Whole genome sequencing of a family with autosomal dominant features within the oculoauriculovertebral spectrum.

Background: Oculoauriculovertebral Spectrum (OAVS) encompasses abnormalities on derivatives from the first and second pharyngeal arches including macrostomia, hemifacial microsomia, micrognathia, preauricular tags, ocular and vertebral anomalies. We present genetic findings on a three-generation family affected with macrostomia, preauricular tags and uni- or bilateral ptosis following an autosomal dominant pattern. Methods: We generated whole genome sequencing data for the proband, affected parent and unaffected paternal grandparent followed by Sanger sequencing on 23 family members for the top 10 candidate genes: KCND2, PDGFRA, CASP9, NCOA3, WNT10A, SIX1, MTF1, KDR/VEGFR2, LRRK1, and TRIM2 We performed parent and sibling-based transmission disequilibrium tests and burden analysis via a penalized linear mixed model, for segregation and mutation burden respectively. Next, via bioinformatic tools we predicted protein function, mutation pathogenicity and pathway enrichment to investigate the biological relevance of mutations identified. Results: Rare missense mutations in SIX1, KDR/VEGFR2, and PDGFRA showed the best segregation with the OAV phenotypes in this family. When considering any of the 3 OAVS phenotypes as an outcome, SIX1 had the strongest associations in parent-TDTs and sib-TDTs (p=0.025, p=0.052) (unadjusted p-values). Burden analysis identified SIX1 (RC=0.87) and PDGFRA (RC=0.98) strongly associated with OAVS severity. Using phenotype-specific outcomes, sib-TDTs identified SIX1 with uni- or bilateral ptosis (p=0.049) and ear tags (p=0.01), and PDGFRA and KDR/VEGFR2 with ear tags (both p<0.01). Conclusion: SIX1, PDGFRA, and KDR/VEGFR2 are strongly associated to OAVS phenotypes. SIX1 has been previously associated with OAVS ear malformations and is co-expressed with EYA1 during ear development. Efforts to strengthen the genotype-phenotype co-relation underlying the OAVS are key to discover etiology, family counseling and prevention.

Preface to the 9th Biennial COAST Conference: Harnessing Technology and Biomedicine for Personalized Orthodontics.

OBJECTIVE: The Consortium on Orthodontic Advances in Science and Technology (COAST) convened for its 9th biennial conference titled 'Harnessing Technology and Biomedicine for Personalized Orthodontics' to explore cutting-edge craniofacial research towards building the foundations for precision care in orthodontics. SETTING AND SAMPLE POPULATION: Seventy-five faculty, scholars, private practitioners, industry, residents and students met at the UCLA Arrowhead Lodge on 6-9 November 2022 for networking, scientific presentations and facilitated discussions. Thirty-three speakers provided state-of-the-art, evidence-based scientific and perspective updates in craniofacial and orthodontic-related fields. The overall format included an Education Innovation Award Faculty Development Career Enrichment (FaCE) workshop focused on faculty career development, three lunch and learns, keynote or short talks and poster presentations. MATERIAL AND METHODS: The 2022 COAST Conference was organized thematically to include (a) genes, cells and environment in craniofacial development and abnormalities; (b) precision modulation of tooth movement, retention and facial growth; (c) applications of artificial intelligence in craniofacial health; (d) precision approaches to Sleep Medicine, OSA and TMJ therapies; and (e) precision technologies and appliances. RESULTS: The collective advances in orthodontics and science represented in the manuscripts of this issue fulfil our goal of laying solid foundations for personalized orthodontics. Participants elevated the need for stronger industry-academic research partnerships to leverage knowledge gained from large datasets with treatment approaches and outcomes; systematizing the potential of big data including through multi-omics and artificial intelligence approaches; refining the genotype: phenotype correlation to create biotechnology that will rescue inherited dental and craniofacial defects; evolving studies of tooth movement, sleep apnoea and TMD treatment to accurately measure dysfunction and treatment successes; and maximizing the integration of newer orthodontic devices and digital workflows. CONCLUSIONS: Technological advances combined with those in biomedicine and machine learning are rapidly changing the delivery of health care including that in orthodontics. These advances promise to lead to enhanced customization, efficiencies and outcomes of patient care in routine orthodontic problems and in severe craniofacial problems, OSA and TMD.

Whole-exome sequencing identified a variant in EFTUD2 gene in establishing a genetic diagnosis.

OBJECTIVES: Craniofacial anomalies are complex and have an overlapping phenotype. Mandibulofacial Dysostosis and Oculo-Auriculo-Vertebral Spectrum are conditions that share common craniofacial phenotype and present a challenge in arriving at a diagnosis. In this report, we present a case of female proband who was given a differential diagnosis of Treacher Collins syndrome or Hemifacial Microsomia without certainty. Prior genetic testing reported negative for 22q deletion and FGFR screenings. The objective of this study was to demonstrate the critical role of whole-exome sequencing in establishing a genetic diagnosis of the proband. SETTING AND SAMPLE POPULATION: The participants were 14½-year-old affected female proband/parent trio. MATERIALS AND METHODS: Proband/parent trio were enrolled in the study. Surgical tissue sample from the proband and parental blood samples were collected and prepared for whole-exome sequencing. Illumina HiSeq 2500 instrument was used for sequencing (125 nucleotide reads/84X coverage). Analyses of variants were performed using custom-developed software, RUNES and VIKING. RESULTS: Variant analyses following whole-exome sequencing identified a heterozygous de novo pathogenic variant, c.259C>T (p.Gln87*), in EFTUD2 (NM_004247.3) gene in the proband. Previous studies have reported that the variants in EFTUD2 gene were associated with Mandibulofacial Dysostosis with Microcephaly. CONCLUSION: Patients with facial asymmetry, micrognathia, choanal atresia and microcephaly should be analyzed for variants in EFTUD2 gene. Next-generation sequencing techniques, such as whole-exome sequencing offer great promise to improve the understanding of etiologies of sporadic genetic diseases.