Molecular analysis of inherited disorders of cornification in polish patients show novel variants and functional data and provokes questions on the significance of secondary findings.

Autor: Wertheim-Tysarowska K; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland. katarzyna.wertheim@imid.med.pl., Osipowicz K; Department of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Warsaw, 02-008, Poland., Woźniak K; Department of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Warsaw, 02-008, Poland.; National Medical Institute of the Ministry of the Interior and Administration, Warsaw, Poland., Sawicka J; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Mika A; Department of Pharmaceutical Biochemistry, Medical University of Gdansk, Gdansk, 80-211, Poland., Kutkowska-Kaźmierczak A; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Niepokój K; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Sobczyńska-Tomaszewska A; Medgen - MedGen Diagnostic Laboratory, MedGen Medical Center, ul. Wiktorii Wiedeńskiej 9a, Warsaw, 02- 954, Poland., Wawrzycki B; Department of Dermatology, Venereology, and Paediatric Dermatology, Medical University of Lublin, Staszica 11, Lublin, 20-080, Poland., Pietrzak A; Department of Dermatology, Venereology, and Paediatric Dermatology, Medical University of Lublin, Staszica 11, Lublin, 20-080, Poland., Śmigiel R; Department of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases, Wroclaw Medical University, Wroclaw, Poland., Wojtaś B; Laboratory of Sequencing, Nencki Institute of Experimental Biology, Wroclaw, Poland., Gielniewski B; Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Wroclaw, Poland., Szabelska-Beresewicz A; Department of Mathematical and Statistical Methods, Poznań University of Life Sciences, Poznań, 60-637, Poland., Zyprych-Walczak J; Department of Mathematical and Statistical Methods, Poznań University of Life Sciences, Poznań, 60-637, Poland., Rygiel AM; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Domaszewicz A; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Braun-Walicka N; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Grabarczyk A; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Rzońca-Niewczas S; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Lidia R; Międzyleski Specialistic Hospital In Warsaw, Bursztynowa 2, Warsaw, 04-749, Poland., Dawidziuk M; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Domański D; Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland., Gambin T; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Jackiewicz M; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Duk K; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Dorożko B; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Szczygielski O; Clinic of Surgery of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland., Krześniak N; Department of Plastic and Reconstructive Surgery, Centre of Postgraduate Medical Education, Prof. W. Orlowski Memorial Hospital, Warsaw, Poland., Noszczyk BH; Department of Plastic and Reconstructive Surgery, Centre of Postgraduate Medical Education, Prof. W. Orlowski Memorial Hospital, Warsaw, Poland., Obersztyn E; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Wierzba J; Department of Internal and Pediatric Nursing, Institute of Nursing and Midwifery, Medical University of Gdańsk, Gdańsk, Poland., Barczyk A; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Castaneda J; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Eckersdorf-Mastalerz A; Medical Center Fundacja PoMoc, ul. Dąbrowskiego 87, Łódź, 93-271, Poland., Jakubiuk-Tomaszuk A; Medical Genetics Unit, Mastermed Medical Center, Bialystok, Poland.; Department of Pediatric Neurology, Medical University of Bialystok, Bialystok, Poland., Własienko P; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Jaszczuk I; Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, Lublin, Poland., Jezela-Stanek A; Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 26 Plocka str, Warsaw, 01-138, Poland., Klapecki J; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., van Geel M; Department of Dermatology, Maastricht University Medical Centre +, Maastricht, The Netherlands., Kowalewski C; Department of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Warsaw, 02-008, Poland.; National Medical Institute of the Ministry of the Interior and Administration, Warsaw, Poland., Bal J; Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland., Gostyński A; Department of Dermatology, Maastricht University Medical Centre +, Maastricht, The Netherlands.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2024 Nov 05; Vol. 19 (1), pp. 413. Date of Electronic Publication: 2024 Nov 05.
DOI: 10.1186/s13023-024-03395-4
Abstrakt: Background: The Mendelian Disorders of Cornification (MeDOC) comprise a large number of disorders that present with either localised (palmoplantar keratoderma, PPK) or generalised (ichthyoses) signs. The MeDOC are highly heterogenic in terms of genetics and phenotype. Consequently, diagnostic process is challenging and before implementation of the next generation sequencing, was mostly symptomatic, not causal, which limited research on those diseases. The aim of the study was to genetically characterise a cohort of 265 Polish patients with MeDOC and to get insight into the skin lesions using transcriptome and lipid profile analyses.
Results: We detected causal variants in 85% (226/265) patients. In addition to the primary gene defect, a pathogenic variant in another gene involved in MeDOC pathology was identified in 23 cases. We found 150 distinct variants in 33 genes, including 32 novel and 16 recurrent (present in > 5 alleles). In 43 alleles large rearrangements were detected, including deletions in the STS, SPINK5, CERS3 and recurrent duplication of exons 10-14 in TGM1. The RNA analysis using samples collected from 18 MeDOC patients and 22 controls identified 1377 differentially expressed genes - DEG. The gene ontology analysis revealed that 114 biological processes were upregulated in the MeDOC group, including i.e. epithelial cell differentiation, lipid metabolic process; homeostasis; regulation of water loss via skin; peptide cross-linking. The DEG between TGM1 and ALOX12B patients, showed that RNA profile is highly similar, though fatty acid profile in epidermal scrapings of those patients showed differences e.g. for the very long chain fatty acids (VLCFAs; FAs ≥ C20), the very long-chain monounsaturated fatty acids (VLC-MUFAs, FAs ≥ C20:1) and the n6 polyunsaturated fatty acids (n6 PUFAs).
Conclusion: Our results show that NGS-based analysis is an effective MeDOC diagnostic tool. The Polish MeDOC patients are heterogenic, however recurrent variants are present. The novel variants and high number of TGM1 and SPINK5 copy number variations give further insight into molecular pathology of MeDOC. We show that secondary variants in MeDOC-related genes are present in a significant group of patients, which should be further investigated in the context of phenotype modifiers. Finally, we provide novel RNA and lipid data that characterise molecularly MeDOC epidermis.
(© 2024. The Author(s).)
Databáze: MEDLINE
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