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Showing content from https://doi.org/10.1136/jmedgenet-2018-105528 below:

Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome

1. Stefano Paolacci1,
2. Yun Li2,
3. Emanuele Agolini3,
4. Emanuele Bellacchio3,
5. Carlos E Arboleda-Bustos4,
6. Dido Carrero5,
7. Debora Bertola6,
8. Lihadh Al-Gazali7,
9. Mariel Alders8,
10. Janine Altmüller9,
11. Gonzalo Arboleda4,
12. Filippo Beleggia10,
13. Alessandro Bruselles11,
14. Andrea Ciolfi3,
15. Gabriele Gillessen-Kaesbach12,
16. Thomas Krieg13,
17. Shehla Mohammed14,
18. Christian Müller2,
19. Antonio Novelli3,
20. Jenny Ortega4,
21. Adrian Sandoval4,
22. Gloria Velasco5,
23. Gökhan Yigit2,
24. Humberto Arboleda4,
25. Carlos Lopez-Otin5,
26. Bernd Wollnik2,
27. Marco Tartaglia3,
28. Raoul C Hennekam15

1. ¹ Department of Experimental Medicine, Sapienza “University of Rome”, Rome, Italy
2. ² Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
3. ³ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Roma, Italy
4. ⁴ Neuroscience and Cell Death Group, Faculty of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogota, Colombia
5. ⁵ Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, and Centro de Investigación Biomédica en Red de Cáncer, Oviedo, Spain
6. ⁶ Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, e Centro de Estudos sobre o Genoma Humano e Células-Tronco do Instituto de Biociências da Universidade de São Paulo, São Paulo, Brazil
7. ⁷ Department of Paediatric, College of Medicine and Health Science, United Arab Emirates University, Al Ain, United Arab Emirates
8. ⁸ Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
9. ⁹ Cologne Centre for Genomics and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
10. ¹⁰ Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany
11. ¹¹ Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy
12. ¹² Institute of Human Genetics, University of Lübeck, Lübeck, Germany
13. ¹³ Department of Dermatology, University Hospital Cologne, Cologne, Germany
14. ¹⁴ Department of Clinical Genetics, Guy’s Hospital, London, UK
15. ¹⁵ Department of Paediatrics, Amsterdam UMC – location AMC, University of Amsterdam, Amsterdam, The Netherlands

1. Correspondence to Dr Raoul C Hennekam, Department of Paediatrics, Amsterdam UMC – location AMC, Amsterdam 1105AZ, The Netherlands; r.c.hennekam{at}amc.uva.nl

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.

• wiedemann-rautenstrauch syndrome
• progeroid
• POLR3A
• aetiology
• modelling

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