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Article Dans Une Revue Genetics in Medicine Année : 2024

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

Alice Goldenberg
Jesús Argente
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Débora G Braslavsky
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Ange-Line Bruel
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An Jacobs
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Paula Scaglia
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Résumé

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 one 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), while 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.
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Dates et versions

hal-04399501 , version 1 (17-01-2024)

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Laurens Hannes, M Atzori, Alice Goldenberg, Jesús Argente, Tania Attie-Bitach, et al.. Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome. Genetics in Medicine, 2024, Genetics in Medicine : Official Journal of the American College of Medical, 26 (4), pp.101059. ⟨10.1016/j.gim.2023.101059⟩. ⟨hal-04399501⟩
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