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A novel homozygous synonymous variant further expands the phenotypic spectrum of POLR3A-related pathologies

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Item Type:Article
Title:A novel homozygous synonymous variant further expands the phenotypic spectrum of POLR3A-related pathologies
Creators Name:Lessel, D. and Rading, K. and Campbell, S.E. and Thiele, H. and Altmüller, J. and Gordon, L.B. and Kubisch, C.
Abstract:Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.
Keywords:Leaky Splicing, Phenotypic Continuum, POLR3A, Synonymous Variant, Wiedemann-Rautenstrauch Syndrome
Source:American Journal of Medical Genetics A
Date:5 October 2021
Official Publication:https://doi.org/10.1002/ajmg.a.62525
PubMed:View item in PubMed

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