Genomic imbalances in craniofacial microsomia

2020 ◽  
Vol 184 (4) ◽  
pp. 970-985 ◽  
Author(s):  
Samira Spineli‐Silva ◽  
Ilária C. Sgardioli ◽  
Ana P. Santos ◽  
Luna L. Bergamini ◽  
Isabella L. Monlleó ◽  
...  
Keyword(s):  
Genomic Imbalances ◽  
Craniofacial Microsomia

scholarly journals Genomic imbalances in the placenta are associated with poor fetal growth

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Giulia F. Del Gobbo ◽  
Yue Yin ◽  
Sanaa Choufani ◽  
Emma A. Butcher ◽  
John Wei ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Sex Chromosome ◽  
Copy Number Variants ◽  
Placental Insufficiency ◽  
Potential Contribution ◽  
Genomic Imbalances ◽  
Significant Difference ◽  
Underlying Causes ◽  
Risk Of Disease ◽  
The Impact

Abstract Background Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth. Methods We used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR. Results Aneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5–107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3. Conclusions We conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.

Novel risk factors for craniofacial microsomia and assessment of their utility in clinic diagnosis

2021 ◽  
Author(s):  
Xiaopeng Xu ◽  
Bingqing Wang ◽  
Zhuoyuan Jiang ◽  
Qi Chen ◽  
Ke Mao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Environmental Risk ◽  
Neural Crest Cell ◽  
Polygenic Risk Score ◽  
Expression Change ◽  
Ontology Term ◽  
Environmental Threats ◽  
Craniofacial Microsomia ◽  
Hypoxic Environment ◽  
Term Enrichment

Abstract Craniofacial microsomia (CFM, OMIM%164 210) is one of the most common congenital facial abnormalities worldwide, but it’s genetic risk factors and environmental threats are poorly investigated, as well as their interaction, making the diagnosis and prenatal screening of CFM impossible. We perform a comprehensive association study on the largest CFM cohort of 6074 samples. We identify 15 significant (P < 5 × 10−8) associated genomic loci (including eight previously reported) and decipher 107 candidates based on multi-omics data. Gene Ontology term enrichment found that these candidates are mainly enriched in neural crest cell (NCC) development and hypoxic environment. Single-cell RNA-seq data of mouse embryo demonstrate that nine of them show dramatic expression change during early cranial NCC development whose dysplasia is involved in pathogeny of CFM. Furthermore, we construct a well-performed CFM risk-predicting model based on polygenic risk score (PRS) method and estimate seven environmental risk factors that interacting with PRS. Single-nucleotide polymorphism-based PRS is significantly associated with CFM [P = 7.22 × 10−58, odds ratio = 3.15, 95% confidence interval (CI) 2.74–3.63], and the top fifth percentile has a 6.8-fold CFM risk comparing with the 10th percentile. Father’s smoking increases CFM risk as evidenced by interaction parameter of −0.324 (95% CI −0.578 to −0.070, P = 0.011) with PRS. In conclusion, the newly identified risk loci will significantly improve our understandings of genetics contribution to CFM. The risk prediction model is promising for CFM prediction, and father’s smoking is a key environmental risk factor for CFM through interacting with genetic factors.

scholarly journals A critical analysis of the management of craniofacial microsomia

2018 ◽  
Vol 1 (1) ◽  
pp. 65-78
Author(s):  
David John David AC
Keyword(s):  
Distraction Osteogenesis ◽  
Critical Analysis ◽  
Long Term Results ◽  
New Techniques ◽  
Technological Advances ◽  
Craniofacial Microsomia ◽  
New Procedures

Distraction Osteogenesis was introduced into the management of Craniofacial Microsomia some decades ago. It assumed almost instant popularity without evidence of advantage. Poor long-term results and high rates of relapse prove this technique is unsuitable for all but the most carefully selected patients. While innovation and technological advances are to be celebrated, it is vital that new procedures are rigorously tested against current protocols. It is also imperative, that thorough knowledge of disease pathology and pathogenesis are applied against new procedures. It is the view of the author that many painful, useless operations would be avoided if surgeons better understood these key fundamentals. Furthermore, there must be clear guidelines for the introduction of new techniques and devices, and this must happen independently of manufacturers.

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