Characterization of de novo structural variants in trios with orofacial clefts

De novo structural variants (deletions, duplications) affecting recurrent genomic disorder regions (22q11.2), genes of autosomal dominant clefting (SATB2) or regulatory elements

This preprint characterises de novo structural variants (dnSVs) in 1549 probands with orofacial clefts analysed as trios. In total, 375 dnSVs were called in 307 probands (0.242 dnSVs per genome), with a higher but not significantly different rate in cleft lip only (0.29) than in cleft lip and palate (0.25) and cleft palate only (0.20); the duplication rate, however, was significantly higher in cleft lip (0.121) and cleft lip and palate (0.096) than in cleft palate (0.028). Twenty-two dnSVs fell in recurrent genomic disorder regions, including seven deletions and one duplication of 22q11.2, eight of twelve dnSVs larger than 1 Mb were classified as likely pathogenic, and four dnSVs affected SATB2, all in children with cleft palate only. Integrating dnSVs and de novo SNVs with Hi-C contact maps and predicted chromatin states from developing craniofacial tissues pointed to new candidate genes (FHAD1, NBEA, NR3C2, SPHKAP), and likely pathogenic dnSVs provided a putative molecular diagnosis in about 1.67% of the cohort.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A modest yield (1.67%, plus 0.96% with plausible variants of uncertain significance), but one that is only reachable if structural variants are actually called and interpreted on trio genomes. The four SATB2 dnSVs, all in cleft palate only, make it a target to check systematically in this indication. The candidate genes rest on recurrence and chromatin evidence without functional validation, and this is a preprint.

Analysis by Dr Thibaut Benquey