Radiographic and clinical outcomes of muenster and sugar tong splints for distal radius fractures: a comparative study.

BACKGROUND: Non-operative management is typically indicated for extra-articular distal radius fractures. Conservative treatments such as Sugar tong splints (STs) and Muenster splints (MUs) are commonly used. However, there is limited research and outcome data comparing the two splint types. Therefore, this study aimed to investigate and compare the radiographic and clinical outcomes of treatment using STs and MUs. METHODS: In this retrospective comparative study, we aimed to evaluate and compare the radiographic and clinical outcomes of STs and MUs for the treatment of distal radius fractures. The study included 64 patients who underwent closed reduction (CR) in the emergency room and were treated with either STs or MUs splints (STs group: n = 38, MUs group: n = 26). Initial X-rays, post-CR X-rays, and last outpatient follow-up X-rays were evaluated. Radial height (RH), ulnar variance (UV), radial inclination (RI), and volar tilt (VT) were measured by a blinded investigator. The Quick DASH form was applied to measure patients' satisfaction after treatments. RESULTS: There were no significant differences in baseline characteristics, initial radiographic measurements, or radiographic measurements immediately after CR between the two groups. However, the overall radiological values deteriorated to some degree in both groups compared to the post-CR images. Furthermore, using a paired test, the STs group showed significant differences in RH and RI, and the MUs group showed significant differences in RH and UV between the last follow-up and post-CR images. CONCLUSIONS: The study concluded that there was no difference in clinical outcomes between the two splint types. However, both STs and MUs groups showed reduced radiographic parameters, and the MUs group showed a significant reduction of RH and UV in the treatment of distal radius fractures. LEVEL OF EVIDENCE: Level IV; Retrospective Comparison; Treatment Study.

Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape.

The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up analyses indicate that these loci overlap with genomic risk loci for sagittal craniosynostosis, show elevated activity cranial neural crest cells, are enriched for processes related to skeletal development, and are shared with the face and brain. We present supporting evidence of regional localization for several of the identified genes based on expression patterns in the cranial vault bones of E15.5 mice. Overall, our study provides a comprehensive overview of the genetics underlying normal-range cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.

Sex Differences in Velopharyngeal Anatomy of 9- and 10-Year-Old Children.

OBJECTIVE: Understanding the normal anatomy of velopharyngeal (VP) mechanism and the emergence of sexual dimorphism provides valuable insights into differences of VP anatomy among males and females. The purpose of this study is to examine sex differences in VP anatomy in a large data set of 3,248 9- and 10-year-old children. METHOD: Static three-dimensional magnetic resonance imaging was used to compare five VP characteristics including velar length, velar thickness, effective velar length, levator veli palatini muscle length, and pharyngeal depth between age-matched males (n = 1,670) and females (n = 1,578). Additionally, these dimensions were used to determine the VP ratio and effective VP ratio. RESULTS: Males showed significantly larger dimensions for all VP distances and significantly lower ratios of velar length and effective velar length to pharyngeal depth (p < .05). The magnitude of these effect sizes was small to medium, with Cohen's d values ranging from 0.12 to 0.63. Additionally, the VP ratio and effective VP ratio are lower among males compared to females (p < .05). CONCLUSIONS: Results suggest the presence of sexual dimorphism in the VP mechanism among 9- and 10-year-old children. These findings emphasize the necessity of using different normative data for males and females when making comparisons to patients with cleft palate.

Comparison of a Cryopneumatic Compression Device and Ice Packs for Cryotherapy Following Anterior Cruciate Ligament Reconstruction.

Background: The purpose of the current study was to evaluate and compare the effectiveness of a cryopneumatic compression device with that of standard ice packs following arthroscopic anterior cruciate ligament (ACL) reconstruction, with a primary focus on early postoperative pain. Methods: Participants were divided into two groups: cryopneumatic compression device group (CC group) and standard ice pack group (IP group). Patients in the CC Group (28 patients) received a cryopneumatic compression device (CTC-7, Daesung Maref) treatment, while patients in the IP group (28 patients) received standard ice pack cryotherapy postoperatively. All cryotherapy was applied three times (every 8 hours) per day for 20 minutes until discharge (postoperative day 7). Pain scores were assessed preoperatively and at 4, 7, and 14 days after surgery, and the primary outcome for analysis was pain at postoperative day 4 assessed using a visual analog scale (VAS). Other variables were opioid and rescue medication use, knee and thigh circumferences, postoperative drainage, and joint effusion quantified by a three-dimensional magnetic resonance imaging (MRI) reconstruction model. Results: The mean pain VAS score and difference in VAS relative to the preoperative measurements for postoperative day 4 were significantly lower in the CC group than in the IP group (p = 0.001 and p = 0.007, respectively). The sum of postoperative drainage and effusion quantified by MRI showed a significant reduction of postoperative effusion in the CC group compared to the IP group (p = 0.015). The average total rescue medication consumption was comparable between the two groups. Circumferential measurements at days 7 and 14 postoperatively relative to those at day 4 (index day) demonstrated no significant differences between the groups. Conclusions: Compared to standard ice packs, application of cryopneumatic compression was associated with a significant reduction in VAS pain scores and joint effusion during the early postoperative period following ACL reconstruction.

Surgical Trends of Shoulder Arthroplasty: Nationwide Epidemiologic Study in South Korea.

Background: The aim of this study was to determine the nationwide shoulder arthroplasty trends in South Korea based on an analysis of nationwide data acquired from the Korean Health Insurance Review and Assessment Service (HIRA). Methods: We analyzed a nationwide database acquired from the HIRA that covered 2008 to 2017. International Classification of Diseases, 10th Revision (ICD-10) codes and procedure codes were used to identify patients who underwent shoulder arthroplasty, including total shoulder arthroplasty (TSA), hemiarthroplasty (HA), and revision shoulder arthroplasty. Results: From 2008 to 2017, a total of 19,831 shoulder arthroplasties were performed; there were 16,162 TSAs and 3,669 hemiarthroplasties. During the 10-year study period, there was an exponential increase in the incidence of TSA (from 513 cases in 2008 to 3,583 cases in 2017), while the number of hemiarthroplasties remained steady. The most common diagnoses for TSA were rotator cuff tears (6,304 cases, 39.0%) and osteoarthritis (6,589 cases, 40.8%) for all 9 years. Osteoarthritis was the most common reason for TSA during the first 3 years (2008-2010), but rotator cuff tears ultimately surpassed osteoarthritis during the last 3 years (2015-2017). HA was performed to treat proximal humerus fracture (1,770 cases, 48.2%) and osteoarthritis (774 cases, 21.1%). In terms of hospital types, the rate of TSA in hospitals with 30-100 inpatient beds increased from 21.83% to 46.27%, while the rates of the other types of surgery decreased. A total of 430 revision surgeries were performed during the study period, and infection (152 cases, 35.3%) was the most common reason for revision surgery. Conclusions: Overall, the total count and incidence of TSA, unlike HA, increased rapidly between 2008 and 2017 in South Korea. Moreover, at the end of the study period, nearly half of the TSAs were performed in small hospitals (30 to 100 beds). Rotator cuff tears were the leading cause of TSA at the end of the study period. These findings revealed an explosive increase in reverse TSA surgery.

Bent pinkies: Quantifying fifth finger clinodactyly in a sample of U.S. adults.

Mild curvature of the fifth finger (or clinodactyly) is a relatively common trait. While severe forms can cause functional impairment and are a feature of certain congenital syndromes, mild clinodactyly is considered a minor morphological variant. Despite exhibiting continuous variation, clinodactyly is rarely treated as a quantitative trait. Consequently, the degree of fifth finger curvature in the general population and the factors that impact this curvature are not well understood. In the present study, we measured fifth finger curvature in a sample of 1,295 U.S. adults and investigated the role of sex, age and body size. We found that clinodactyly exhibited a non-normal distribution. All participants displayed some degree of curvature, but it tended to be slight with an overall mean of 3.68 degrees (median: 3.58 degrees). In only 0.8% of cases did the curvature exceed the nominal 10-degree threshold for clinically meaningful clinodactyly. We did not find statically significant sex differences. Further, there was no meaningful relationship with height and only a weak positive relationship with age. We found that clinodactyly showed asymmetry; the curvature was greater on the left than on the right fifth finger (p < 2.2e-16), but this was not influenced by sex, age, or height. These results suggest the possibility that the kind of ubiquitous mild clinodactyly observed in the general population may be etiologically distinct from more rare and severe forms of the condition.

U.S. Adult Perspectives on Facial Images, DNA, and Other Biometrics.

Applications of biometrics in various societal contexts have been increasing in the United States, and policy debates about potential restrictions and expansions for specific biometrics (such as facial recognition and DNA identification) have been intensifying. Empirical data about public perspectives on different types of biometrics can inform these debates. We surveyed 4048 adults to explore perspectives regarding experience and comfort with six types of biometrics; comfort providing biometrics in distinct scenarios; trust in social actors to use two types of biometrics (facial images and DNA) responsibly; acceptability of facial images in eight scenarios; and perceived effectiveness of facial images for five tasks. Respondents were generally comfortable with biometrics. Trust in social actors to use biometrics responsibly appeared to be context specific rather than dependent on biometric type. Contrary to expectations given mounting attention to dataveillance concerns, we did not find sociodemographic factors to influence perspectives on biometrics in obvious ways. These findings underscore a need for qualitative approaches to understand the contextual factors that trigger strong opinions of comfort with and acceptability of biometrics in different settings, by different actors, and for different purposes and to identify the informational needs relevant to the development of appropriate policies and oversight.

Heritability Analysis in Twins Indicates a Genetic Basis for Velopharyngeal Morphology.

The velopharyngeal mechanism is comprised of several muscular components that act in a coordinated manner to control airflow through the nose and mouth. Proper velopharyngeal function is essential for normal speech, swallowing, and breathing. The genetic basis of normal-range velopharyngeal morphology is poorly understood. The purpose of this study was to estimate the heritability of velopharyngeal dimensions.We measured five velopharyngeal variables (velar length, velar thickness, effective velar length, levator muscle length and pharyngeal depth) from MRIs of 155 monozygotic and 208 dizygotic twin pairs and then calculated heritability for these traits using a structural equation modeling approach.The heritability estimates were statistically significant (95% confidence intervals excluded zero) and ranged from 0.19 to 0.46. There was also evidence of significant genetic correlations between pairs of traits, pointing to the influence of common genetic effects.These results indicate that genetic factors influence variation in clinically relevant velopharyngeal structures.

Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study.

Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the ß-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10−6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes.

A survey of U.S. public perspectives on facial recognition technology and facial imaging data practices in health and research contexts.

Facial imaging and facial recognition technologies, now common in our daily lives, also are increasingly incorporated into health care processes, enabling touch-free appointment check-in, matching patients accurately, and assisting with the diagnosis of certain medical conditions. The use, sharing, and storage of facial data is expected to expand in coming years, yet little is documented about the perspectives of patients and participants regarding these uses. We developed a pair of surveys to gather public perspectives on uses of facial images and facial recognition technologies in healthcare and in health-related research in the United States. We used Qualtrics Panels to collect responses from general public respondents using two complementary and overlapping survey instruments; one focused on six types of biometrics (including facial images and DNA) and their uses in a wide range of societal contexts (including healthcare and research) and the other focused on facial imaging, facial recognition technology, and related data practices in health and research contexts specifically. We collected responses from a diverse group of 4,048 adults in the United States (2,038 and 2,010, from each survey respectively). A majority of respondents (55.5%) indicated they were equally worried about the privacy of medical records, DNA, and facial images collected for precision health research. A vignette was used to gauge willingness to participate in a hypothetical precision health study, with respondents split as willing to (39.6%), unwilling to (30.1%), and unsure about (30.3%) participating. Nearly one-quarter of respondents (24.8%) reported they would prefer to opt out of the DNA component of a study, and 22.0% reported they would prefer to opt out of both the DNA and facial imaging component of the study. Few indicated willingness to pay a fee to opt-out of the collection of their research data. Finally, respondents were offered options for ideal governance design of their data, as "open science"; "gated science"; and "closed science." No option elicited a majority response. Our findings indicate that while a majority of research participants might be comfortable with facial images and facial recognition technologies in healthcare and health-related research, a significant fraction expressed concern for the privacy of their own face-based data, similar to the privacy concerns of DNA data and medical records. A nuanced approach to uses of face-based data in healthcare and health-related research is needed, taking into consideration storage protection plans and the contexts of use.

Reproducibility and Accuracy of Pelvic Tilt in Predicting the Difference Between Pelvic Incidence and Lumbar Lordosis Value.

OBJECTIVE: We investigated the pelvic morphologic factors that determine the degree of pelvic incidence (PI)-lumbar lordosis (LL) mismatch. METHODS: Overall, 306 patients were included. The regional and global sagittal parameters were measured. Linear regression analyses were performed for 4 pelvic parameters and PI-LL mismatch. E1 and E2 were defined as linear regression equations between pelvic tilt (PT) and PI-LL mismatch and PI and PI-LL mismatch, respectively. The patients were categorized by cluster analysis using the hierarchal method for the 4 pelvic parameters. RESULTS: E1 and E2 showed statistical significance; however, the coefficient of determination of E1 was higher than that of E2 (R2 = 0.675 vs. 0.238; P < 0.01). Sex, LL, E1, and E2 showed significant differences in the regional parameters. The T1 pelvic angle (TPA), spinosacral angle (SSA), and incidence angle of inflection points (IAIPs) showed significant differences in global parameters (P < 0.01). The IAIPs and TPA were low in the anteverted pelvis group and high in the retroverted pelvis group (P < 0.001). The SSA was low in the small pelvis group and high in the large pelvis group (P < 0.001). The proportion of women in the large pelvis group (93%) was significantly higher than that in the other groups (P < 0.01). CONCLUSIONS: The individual differences between the PI and LL values can be more accurately determined using the individual PT, and the optimal PT amount will differ depending on the pelvis shape. The increase in the TPA and IAIPs corresponded to the PT, and the SSA increased in accordance with the pelvic size.

PRICKLE1 × FOCAD Interaction Revealed by Genome-Wide vQTL Analysis of Human Facial Traits.

The human face is a highly complex and variable structure resulting from the intricate coordination of numerous genetic and non-genetic factors. Hundreds of genomic loci impacting quantitative facial features have been identified. While these associations have been shown to influence morphology by altering the mean size and shape of facial measures, their effect on trait variance remains unclear. We conducted a genome-wide association analysis for the variance of 20 quantitative facial measurements in 2,447 European individuals and identified several suggestive variance quantitative trait loci (vQTLs). These vQTLs guided us to conduct an efficient search for gene-by-gene (G × G) interactions, which uncovered an interaction between PRICKLE1 and FOCAD affecting cranial base width. We replicated this G × G interaction signal at the locus level in an additional 5,128 Korean individuals. We used the hypomorphic Prickle1 Beetlejuice (Prickle1 Bj ) mouse line to directly test the function of Prickle1 on the cranial base and observed wider cranial bases in Prickle1 Bj/Bj . Importantly, we observed that the Prickle1 and Focadhesin proteins co-localize in murine cranial base chondrocytes, and this co-localization is abnormal in the Prickle1 Bj/Bj mutants. Taken together, our findings uncovered a novel G × G interaction effect in humans with strong support from both epidemiological and molecular studies. These results highlight the potential of studying measures of phenotypic variability in gene mapping studies of facial morphology.

Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations.

Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10-8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10-10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation.

3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies.

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17-0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.

Outcomes of the use of cement-augmented cannulated pedicle screws in lumbar spinal fusion.

BACKGROUND CONTEXT: There are few studies of the radio-clinical outcomes of cement-augmented cannulated pedicle screw (CPS) fixation in osteoporotic patients. PURPOSE: To compare the radiological and clinical outcomes between groups receiving cement-augmented CPS and solid pedicle screws (SPS) in lumbar fusion surgery. STUDY DESIGN/SETTING: Retrospective comparative study PATIENT SAMPLE: A total of 187 patients who underwent lumbar fusion surgery for degenerative spinal stenosis or spondylolisthesis from 2014 to 2019. OUTCOME MEASURES: Radiological evaluation included screw failure, cage failure, rod breakage, and fusion grade at postoperative 6 months and 1 year. Pre- and postoperative visual analog scales for back pain (VAS-BP), leg pain (VAS-LP), Korean Oswestry disability index (K-ODI), and postoperative complications were also compared. METHODS: Outcomes of patients with high risk factors for implant failure [old age, osteoporosis, autoimmune disease or chronic kidney disease (CKD)] who underwent open transforaminal lumbar interbody fusion with cement-augmented CPS fixation (Group C, n=55) or SPS fixation (Group S, n=132) were compared. RESULTS: 324 pedicle screws in Group C and 775 pedicle screws in Group S were analyzed. Group C had a significantly higher average age and lower T-score, and included more patients with autoimmune disease and CKD than group S (all p<.05). Clear zones, screw migration and loss of correction were significantly less frequent in Group C (all p<.05). Thirteen screw breakages were observed; they were only in Group C (4.0%) and all were in the proximal of the two holes. Interbody and posterolateral fusion rates were not significantly different. At last follow-up, all clinical parameters including VAS-BP, VAS-LP, and K-ODI scores had improved significantly in both groups. Postoperative complications were not significantly different in the two groups. CONCLUSION: In lumbar fusion surgery, using cement-augmented CPS in high-risk groups for implant failure could be a useful technical option for reducing acute radiological complications and obtaining clinical results comparable to those obtained using SPS in patients with low risk of implant failure. LEVEL OF EVIDENCE: Level 4.

Efficacy and safety of Escherichia coli-derived recombinant human bone morphogenetic protein-2 in additional lumbar posterolateral fusion: minimum 1-year follow-up.

BACKGROUND CONTEXT: Recombinant human bone morphogenetic protein-2 (BMP-2) is the growth factor with the most striking osteoinductive performance in orthopedic operations; it is also able to induce heterotopic bone formation. However, there has been little clinical research on Escherichia coli-derived BMP-2 (E.BMP-2). PURPOSE: To confirm the efficacy and safety of E.BMP-2 with a hydroxyapatite carrier when applied to one-sided posterolateral fusion (PLF) in addition to lumbar interbody fusion (LIF), and to measure the lower dose of E.BMP-2 ever reported achieving solid fusion. STUDY DESIGN/SETTING: Retrospective case-control study PATIENT SAMPLE: A total of 121 patients who received surgery for one or two levels of fusion for lumbar degenerative spinal stenosis or spondylolisthesis from January 2009 to December 2019 were included. OUTCOME MEASURES: Clinical and functional outcomes were evaluated using preoperative and final follow-up visual analogue scales for back pain (VAS-BP) and leg pain (VAS-LP), and Korean Oswestry disability index (K-ODI) scores. Fusion rates were evaluated by computed tomography at six months and one year after surgery. In addition, a subgroup analysis of group E according to number of fusion levels was conducted, and the fusion rates in the one-level and two-level fusion groups were compared. METHODS: LIF and additional one-sided PLF was performed in all patients. They received autogenous iliac bone grafts (Group C, n=69) or 1mg of E.BMP-2 (Group E, n=52). RESULTS: There were no significant differences between preoperative and final VAS-BP, VAS-LP and K-ODI. The PLF rate was 79.7% for Group C and 82.7% for Group E at postoperative six months, and 94.2% for Group C and 100% for Group E at postoperative one year (p =.679, 0.134, respectively). The LIF rate was 71.0% in Group C and 71.2% in Group E at six months after surgery, and 97.1% in Group C and 100% in Group E at one year (p =.987, 0.506, respectively). In terms of numbers of fusion levels in Group E, PLF rates at six months (p =.486) and one year after surgery were similar in the two groups, as were LIF rates at six months (p =.822) and one year after surgery. There were no cases of malignancy or radiculopathy in Group E during one-year of follow-up. CONCLUSIONS: One milligram of E.BMP-2 is a safe and effective osteoinductive material in short-level lumbar PLF surgery.

The PAX1 locus at 20p11 is a potential genetic modifier for bilateral cleft lip.

Nonsyndromic orofacial clefts (OFCs) are a common birth defect and are phenotypically heterogenous in the structure affected by the cleft - cleft lip (CL) and cleft lip and palate (CLP) - as well as other features, such as the severity of the cleft. Here, we focus on bilateral and unilateral clefts as one dimension of OFC severity, because the genetic architecture of these subtypes is not well understood. We tested for subtype-specific genetic associations in 44 bilateral CL (BCL) cases, 434 unilateral CL (UCL) cases, 530 bilateral CLP cases (BCLP), 1123 unilateral CLP (UCLP) cases, and unrelated controls (N = 1626), using a mixed-model approach. While no novel loci were found, the genetic architecture of UCL was distinct compared to BCL, with 44.03% of suggestive loci having different effects between the two subtypes. To further understand the subtype-specific genetic risk factors, we performed a genome-wide scan for modifiers and found a significant modifier locus on 20p11 (p=7.53×10-9), 300kb downstream of PAX1, that associated with higher odds of BCL vs. UCL, and replicated in an independent cohort (p=0.0018) with no effect in BCLP (p>0.05). We further found that this locus was associated with normal human nasal shape. Taken together, these results suggest bilateral and unilateral clefts may have different genetic architectures. Moreover, our results suggest BCL, the rarest form of OFC, may be genetically distinct from the other OFC subtypes. This expands our understanding of modifiers for OFC subtypes and further elucidates the genetic mechanisms behind the phenotypic heterogeneity in OFCs.

The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation.

Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10-3), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated (p < 5 × 10-8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10-10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.

Impact of low-frequency coding variants on human facial shape.

The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) in 8091 genes on multi-dimensional facial shape phenotypes in a European cohort of 2329 healthy individuals. Using three-dimensional images, we partitioned the full face into 31 hierarchically arranged segments to model facial morphology at multiple levels, and generated multi-dimensional phenotypes representing the shape variation within each segment. We used MultiSKAT, a multivariate kernel regression approach to scan the exome for face-associated low-frequency variants in a gene-based manner. After accounting for multiple tests, seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 in NECTIN1 had a significant effect on chin morphology and was predicted bioinformatically to have a deleterious effect on protein function. Notably, NECTIN1 is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed that nectin1a mutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. Findings from this study expanded our understanding of the genetic basis of normal-range facial shape by highlighting the role of low-frequency coding variants in several novel genes.

Insights into the genetic architecture of the human face.

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions.