MRPL53, a New Candidate Gene for Orofacial Clefting, Identified Using an eQTL Approach.

A valuable approach to understand how individual and population genetic differences can predispose to disease is to assess the impact of genetic variants on cellular functions (e.g., gene expression) of cell and tissue types related to pathological states. To understand the genetic basis of nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility, a complex and highly prevalent congenital malformation, we searched for genetic variants with a regulatory role in a disease-related tissue, the lip muscle (orbicularis oris muscle [OOM]), of affected individuals. From 46 OOM samples, which are frequently discarded during routine corrective surgeries on patients with orofacial clefts, we derived mesenchymal stem cells and correlated the individual genetic variants with gene expression from these cultured cells. Through this strategy, we detected significant cis-eQTLs (i.e., DNA variants affecting gene expression) and selected a few candidates to conduct an association study in a large Brazilian cohort (624 patients and 668 controls). This resulted in the discovery of a novel susceptibility locus for NSCL/P, rs1063588, the best eQTL for the MRPL53 gene, where evidence for association was mostly driven by the Native American ancestry component of our Brazilian sample. MRPL53 (2p13.1) encodes a 39S protein subunit of mitochondrial ribosomes and interacts with MYC, a transcription factor required for normal facial morphogenesis. Our study illustrates not only the importance of sampling admixed populations but also the relevance of measuring the functional effects of genetic variants over gene expression to dissect the complexity of disease phenotypes.

Impact of rare variants in ARHGAP29 to the etiology of oral clefts: role of loss-of-function vs missense variants.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a prevalent, complex congenital malformation. Genome-wide association studies (GWAS) on NSCL/P have consistently identified association for the 1p22 region, in which ARHGAP29 has emerged as the main candidate gene. ARHGAP29 re-sequencing studies in NSCL/P patients have identified rare variants; however, their clinical impact is still unclear. In this study we identified 10 rare variants in ARHGAP29, including five missense, one in-frame deletion, and four loss-of-function (LoF) variants, in a cohort of 188 familial NSCL/P cases. A significant mutational burden was found for LoF (Sequence Kernel Association Test, p = 0.0005) but not for missense variants in ARHGAP29, suggesting that only LoF variants contribute to the etiology of NSCL/P. Penetrance was estimated as 59%, indicating that heterozygous LoF variants in ARHGAP29 confer a moderate risk to NSCL/P. The GWAS hits in IRF6 (rs642961) and 1p22 (rs560426 and rs4147811) do not seem to contribute to the penetrance of the phenotype, based on co-segregation analysis. Our data show that rare variants leading to haploinsufficiency of ARHGAP29 represent an important etiological clefting mechanism, and genetic testing for this gene might be taken into consideration in genetic counseling of familial cases.

[The anthropomorphic proportions of the face: an evaluation of the response to orthodontic surgical treatment of Angle class III]. / Proporzioni antropometriche del volto: valutazione della risposta al trattamento ortodontico-chirurgico delle terze classi.

The purpose of this investigation was: to examine the anthropometric facial presurgical and postsurgical indices of patients having a dento-skeletal class III malocclusion and who were treated with the orthodontic-surgical procedure. To evaluate the postsurgical response of the soft tissues, according to the type of approach: mandibular surgery or maxillo-mandibular surgery. To recognize, if it is possible, what indices are to be considered more involved in the esthetic change. Ninety pre and postoperative frontal photographs of 45 subjects were studied. The subjects were 32 females and 15 males who had a dento-skeletal class III malocclusion and who had undergone the orthodontic-surgical treatment (21 had sagittal bilateral mandibular osteotomy, 24 had sagittal bilateral mandibular osteotomy + Le Fort I). The photographs were taken with lips in repose, relaxed soft tissue and centric occlusion. The mean age of the patients was 23 years (ranging 16-35). The post-treatment follow-up went from 1 to 3 years. 11 frontal landmarks: n = nasion, sn = subnasale, sto = stomion, sl = sublabiale, gn = gnathion, go = gonion (bilateral), zy = zygoma (bilateral), ch = cheilion (bilateral) were recognized and 3 horizontal and 5 vertical measurements were taken: zygomatic width (zy-zy), mouth width (ch-ch), gonial width (go-go); face height (n-gn), lower face height (sn-gn), upper face height (n-sto), height of lower third of the face (sto-gn), medial vertical chin height (sl-gn). 11 pre and post-treatment facial indices were obtained from the ratio per cent of the measurements previously mentioned using the method of Farkas: Facial (n-gn-zy-zy), Mandible-face width (go-go/zy-zy), Upper face (n-sto/zy-zy), Mandible width-face height (go-go/n-gn), Mandibular (sto-gn/go-go), Mouth face width (ch-ch/zy-zy), Lower face-face height (sn-gn/n-gn), Mandible face height (sto-gn/n-gn), Mandible-upper face height (sto-gn/n-sto), Mandible-lower face height (sto-gn/sn-gn), Chin-face height (sl-gn/sn-gn). In each patient the mean values, with their standard deviations, were calculated according to the sex for each index. A different group of average values was calculated according to the sex and to the type of surgical approach; 17 females and 4 males underwent a mandibular setback osteotomy and 15 females and 9 males underwent a sagittal bilateral mandibular osteotomy + Le Fort I osteotomy.(ABSTRACT TRUNCATED AT 400 WORDS)

[Inclination of the temporomandibular eminence and craniomandibular disorders]. / Inclinazione dell'eminenza temporo-mandibolare e disordini cranio-mandibolari.

The articular eminence angle of 30 patients with TMJ dysfunctions was measured on cephalometric X-ray and compared with the joints of 30 patients without TMJ disorders. The inclination of the posterior slope of the articular eminence was 52.9 degrees with a mean difference compared to the control group of 1.7 degrees. The vertical parameters appeared of less importance than the antero-posterior to produce TMJ dysfunction. In the skeletal class II group a steeper inclination, with a mean difference compared to the control group of 8.6 degrees, was seen in the symptomatic patients. The study of this angle could have a diagnostic and prognostic utility in the treatment of dysfunctional class II malocclusions.