Haploinsufficiency of SF3B2 causes craniofacial microsomia

Abstract

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10−10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.

The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development

“…Upon differentiation of the patient iPSCs into neural crest cells, RNA-Seq analysis revealed mis-splicing events preferentially affecting genes involved in neural crest specification as well as epithelial-to-mesenchymal transition, a fundamental process for the dissemination of neural crest cells in the embryo [ 39 ]. Models for other craniofacial spliceosomopathies such as CFM (OMIM#605591) and RCPS (OMIM#268305), which are due to mutations in SF3B2 (a binding partner of SF3B4) and EIF4A3 (a core component of the exon junction complex), respectively, also point to defects in neural crest development and function [ 40 , 41 , 42 ]. MO-mediated knockdown of eif4a3 in zebrafish causes underdevelopment of craniofacial cartilages and clefting of the lower jaw, defects that are associated with increased cell death and reduced neural crest gene expression [ 40 ].…”

“…MO-mediated knockdown of eif4a3 in zebrafish causes underdevelopment of craniofacial cartilages and clefting of the lower jaw, defects that are associated with increased cell death and reduced neural crest gene expression [ 40 ]. RCPS patient-derived iPSCs and mouse mutants both support a requirement of Eif4a3 in cranial neural crest cells and their derivatives, and in the regulation of osteochondrogenic differentiation during craniofacial development [ 42 ].…”

Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease

“…Recently, SF3B2 was ascertained as a major OAVS gene with seven kindreds with loss-of-function variants identified in three families, three sporadic cases with de novo variants and one germline mosaicism (table 3). Exome or genome sequencing of 138 cases in trio strategy was performed to reveal two loss-of-function variants in SF3B2 54. SF3B2 is included in the U2 small nuclear ribonucleoprotein complex (U2 snRNP) involved in the spliceosome.…”

“…Finally, a transient knockdown xenopus model of SF3B2 homologue was performed to validate its involvement in craniofacial and ear structures development. Although sf3b2 is ubiquitously expressed, specific molecular markers of neural crest progenitors demonstrated the specific craniofacial alterations induced such as hypoplastic or missing cartilages54 (table 4).…”

Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome

“…With the widespread adoption of exome or genome sequencing, several genes have now been associated with OAVS [6][7][8][9][10][11], although many have only been identified through segregation in multi-generational single families. Most recently, a large exome/ genome sequencing effort of trios identified haploinsufficient variants in SF3B2 in multiple families segregating OAVS [12]. Variants were identified in 3% of sporadic and 25% of familial cases, indicating that while SF3B2 genetic alterations are the most common cause of OAVS identified to date, there is wide genetic heterogeneity for this condition.…”