Phenotypes, Developmental Basis, and Genetics of Pierre Robin Complex

Perrine, Susan M. Motch; Wu, Meng; Holmes, Greg; Bjork, Bryan C.; Jabs, Ethylin Wang; Richtsmeier, Joan T.

doi:10.3390/jdb8040030

Cited by 13 publications

(18 citation statements)

References 109 publications

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Section: Resultsmentioning

confidence: 99%

“…We first examined known craniofacial disorder associations of genes that are downregulated upon SOX9 depletion, also considering the relation to PRS, which is caused by heterozygous LoF coding or noncoding mutations at the SOX9 locus. However, mutations in genes other than SOX9 have also been associated with PRS-like micrognathia phenotypes in either humans or mice (reviewed in 46 ). We observed that SOX9-dependent genes associated with dominant (likely more dosage-sensitive) craniofacial disorders unrelated to PRS had lower ED50 values than genes not associated with craniofacial disorders, while genes associated with recessive (likely less dosage-sensitive) disorders had higher ED50 values (Fig.…”

Section: Ro Chondrogenic Genesmentioning

confidence: 99%

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Precise modulation of transcription factor levels reveals drivers of dosage sensitivity

Naqvi

Kim

Hoskens

et al. 2022

Preprint

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Transcriptional regulation displays extensive robustness, but human genetics indicate sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, which are lacking to date. TFs play central roles in both normal-range and disease-associated variation in facial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitors and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin Sequence, PRS). We found that most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses predict gene expression responses. Sensitive REs and genes underlie the vulnerability of chondrogenesis and PRS-like craniofacial shape variation to SOX9 dosage perturbation. We propose that such REs and genes drive the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.

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Section: Resultsmentioning

confidence: 99%

Section: Ro Chondrogenic Genesmentioning

confidence: 99%

Precise modulation of transcription factor levels reveals drivers of dosage sensitivity

Naqvi

Kim

Hoskens

et al. 2022

Preprint

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“…ERK1/2 is the main effector of FGF signaling [ 99 , 100 ]. Disruption of the ERK/MAPK pathway in neural crest cells of Wnt1-Cre ; Erk2 fl/fl mice causes cleft palate, malformed tongue, micrognathia and mandibular asymmetry [ 101 ], similar to the Pierre Robin complex, triad of mandibular dysmorphology, glossoptosis, and respiratory obstruction with or without cleft palate [ 102 ]. However, when Erk2 deletion is restricted to the palatal mesenchyme in Osr2-Cre ; Erk2 fl/fl mice, cleft palate was not observed, indicating that the cleft palate in Wnt1-Cre ; Erk2 fl/fl mice is a secondary defect.…”

Section: Molecular and Cellular Mechanismsmentioning

confidence: 99%

Cleft Palate in Apert Syndrome

Willie

Holmes

Jabs

et al. 2022

JDB

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Apert syndrome is a rare genetic disorder characterized by craniosynostosis, midface retrusion, and limb anomalies. Cleft palate occurs in a subset of Apert syndrome patients. Although the genetic causes underlying Apert syndrome have been identified, the downstream signaling pathways and cellular mechanisms responsible for cleft palate are still elusive. To find clues for the pathogenic mechanisms of palatal defects in Apert syndrome, we review the clinical characteristics of the palate in cases of Apert syndrome, the palatal phenotypes in mouse models, and the potential signaling mechanisms involved in palatal defects. In Apert syndrome patients, cleft of the soft palate is more frequent than of the hard palate. The length of the hard palate is decreased. Cleft palate is associated most commonly with the S252W variant of FGFR2. In addition to cleft palate, high-arched palate, lateral palatal swelling, or bifid uvula are common in Apert syndrome patients. Mouse models of Apert syndrome display palatal defects, providing valuable tools to understand the underlying mechanisms. The mutations in FGFR2 causing Apert syndrome may change a signaling network in epithelial–mesenchymal interactions during palatogenesis. Understanding the pathogenic mechanisms of palatal defects in Apert syndrome may shed light on potential novel therapeutic solutions.

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“…Most of the cleft lip and/or palate are nonsyndromic and multifactorial (Jakobsen et al, 2007). Pierre Robin sequence (PRS) is a clinical entity characterized by micrognathia/retrognathia leading to glossoptosis, respiratory obstruction, and a U-shaped cleft palate (Hanson and Smith, 1975; Motch Perrine et al, 2020). Microganthia in PRS can be caused by extrinsic, intrinsic, or neuromuscular abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Next Generation Sequencing and Cytogenetic Based Evaluation of Indian Pierre Robin Sequence Families Reveals CNV Regions of Modest Effect and a NovelLOXL3Mutation

Sood

Shamim

Kharbanda

et al. 2021

The Cleft Palate-Craniofacial Journal

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Background Pierre Robin Sequence (PRS) affects approximately 1 per 8500 to 14000 new-borns worldwide. Although the clinical entity is well deﬁned, the pathogenesis of PRS is debated. The present study aims to understand the contribution of genomic imbalances and genetic variants in patients clinically diagnosed of PRS. Methodology A total of 7 independent patients with nonsyndromic PRS thoroughly evaluated by a medical geneticist at a tertiary care hospital, were included in the study. Blood samples were collected from these patients and their family members. Array CGH was performed on all 7 patients and their respective family members for detection of underlying cytogenetic defects. Whole exome sequencing (WES) was performed for 5 families to capture single nucleotide variants or small indels. Results Cytogenetic analyses did not detect any previously reported gross chromosomal aberrations for PRS in the patient cohort. However, copy number variations (CNVs) of size <1 Mb were detected in patients which may have implications in PRS. The present study provided evidence for the occurrence of de novo deletions at 7p14.1 locus in PRS patients: further validating the candidate loci susceptibility in oral clefts. WES data identified LOXL3 as candidate gene, carrying novel deleterious variant, which is suggestive of the role of point mutations in the pathogenesis of PRS. Conclusion The present study offered considerable insight into the contribution of cytogenetic defects and novel point mutation in the etiology of nonsyndromic PRS. Studies comprising large number of cases are required to fully elucidate the genetic mechanisms underlying the PRS phenotype.

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Phenotypes, Developmental Basis, and Genetics of Pierre Robin Complex

Cited by 13 publications

References 109 publications

Precise modulation of transcription factor levels reveals drivers of dosage sensitivity

Precise modulation of transcription factor levels reveals drivers of dosage sensitivity

Cleft Palate in Apert Syndrome

Next Generation Sequencing and Cytogenetic Based Evaluation of Indian Pierre Robin Sequence Families Reveals CNV Regions of Modest Effect and a NovelLOXL3Mutation

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