scholarly journals A Synonymous Exonic Splice Silencer Variant in IRF6 as a Novel and Cryptic Cause of Non-Syndromic Cleft Lip and Palate

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 903
Author(s):  
Beau Sylvester ◽  
Frederick Brindopke ◽  
Akiko Suzuki ◽  
Melissa Giron ◽  
Allyn Auslander ◽  
...  
Keyword(s):  
Splice Site ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Donor Site ◽  
Regulatory Region ◽  
Ectopic Expression ◽  
Incomplete Penetrance ◽  
Exonic Splice Silencer ◽  
Exonic Splice ◽  
Synonymous Variant

Missense, nonsense, splice site and regulatory region variants in interferon regulatory factor 6 (IRF6) have been shown to contribute to both syndromic and non-syndromic forms of cleft lip and/or palate (CL/P). We report the diagnostic evaluation of a complex multigeneration family of Honduran ancestry with a pedigree structure consistent with autosomal-dominant inheritance with both incomplete penetrance and variable expressivity. The proband’s grandmother bore children with two partners and CL/P segregates on both sides of each lineage. Through whole-exome sequencing of five members of the family, we identified a single shared synonymous variant, located in the middle of exon 7 of IRF6 (p.Ser307Ser; g.209963979 G>A; c.921C>T). The variant was shown to segregate in the seven affected individuals and through three unaffected obligate carriers, spanning both sides of this pedigree. This variant is very rare, only being found in three (all of Latino ancestry) of 251,352 alleles in the gnomAD database. While the variant did not create a splice acceptor/donor site, in silico analysis predicted it to impact an exonic splice silencer element and the binding of major splice regulatory factors. In vitro splice assays supported this by revealing multiple abnormal splicing events, estimated to impact >60% of allelic transcripts. Sequencing of the alternate splice products demonstrated the unmasking of a cryptic splice site six nucleotides 5′ of the variant, as well as variable utilization of cryptic splice sites in intron 6. The ectopic expression of different splice regulatory proteins altered the proportion of abnormal splicing events seen in the splice assay, although the alteration was dependent on the splice factor. Importantly, each alternatively spliced mRNA is predicted to result in a frame shift and prematurely truncated IRF6 protein. This is the first study to identify a synonymous variant as a likely cause of NS-CL/P and highlights the care that should be taken by laboratories when considering and interpreting variants.

Iliac Crest Donor Site for Children With Cleft Lip and Palate Undergoing Alveolar Bone Grafting

2016 ◽  
Vol 27 (3) ◽  
pp. 598-601 ◽  
Author(s):  
Jonathan Wheeler ◽  
Megan Sanders ◽  
Stanley Loo ◽  
Zac Moaveni ◽  
Glenn Bartlett ◽  
...  
Keyword(s):  
Bone Grafting ◽  
Cleft Lip ◽  
Iliac Crest ◽  
Cleft Lip And Palate ◽  
Alveolar Bone ◽  
Donor Site ◽  
Alveolar Bone Grafting

Alveolar Bone Grafting: Donor Site Review of 100 Consecutive Cases in Cleft Lip and Palate

2017 ◽  
Vol 54 (2) ◽  
pp. 137-141 ◽  
Author(s):  
Kavit Amin ◽  
Wee Sim Khor ◽  
Anais Rosich-Medina ◽  
Victoria Beale
Keyword(s):  
Bone Grafting ◽  
Cleft Lip ◽  
Iliac Crest ◽  
Cleft Lip And Palate ◽  
Alveolar Bone ◽  
Donor Site ◽  
Oral Morphine ◽  
Unknown Origin ◽  
Pyrexia Of Unknown Origin ◽  
Alveolar Bone Grafting

Objective Review of patients who underwent secondary alveolar bone grafting for total inpatient stay, postoperative complications, and postoperative analgesic requirements. Design Retrospective analysis of medical records. Setting Tertiary care center as part of a regional cleft lip and palate network. Patients All patients who underwent secondary alveolar bone grafting from the iliac crest. Interventions Local anesthetic was infiltrated overlying the anterior iliac crest. An incision was made to conform to the future skin crease and avoid muscle dissection. The cartilaginous cap was incised and raised, and cancellous bone was then harvested. The cavity was packed with hemostatic cellulose and closed in layers. All patients received postoperative antibiotics. All patients were prescribed regular paracetamol (acetaminophen) and ibuprofen if there were no contraindications. Oral morphine was available when requested. Main Outcome Measures Length of stay, postoperative analgesic requirements, and postoperative donor site and oral complications. Results From 100 consecutive patients, 92 (92%) of the patients were discharged the day after surgery; one (1%) patient required four nights of monitoring for postoperative pyrexia of unknown origin. All patients received regular paracetamol, and the majority (86%) did not require oral morphine. Complications included seroma (4%), superficial donor site abscess (1%), postoperative pyrexia of unknown origin (2%), gingival bleeding (2%), and oral infection (2%). Conclusion The findings suggest that donor site pain may be well controlled with simple, regular analgesia. Children tolerated this procedure well and were safely discharged the day after surgery. Alveolar bone grafting from the iliac crest was found to have low complication rates.

Bilateral Superiorly Based Full-Thickness Nasolabial Island Flaps for Closure of Residual Anterior Palatal Fistulas in an Unoperated Elderly Patient

2003 ◽  
Vol 40 (1) ◽  
pp. 91-99 ◽  
Author(s):  
A.R. Erçöçen ◽  
S. Yilmaz ◽  
M. Saydam
Keyword(s):  
Elderly Patient ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Donor Site ◽  
Donor Site Morbidity ◽  
Retrograde Flow ◽  
Full Thickness ◽  
Knowledge Based ◽  
Straight Line ◽  
Pharyngeal Flap

Objective Unoperated bilateral complete cleft lip and palate in an adult or elderly patient is seen rarely, and the existence of unoperated clefts is a result of unfavorable economic and social circumstances. We report an unoperated 65-year-old patient with bilateral complete cleft lip and palate and present our preference for the surgical management. Interventions Repair of the bilateral complete cleft lip and palate was successfully carried out using straight-line closure for the bilateral cleft lip and two-flap pushback palatoplasty with superiorly based lateral port control pharyngeal flap for the wide cleft palate at the first stage, and large residual anterior palatal fistulas were closed using bilateral superiorly based (retrograde flow) full-thickness nasolabial island flaps at the second stage. Conclusions To our knowledge based on a review of the literature, this is the first report of an elderly patient with bilateral complete cleft lip and palate and the first application of bilateral superiorly based (retrograde flow) full-thickness nasolabial island flaps for closure of large residual anterior palatal fistulas or alveolar clefts. The bilateral superiorly based (retrograde flow) full-thickness nasolabial island flap may be a good solution in large anterior palatal defects using unilaterally or bilaterally in a single stage with minimal donor site morbidity, in which there is not enough tissue for local repair or if previous attempts are unsuccessful.

Morbidity of iliac crest donor site in cleft lip and palate infants

2000 ◽  
Vol 23 (7) ◽  
pp. 366-368 ◽  
Author(s):  
I. T. Jackson ◽  
J. Yousefi ◽  
R. Yavuzer ◽  
G. Yavuzer
Keyword(s):  
Cleft Lip ◽  
Iliac Crest ◽  
Cleft Lip And Palate ◽  
Donor Site

scholarly journals A novel synonymous ABCA3 variant identified in a Chinese family with lethal neonatal respiratory failure

2021 ◽  
Author(s):  
Weifeng Zhang ◽  
Zhiyong Liu ◽  
Yiming Lin ◽  
Ruiquan Wang ◽  
Jinglin Xu ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Splice Site ◽  
Quantitative Polymerase Chain Reaction ◽  
Donor Site ◽  
Splice Donor Site ◽  
Patient Specific ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Synonymous Variant

Abstract Background: Lethal respiratory failure is mostly caused by pulmonary surfactant (PS) deficiency and is the main cause of neonatal death. PS metabolism dysfunction caused by mutations in the ABCA3 gene is a rare disease with very poor prognosis. However, the underlying mechanism of genetic mutations causing PS metabolism dysfunction has not been fully elucidated yet. This study aimed to identify the genetic features in a family with lethal respiratory failure.Methods: We studied members of a two-generation Chinese family including a female proband, her parents, her identical twin sister, and her older sister. Whole exome sequencing (WES), Sanger sequencing, and real-time quantitative polymerase chain reaction （PCR） were used to identify and validate the ABCA3 mutation. The potential pathogenicity of the identified synonymous variant was predicted using splice site algorithms (dbscSNV11_AdaBoost, dbscSNV11_RandomForest, and HSF).Results: All patients showed severe respiratory distress, which could not be relieved by mechanical ventilation, supplementation of surfactants, or steroid therapy, and died at an early age. Molecular genetic analysis revealed that the patients had compound heterozygous ABCA3 variants, including a novel synonymous variant c.G873A (p.Lys291Lys) in exon 8 derived from the mother and a heterozygous deletion of exons 4-7 derived from the father. The synonymous variant was consistently predicted to be a cryptic splice donor site that may lead to aberrant splicing of the pre-mRNA by three different splice site algorithms. The deletion of exons 4-7 of the ABCA3 gene was determined to be a loss-of-function pathogenic variant.Conclusions: We identified a novel synonymous variant and a deletion in the ABCA3 gene that may be responsible for the pathogenesis in patients in this family. These results enrich the known mutational spectrum of the ABCA3 gene. Moreover, the study of ABCA3 mutations is helpful for the realization of patient-specific therapies.

Treating Velopharyngeal Inadequacy Using Bilateral Buccal Flap Revision Palatoplasty

2019 ◽  
Vol 4 (5) ◽  
pp. 878-892
Author(s):  
Joseph A. Napoli ◽  
Linda D. Vallino
Keyword(s):  
Systematic Review ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
A Priori ◽  
Sufficient Evidence ◽  
Obstructive Sleep ◽  
Before And After ◽  
Buccal Flap

Purpose The 2 most commonly used operations to treat velopharyngeal inadequacy (VPI) are superiorly based pharyngeal flap and sphincter pharyngoplasty, both of which may result in hyponasal speech and airway obstruction. The purpose of this article is to (a) describe the bilateral buccal flap revision palatoplasty (BBFRP) as an alternative technique to manage VPI while minimizing these risks and (b) conduct a systematic review of the evidence of BBFRP on speech and other clinical outcomes. A report comparing the speech of a child with hypernasality before and after BBFRP is presented. Method A review of databases was conducted for studies of buccal flaps to treat VPI. Using the principles of a systematic review, the articles were read, and data were abstracted for study characteristics that were developed a priori. With respect to the case report, speech and instrumental data from a child with repaired cleft lip and palate and hypernasal speech were collected and analyzed before and after surgery. Results Eight articles were included in the analysis. The results were positive, and the evidence is in favor of BBFRP in improving velopharyngeal function, while minimizing the risk of hyponasal speech and obstructive sleep apnea. Before surgery, the child's speech was characterized by moderate hypernasality, and after surgery, it was judged to be within normal limits. Conclusion Based on clinical experience and results from the systematic review, there is sufficient evidence that the buccal flap is effective in improving resonance and minimizing obstructive sleep apnea. We recommend BBFRP as another approach in selected patients to manage VPI. Supplemental Material https://doi.org/10.23641/asha.9919352

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