Haploinsufficiency of SF3B2 causes craniofacial microsomia

Andrew T Timberlake,Michael L Cunningham,Casey Griffin,Ignacio Zarante,Carrie L Heike,Alexis L Johns ,Mark Davis ,Gloria Liliana Porras-Hurtado ,Cheryl Wise ,Soghra Jougheh Doust ,Steven R Singer ,Jonas Gustafson ,Sureni V Mullegama ,Jean‐Pierre Saint‐Jeannet ,Paula Hurtado‐Villa ,Milagros Dueñas‐Roque ,Jennie Slee,Andrew E Timms,David Chitayat,David A Staffenberg,Amelia F Drake,Nigel G Laing,Jack Goldblatt,Anne V Hing,Leanne Magee,Harry Pachajoa,Natalya Karp,Rhonda E Schnur,Daniela V Luquetti

doi:10.1038/s41467-021-24852-9

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.

Highlights

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown
We show a role for haploinsufficient variants in SF3B2 as the most frequent genetic cause of CFM identified to date
In comparing the burden of de novo variants in 138 trios with sporadic CFM to expectation, a significant excess of loss of function (LOF) variants was identified in cases (1.7-fold excess, P = 0.01)

Summary

Introduction

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. The two largest families described in the literature to date demonstrating dominant inheritance of CFM identified linkage of the trait to chromosomal bands 11q12-13 and 14q32; the responsible gene within each linkage interval was not identified at the time of study[10,11]. Despite these advances, the role of rare variants with large effect on disease risk remains unknown. We identified a transmitted LOF in SF3B2 (p.A827RfsX5; Kindred 2) in a proband with bilateral CFM, in whom the variant was inherited from an affected father (Fig. 1; Table 2). SF3B2 lies within the 11q12-13 linkage region

Methods

Results

Conclusion