, likely-pathogenic variant. In addition, we present mechanistic evidence supporting the deleterious nature of this variant. A male infant was born via uncomplicated vaginal delivery at 35-6/7 weeks to a 27yoG4P2; late preterm induction of labor was performed for debilitating maternal headaches. A course of betamethasone was administered prior to induction. The pregnancy was otherwise uncomplicated. Family history significant for bronchiectasis in an older sister. Physical exam and newborn screen evaluation were normal at birth, but poor suck was noted immediately. The infant was discharged on day 2 of life but readmitted day 11 due to dehydration, lack of weight gain and inability to coordinate feeds. At three months, persistent difficulty with oral skills and lack of weight gain were noted. Upper GI and swallowing studies were normal. A G-tube was placed. At 4 months, a history of recurrent ear and urinary infections were noted. At 7 months, the patient was diagnosed with laryngomalacia and developed unexplained right sided Horner’s syndrome. MRI brain noted an incidental Chiari 1 malformation but no acute process. Genetics consult at 7 months noted anisocoria, mild bilateral conductive hearing loss and a presacral dimple. Metabolic testing was normal for lysosomal/peroxisomal storage disorders, aminoacidopathy, congenital disorders of glycosylation, carnitine, purine and pyrimidine disorders, and pyruvic defects. Chromosomal microarray was normal. Exome sequencing (ES) trio testing through GeneDx, a CAP/CLIA-certified lab, revealed a de novo, likely pathogenic, heterozygous variant in STAG1 c.643G>A, p.V215I consistent with STAG1-related disorders. Following initial WES, he was diagnosed with non-CF bronchiectasis (negative sweat test) and low IgM and IgA levels; he has had episodes of hypoglycemia, with negative metabolic evaluation. WES reanalysis with updated phenotype was non-diagnostic. At 3 years, height is 87.6cm (2%ile), weight 12.75 kg. He has diagnoses of developmental delay including expressive speech delay, receives IVIG infusions, chest therapy and remains G tube dependent with food aversion. He receives educational services and qualified for an IEP at age 3. Our patient’s variant occurred at a highly conserved amino acid region in the cohesin complex interface between STAG1 and RAD21. Although reported as likely pathogenic, the deleteriousness of the variant was questioned because the physiochemical change from valine to isoleucine is small and isoleucine occurs in lower species (yeast and fruit fly). Molecular dynamic simulation on this variant and two published deleterious STAG1 variants showed similar altered protein conformation at the RAD21 interface. This report contributes to the expanding literature for STAG1 cohesinopathy phenotypes and mechanistic evidence of the pathogenicity of the genetic variant.
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Safgren et al. (2024) studied this question.