Whole-Transcriptome Analysis by RNA Sequencing for Genetic Diagnosis of Mendelian Skin Disorders in the Context of Consanguinity

Author:

Youssefian Leila123,Saeidian Amir Hossein123,Palizban Fahimeh4,Bagherieh Atefeh5,Abdollahimajd Fahimeh6,Sotoudeh Soheila7,Mozafari Nikoo6,Farahani Rahele A8,Mahmoudi Hamidreza9,Babashah Sadegh5,Zabihi Masoud10,Zeinali Sirous10,Fortina Paolo1112,Salas-Alanis Julio C13,South Andrew P2,Vahidnezhad Hassan12,Uitto Jouni12

Affiliation:

1. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA

2. Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

3. Genetics, Genomics and Cancer Biology PhD Program, Thomas Jefferson University, Philadelphia, PA, USA

4. Laboratory of Complex Biological Systems and Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

5. Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

6. Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

7. Department of Dermatology, Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran

8. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States of America

9. Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran

10. Kawsar Human Genetics Research Center, Tehran, Iran

11. Cancer Genomics and Bioinformatics, Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

12. Department of Translation and Precision Medicine, Sapienza University, Rome, Italy

13. Dystrophic Epidermolysis Bullosa Research Association, Mexico

Abstract

Abstract Background Among the approximately 8000 Mendelian disorders, >1000 have cutaneous manifestations. In many of these conditions, the underlying mutated genes have been identified by DNA-based techniques which, however, can overlook certain types of mutations, such as exonic-synonymous and deep-intronic sequence variants. Whole-transcriptome sequencing by RNA sequencing (RNA-seq) can identify such mutations and provide information about their consequences. Methods We analyzed the whole transcriptome of 40 families with different types of Mendelian skin disorders with extensive genetic heterogeneity. The RNA-seq data were examined for variant detection and prioritization, pathogenicity confirmation, RNA expression profiling, and genome-wide homozygosity mapping in the case of consanguineous families. Among the families examined, RNA-seq was able to provide information complementary to DNA-based analyses for exonic and intronic sequence variants with aberrant splicing. In addition, we tested the possibility of using RNA-seq as the first-tier strategy for unbiased genome-wide mutation screening without information from DNA analysis. Results We found pathogenic mutations in 35 families (88%) with RNA-seq in combination with other next-generation sequencing methods, and we successfully prioritized variants and found the culprit genes. In addition, as a novel concept, we propose a pipeline that increases the yield of variant calling from RNA-seq by concurrent use of genome and transcriptome references in parallel. Conclusions Our results suggest that “clinical RNA-seq” could serve as a primary approach for mutation detection in inherited diseases, particularly in consanguineous families, provided that tissues and cells expressing the relevant genes are available for analysis.

Funder

National Institutes of Health

DEBRA International

Publisher

Oxford University Press (OUP)

Subject

Biochemistry (medical),Clinical Biochemistry

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