RT Journal Article SR Electronic T1 Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 837 OP 846 DO 10.1136/jmedgenet-2018-105528 VO 55 IS 12 A1 Stefano Paolacci A1 Yun Li A1 Emanuele Agolini A1 Emanuele Bellacchio A1 Carlos E Arboleda-Bustos A1 Dido Carrero A1 Debora Bertola A1 Lihadh Al-Gazali A1 Mariel Alders A1 Janine Altmüller A1 Gonzalo Arboleda A1 Filippo Beleggia A1 Alessandro Bruselles A1 Andrea Ciolfi A1 Gabriele Gillessen-Kaesbach A1 Thomas Krieg A1 Shehla Mohammed A1 Christian Müller A1 Antonio Novelli A1 Jenny Ortega A1 Adrian Sandoval A1 Gloria Velasco A1 Gökhan Yigit A1 Humberto Arboleda A1 Carlos Lopez-Otin A1 Bernd Wollnik A1 Marco Tartaglia A1 Raoul C Hennekam YR 2018 UL http://jmg.bmj.com/content/55/12/837.abstract AB Background Wiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause.Methods We performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants.Results Biallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function.Conclusion Biallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.