Genomic Etiology of Pierre Robin Sequence in Africans with Orofacial Clefts

Background Pierre Robin Sequence (PRS), characterized by micrognathia, glossoptosis, airway obstruction, and frequently cleft palate, presents significant clinical and genetic complexity, particularly within African populations, where its genetic etiology remains understudied. This study examines genetic architecture of PRS in a Ghanaian cohort with orofacial clefts (OFCs). Materials and Methods DNA samples were obtained from saliva and cheek swab samples from 18 Ghanaian families with PRS. Whole-exome sequencing (WES) on DNA was performed at 100X, using paired-end configuration on Illumina HiSeq. Quality control checks on sequencing reads and their alignment to GRCh38, and variant calling (including single-nucleotide variants [SNVs] and small insertions/deletions), were conducted using Sentieon v202112.01. Variants were annotated using Ensembl VEP and prioritized based on guidelines proposed by the American College of Medical Genetics and Genomics (ACMG). Pathway, interactome and gene expression analyses were conducted using g:Profiler, Cytoscape, STRING Database, and Mouse Genome Informatics. Results Rare and potentially pathogenic variants were identified in genes involved in craniofacial development. Novel and de novo variants were identified in SATB2 and PRDM9 . Additionally, pathogenic variants were identified in COL2A1, MED13L, CTNND2, TBX3, ABCA4, COL5A1, CREBBP, JARID2 and AGRN . However, the lack of some paternal samples restricted the ability to confirm whether these variants were de novo . Furthermore, inherited pathogenic variants were observed in HERC2 and POLR1D . The recurrence of pathogenic variants in PRDM9, ABCA4, POLR1D , and collagen genes ( COL2A1, COL5A1, COL6A3 ) across multiple unrelated individuals suggests their potential role in the genetic basis of PRS within the studied population. These genes demonstrate craniofacial expression and are enriched in processes like extracellular matrix (ECM) organization, collagen biosynthesis, and abnormal mandible, skeleton and palate morphology. Conclusion Though many syndromes may present with PRS, Stickler Syndrome (collagen genes) is likely a major contributor. These findings will inform genetic counselling and interventions specifically tailored for populations with analogous genetic backgrounds.