A novel homozygous synonymous variant further expands the phenotypic spectrum of POLR3A-related pathologies.
POLR3A
Wiedemann-Rautenstrauch syndrome
leaky splicing
phenotypic continuum
synonymous variant
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
21
08
2021
received:
11
06
2021
accepted:
06
09
2021
pubmed:
7
10
2021
medline:
8
4
2022
entrez:
6
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34611991
doi: 10.1002/ajmg.a.62525
doi:
Substances chimiques
POLR3A protein, human
EC 2.7.7.6
RNA Polymerase III
EC 2.7.7.6
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
216-223Informations de copyright
© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
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