TY - JOUR T1 - Specific combinations of biallelic <em>POLR3A</em> variants cause Wiedemann-Rautenstrauch syndrome JF - Journal of Medical Genetics JO - J Med Genet SP - 837 LP - 846 DO - 10.1136/jmedgenet-2018-105528 VL - 55 IS - 12 AU - Stefano Paolacci AU - Yun Li AU - Emanuele Agolini AU - Emanuele Bellacchio AU - Carlos E Arboleda-Bustos AU - Dido Carrero AU - Debora Bertola AU - Lihadh Al-Gazali AU - Mariel Alders AU - Janine Altmüller AU - Gonzalo Arboleda AU - Filippo Beleggia AU - Alessandro Bruselles AU - Andrea Ciolfi AU - Gabriele Gillessen-Kaesbach AU - Thomas Krieg AU - Shehla Mohammed AU - Christian Müller AU - Antonio Novelli AU - Jenny Ortega AU - Adrian Sandoval AU - Gloria Velasco AU - Gökhan Yigit AU - Humberto Arboleda AU - Carlos Lopez-Otin AU - Bernd Wollnik AU - Marco Tartaglia AU - Raoul C Hennekam Y1 - 2018/12/01 UR - http://jmg.bmj.com/content/55/12/837.abstract N2 - 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. ER -