Universität zu Köln

Lessel, Davor ORCID: 0000-0003-4496-244X, Rading, Katrin, Campbell, Susan E., Thiele, Holger, Altmueller, Janine, Gordon, Leslie B. and Kubisch, Christian (2022). A novel homozygous synonymous variant further expands the phenotypic spectrum of POLR3A-related pathologies. Am. J. Med. Genet. A, 188 (1). S. 216 - 224. HOBOKEN: WILEY. ISSN 1552-4833

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lessel, Davor UNSPECIFIED orcid.org/0000-0003-4496-244X UNSPECIFIED Rading, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Campbell, Susan E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Gordon, Leslie B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-599971
DOI:	10.1002/ajmg.a.62525
Journal or Publication Title:	Am. J. Med. Genet. A
Volume:	188
Number:	1
Page Range:	S. 216 - 224
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1552-4833
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RNA-POLYMERASE III; POLR3A; MUTATIONS; SUBUNIT Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59997