Abstract
Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). We report rare FAM50A missense variants in the original Armfield XLID syndrome family localized in Xq28 and four additional unrelated males with overlapping features. Our fam50a knockout (KO) zebrafish model exhibits abnormal neurogenesis and craniofacial patterning, and in vivo complementation assays indicate that the patient-derived variants are hypomorphic. RNA sequencing analysis from fam50a KO zebrafish show dysregulation of the transcriptome, with augmented spliceosome mRNAs and depletion of transcripts involved in neurodevelopment. Zebrafish RNA-seq datasets show a preponderance of 3′ alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex. These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. In sum, Armfield XLID syndrome is a spliceosomopathy associated with aberrant mRNA processing during development.
Highlights
Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID)
The causal locus was localized to Xq284, and within this chromosome band, a hitherto uncharacterized gene, FAM50A/ XAP5, was reported in which the 5′ untranslated region contained a run of GGC repeats[8]
We performed bidirectional Sanger sequencing of the coding regions and exon–intron boundaries of five candidate genes located in Xq28 (GDI1, MECP2, L1CAM, AFF2/FMR2, FAM50A/XAP5) in affected males
Summary
Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). Zebrafish RNAseq datasets show a preponderance of 3′ alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. Exome sequencing has accelerated mutational analysis of the coding regions of the X-chromosome and identified 28 of the 145 XLID genes in the past decade[3] Despite these accomplishments, more than 56 XLID syndromes and 33 non-syndromic XLID entities remain without a molecular diagnosis. We use GeneMatcher[5], to identify four unrelated males who have undergone whole-exome sequencing (WES), and who each bear a rare missense variant in FAM50A These males display phenotypes similar to Armfield XLID syndrome. We propose that aberrant spliceosome C-complex function is the molecular mechanism underpinning Armfield XLID, defining it as a spliceosomopathy
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