Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation

Abstract

De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A , detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance—with yeast functional assays further supporting altered function—one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A -related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous POLR2A Variant

“…She briefly enrolled in college before opting to work a part-time occupation instead. Targeted review of systems, focusing on key clinical features identified by Hansen and colleagues [ 16 ] were negative for ataxia, joint hypermobility, skin abnormalities, recurrent fever of unknown etiology, congenital heart disease, immune dysfunction or developmental dysplasia of the hip.…”

“…Subsequently, Hansen and colleagues identified deleterious POLR2A variants in a cohort of 12 individuals ascertained through an online data lake, a pediatrics clinic and an online community for affected individuals [ 16 ]. Their analysis included one individual who was previously reported by Haijes and colleagues [ 15 ].…”

Evolutionary conservation of the fidelity of transcription

“…Interestingly, a primary 20 and secondary 20,21 cohort of patients was recently identified that carry mutations in POLR2A, the major catalytic subunit of RNAPII in human cells. These patients suffer from muscle weakness, enlarged ventricles, white matter abnormalities and cerebellar problems.…”

Yeast as a Tool to Understand the Significance of Human Disease-Associated Gene Variants

“…Altogether, on the basis of the results of both predictive and functional analyses, eleven variants were classified as probably disease-causing [ 52 ]. Recently, the yeast model for POLR2A variant classification was leveraged to study other cases of individuals with neurodevelopmental syndromes, strengthening the association of POLR2A with this disease [ 53 ].…”