Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome.
Genet Med
; 26(4): 101059, 2024 04.
Article
em En
| MEDLINE
| ID: mdl-38158857
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_005089.4c.1211_1212del NP_005080.1p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4c.1207_1208del NP_005080.1p.(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_005089.4c.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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Síndromes Orofaciodigitais
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Processamento Alternativo
Limite:
Humans
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Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article