Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.

María Inés Pérez Millán, Jeroen Breckpot, Brunella Franco, Christel Thauvin-Robinet, Sylvie Odent, Frederic Tran Mau-Them, Roberta Tammaro, Alejandro Sifrim, Ann Swillen, Paula Scaglia, Anne Rochtus, Marijke Bauters, Mio Aerden, Elise Pelgrims, Nunziana Pezzella, Laurens Hannes, Julian Martinez-Mayer, Stanislas Lyonnet, An Jacobs, Christèle Dubourg, Mireille Castanet, Ange-Line Bruel, Débora G Braslavsky, Catia Attanasio, Jeanne Amiel, Tania Attie-Bitach, Jesús Argente, Alice Goldenberg, Marta Atzori

Journal: Genetics in medicine : official journal of the American College of Medical Genetics 2024;26(4):101059

PMID: 38158857

Free Full Text on Elsevier Science View on PubMed

Abstract

PURPOSE

Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families.

METHODS

Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts.

RESULTS

In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation.

CONCLUSION

We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2.

Address: Department of Human Genetics, KU Leuven, Leuven, Belgium; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.; Department of Human Genetics, KU Leuven, Leuven, Belgium.; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Rouen, Rouen, France.; Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain; CIBEROBN de fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain; IMDEA Food Institute, Madrid, Spain.; Université Paris Cité, INSERM, IHU Imagine - Institut des maladies génétiques, Paris, France; Service de médecine génomique des maladies rares, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Institut Imagine, Paris, France.; Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez. Buenos Aires, Argentina.; INSERM, U1231, Génétique des Anomalies du Développement, Université de Bourgogne Franche-Comté, UMR Lipides, Nutrition, Dijon, France; UF Innovation diagnostique des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France.; Normandie Univ, UNIROUEN, Inserm U1239, CHU Rouen, Department of Pediatrics, Rouen, France.; Department of Molecular Genetics and Genomics, Rennes University Hospital, Rennes, France; Univ Rennes, CNRS, INSERM, IGDR, UMR 6290, ERL U1305, Rennes, France.; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.; Instituto de Biociencias, Biotecnología y Biología Traslacional (IB3), Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.; Telethon Institute of Genetics and Medicine-TIGEM, Naples, Italy; Scuola Superiore Meridionale, School for Advanced Studies, Genomics and Experimental Medicine program, Naples, Italy.; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.; Telethon Institute of Genetics and Medicine-TIGEM, Naples, Italy.; INSERM, U1231, Génétique des Anomalies du Développement, Université de Bourgogne Franche-Comté, UMR Lipides, Nutrition, Dijon, France; UF Innovation diagnostique des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic Génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.; Department of Molecular Genetics and Genomics, Rennes University Hospital, Rennes, France; Univ Rennes, CNRS, INSERM, IGDR, UMR 6290, ERL U1305, Rennes, France; Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Ouest, ERN ITHACA, FHU GenOmedS, Centre Hospitalier Universitaire Rennes, Rennes, France.; INSERM, U1231, Génétique des Anomalies du Développement, Université de Bourgogne Franche-Comté, UMR Lipides, Nutrition, Dijon, France; UF Innovation diagnostique des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France; Centre de Référence Anomalies du Développement de l'Est, Centre de Génétique, Centre Hospitalier Universitaire Dijon Bourgogne, Dijon, France.; Telethon Institute of Genetics and Medicine-TIGEM, Naples, Italy; Scuola Superiore Meridionale, School for Advanced Studies, Genomics and Experimental Medicine program, Naples, Italy; Department of Translational Medicine, Medical Genetics Federico II University of Naples, Naples, Italy.; Department of Human Genetics, KU Leuven, Leuven, Belgium; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium. Electronic address: [email protected].

DOI: 10.1016/j.gim.2023.101059

Link outs

Free resources

Full Text Sources:

https://linkinghub.elsevier.com/retrieve/pii/S1098...

Miscellaneous:

https://assays.cancer.gov/CPTAC-570

Molecular Biology Databases:

https://glygen.org/publication/PubMed/38158857/

MeSH Terms: Male, Humans, Alternative Splicing, Orofaciodigital Syndromes, RNA Splicing, Introns, Spliceosomes, Ribonucleoproteins