Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes.

Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.

Assessment of the 2021 AASLD Practice Guidance for Albumin Infusion in Elective Therapeutic Paracentesis: A Regression Discontinuity Design.

INTRODUCTION: The 2021 American Association for the Study of Liver Disease (AASLD) Practice Guidance recommends albumin infusion when removing ≥5 L of ascites to prevent post-paracentesis circulatory dysfunction. However, the optimal criteria and scenarios for initiating albumin infusion subsequent to therapeutic paracentesis (TP) have been subject to limited scientific inquiry. METHODS: We conducted a retrospective cohort study at a US academic healthcare center. Participants received elective, outpatient TP between July 2019 and December 2022. Patients with spontaneous bacterial peritonitis, post-TP clinical adjustments, and/or hospitalization were excluded. The institution strictly followed the AASLD Guidance. We used a sharp regression discontinuity (RD) design to estimate the effect of albumin infusion at the AASLD Guidance-recommended cutoff of 5 L on serum creatinine and sodium trajectory after TP. RESULTS: Over the study period, 1,457 elective TPs were performed on 235 unique patients. Albumin infusion at the threshold of 5 L of ascites removal reduced serum creatinine levels by 0.046 mg/dL/d (95% confidence interval 0.003-0.116, P = 0.037) and increased serum sodium levels by 0.35 mEq/L/d (95% confidence interval 0.15-0.55, P = 0.001) compared with those who did not receive albumin infusion. The RD plots indicated worsened serum creatine/sodium levels after draining 3 L of fluid, approaching levels similar to or worse than with albumin infusion at 5 L or more. DISCUSSION: Our RD models supported the 2021 AASLD Guidance with robust estimation of causal effect sizes at the cutoff level of 5 L. Nevertheless, the findings also highlight the need to further evaluate the efficacy of albumin infusion in patients who undergo elective TP and have 3-5 L of ascites removed.

Genome-wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes.

Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study.genome-wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome-wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p ≤ 1.0E-05) within previously confirmed OFC loci-PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster-were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft- or family-specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios.

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting.

PURPOSE: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls. METHODS: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria. RESULTS: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance. CONCLUSION: These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

Revisiting the effects of state earned income tax credits on infant health: a quasi-experimental study using contiguous border counties approach.

BACKGROUND: To examine the effects of refundable state earned income tax credits (EITC) on infant health. METHODS: We use the restricted-access U.S. birth certificate data with county codes from 1989 to 2018. Birth outcomes include birth weight, low birth weight, gestational weeks, preterm birth, and the fetal growth rate. The analytical sample includes single mothers with high school education or less. Two specifications of two-way fixed effects models are employed. The first specification accounts for shared time trends across all states/counties. The second specification estimates effects based on EITC changes within contiguous counties across state borders which accounts for contemporaneous events specific to each contiguous county pair. Models are estimated pooling and stratifying by parity subgroups. RESULTS: Under the first specification, refundable state EITC is associated with improved birth outcomes. Pooling all parity, a 10%-point increase in refundable EITC is associated with an 8-gram increase in birth weight (95% CI: 2.9,14.6). The effect increases by parity. In contrast, the estimates from the second model are much smaller and statistically non-significant, both pooling and stratifying by parity. CONCLUSIONS: Comparing contiguous counties across state borders, there is no evidence that refundable state EITC affects birth outcomes. However, the estimates still do not rule out moderate to large benefits for third or higher born infants.

Changes in birth outcomes and utilization of prenatal care during the COVID-19 pandemic in 2020: a secondary analysis of vital statistics in Colombia.

BACKGROUND: Birth outcomes could have been affected by the COVID-19 pandemic through changes in access to prenatal services and other pathways. The aim of this study was to examine the effects of the COVID-19 pandemic on fetal death, birth weight, gestational age, number of prenatal visits, and caesarean delivery in 2020 in Colombia. METHODS: We conducted a secondary analysis of data on 3,140,010 pregnancies and 2,993,534 live births from population-based birth certificate and fetal death certificate records in Colombia between 2016 and 2020. Outcomes were compared separately for each month during 2020 with the same month in 2019 and pre-pandemic trends were examined in regression models controlling for maternal age, educational level, marital status, type of health insurance, place of residence (urban/rural), municipality of birth, and the number of pregnancies the mother has had before last pregnancy. RESULTS: We found some evidence for a decline in miscarriage risk in some months after the pandemic start, while there was an apparent lagging increase in stillbirth risk, although not statistically significant after correction for multiple comparisons. Birth weight increased during the onset of the pandemic, a change that does not appear to be driven by pre-pandemic trends. Specifically, mean birth weight was higher in 2020 than 2019 for births in April through December by about 12 to 21 g (p < 0.01). There was also a lower risk of gestational age at/below 37 weeks in 2020 for two months following the pandemic (April, June), but a higher risk in October. Finally, there was a decline in prenatal visits in 2020 especially in June-October, but no evidence of a change in C-section delivery. CONCLUSIONS: The study findings suggest mixed early effects of the pandemic on perinatal outcomes and prenatal care utilization in Colombia. While there was a significant decline in prenatal visits, other factors may have had counter effects on perinatal health including an increase in birth weight on average.

Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts.

Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 510-8), and many suggestive association signals (510-8 < P < 510-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.5710-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.

Effects of Repealing the ACA Individual Mandate Penalty on Insurance Coverage and Marketplace Enrollment: Evidence From State Mandates in Massachusetts and New Jersey.

BACKGROUND: Congress eliminated the individual mandate penalty of the Affordable Care Act (ACA) effective January 1, 2019. OBJECTIVE: To examine the effects of repealing the ACA mandate penalty on private health insurance coverage and marketplace enrollment by leveraging state-based mandates in Massachusetts and New Jersey. RESEARCH DESIGN: We employ synthetic control and difference-in-differences methods to compare insurance and enrollment changes separately in Massachusetts and New Jersey, which had insurance mandates effective in 2019, to other states without such mandates. SUBJECTS: Adults aged 18-64 years with income of 150-300% and above 300% of the Federal Poverty Level who participated in the 2016-2019 American Community Survey (ACS) and adults aged 18-64 enrolled in insurance marketplaces based on state-level data from the 2016-2021 Marketplace Open Enrollment Period Public Use Files (MOEP-PUF). MEASURES: Any insurance, individually purchased coverage, and employer-sponsored coverage from the ACS and marketplace enrollment from the MOEP-PUF. RESULTS: Changes in any coverage, individually purchased coverage, and employer-sponsored coverage rates are relatively small (generally in the range of 1-2 percentage points) and statistically nonsignificant in both Massachusetts and New Jersey compared with states without mandates. Furthermore, there is no discernable difference by eligibility for marketplace subsidies based on income level in the ACS data. Similarly, estimates for changes in marketplace enrollment are also small overall and statistically nonsignificant. CONCLUSION: Private insurance coverage rates and marketplace enrollment for adults 18-64 do not appear to have changed thus far owing to the 2019 repeal of the ACA individual mandate penalty.

Academic outcomes of children with orofacial clefts: A review of the literature and recommendations for future research.

This paper summarizes the main findings of population-based studies of the academic outcomes of children with isolated orofacial clefts compared to peers, general samples, or siblings, published over the past decade. Most of the reviewed papers report that children with orofacial clefts, particularly children with cleft palate only or in some studies children with cleft lip and palate, may have on average lower achievement on certain outcomes like test scores when comparing to non-siblings. However, there are important differences across studies including designs, populations, outcome measures, and findings. The paper also offers recommendations for future research priorities including controlling for confounding, examining mechanisms and potential heterogeneity across family sociodemographic and contextual factors, and understanding outcomes in less developed settings.

The effects of state facial surgery mandates on timeliness of primary cleft repair surgery in the United States.

OBJECTIVE: This study examines the effects of state facial surgery mandates on the timeliness of primary cleft repair surgery for privately insured children with oral clefts in the United States. MATERIALS AND METHODS: Using IBM Health MarketScan® Database from 2001 to 2017, we estimate regression models separately for age at cleft lip repair and cleft palate repair by having a mandate while considering child-level factors and other state differences. The sample includes 1,451 children who had primary cleft lip repair by age 12 months, and 1,402 children who had primary cleft palate repair by age 18 months. RESULTS: A mandate was associated with earlier cleft lip repair by 13 days (95% CI, -21.5 to -4.7 days) when controlling for state differences, regardless if the child had other birth defects. For children needing cleft palate repair, a mandate was associated with earlier surgery by 87 days (95% CI, -136.1 to -38.4 days) only when no other birth defects were present. CONCLUSIONS: State facial surgery mandates were associated with earlier cleft lip repair for children with or without other birth defects, and earlier cleft palate repair for children without other birth defects (besides oral clefts). Findings suggest benefits to privately insured children with oral clefts from state mandates to cover needed services.

Effects of the ACA Medicaid expansions on access and health by nurse practitioner scope of practice laws.

BACKGROUND: The Affordable Care Act (ACA) Medicaid expansions increased demand for care whereas the Scope of Practice (SOP) laws for nurse procatitioners affect the supply of primary care providers. It is important to udnerstand the interaction of the demand and supply side policies on measures of access to care and health status. PURPOSE: To examine whether effects of the Affordable Care Act (ACA) Medicaid expansions on access to care and health status are moderated by state scope of practice (SOP) laws for nurse practitioners. METHODS: Using data from the 2011 to 2019 Behavioral Risk Factor Surveillance System, the study used a difference-in-differences design that compared outcome changes between expansion and non-expansion states and evaluated whether these changes differed by state SOP laws. DISCUSSION: Following Medicaid expansion, forgoing a needed doctor's visit due to cost declined more in expansion states with full SOP laws than states with reduced SOP laws by 3.0 percentage-points in years 1 to 3 after the expansion (p < .05). Furthermore, completing a routine checkup with a doctor increased more in expansion states with full SOP laws by 3.2 percentage-points in 4 to 6 years (p < .05). CONCLUSION: The ACA Medicaid expansions were associated with larger gains in certain access measures in states with full SOP laws.

Genome-Wide Association Study (GWAS) of dental caries in diverse populations.

BACKGROUND: Dental caries is one of the most common chronic diseases and is influenced by a complex interplay of genetic and environmental factors. Most previous genetic studies of caries have focused on identifying genes that contribute to dental caries in specific ethnic groups, usually of European descent. METHODS: The aim of this study is to conduct a genome-wide association study (GWAS) to identify associations affecting susceptibility to caries in a large multiethnic population from Argentina, the Philippines, Guatemala, Hungary, and the USA, originally recruited for studies of orofacial clefts (POFC, N = 3686). Ages of the participants ranged from 2 to 12 years for analysis of the primary dentition, and 18-60 years for analysis of the permanent dentition. For each participant, dental caries was assessed by counts of decayed and filled teeth (dft/DFT) and genetic variants (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Caries was analyzed separately for the primary and permanent dentitions, with age, gender, and presence/absence of any type of OFC treated as covariates. Efficient Mixed-Model Association eXpedited (EMMAX) was used to test genetic association, while simultaneously accounting for relatedness and stratification. RESULTS: We identified several suggestive loci (5 × 10-8 < P < 5 × 10-6) within or near genes with plausible biological roles for dental caries, including a cluster of taste receptor genes (TAS2R38, TAS2R3, TAS2R4, TASR25) on chromosome 7 for the permanent dentition analysis, and DLX3 and DLX4 on chromosome 17 for the primary dentition analysis. Genome-wide significant results were seen with SNPs in the primary dentition only; however, none of the identified genes near these variants have known roles in cariogenesis. CONCLUSION: The results of this study warrant further investigation and may lead to a better understanding of cariogenesis in diverse populations, and help to improve dental caries prediction, prevention, and/or treatment in future.

A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals.

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment.

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10-8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.

Effects of the Recent Medicaid Expansions on Dental Preventive Services and Treatments.

BACKGROUND: Low-income adults in the United States have historically had poor access to dental services largely due to limited dental coverage. OBJECTIVE: We examined the effects of recent Medicaid income-eligibility expansions under the Affordable Care Act on dental visits separately for preventive care and treatments. RESEARCH DESIGN: We used restricted data from the 2011 to 2016 Medical Expenditure Panel Survey with state geocodes. The main analytical sample included nearly 21,000 individuals who were newly eligible for Medicaid. We employed a quasi-experimental difference-in-differences design to identify the impact of the state Medicaid expansions effective in 2014 on dental services use by the level of state Medicaid dental benefit for the newly eligible. RESULTS: Expanding Medicaid in 2014 with extensive or limited dental coverage increased preventive dental visits and use of major dental treatments by over 5 percentage-points in 2014 and 2015. The increase in preventive visits continued in 2016 in expanding states with extensive coverage, while increase in major dental treatments continued in 2016 in expanding states with limited coverage. There is some but less consistent evidence of an increase in dental treatment with emergency-only coverage. CONCLUSIONS: Medicaid expansions with dental coverage beyond emergency-only services have increased access of the newly eligible low-income adults to dental treatments and preventive services, with extensive coverage showing continuing increase in preventive services use 3 years after the expansion. With limited coverage, there is some evidence of individuals needing to stretch treatments over a longer period. Providing comprehensive dental coverage can address unmet dental needs and improve oral health among low-income adults.

State-Mandated Coverage of Cleft Lip and Cleft Palate Treatment.

OBJECTIVE: We conducted a comprehensive review of state laws and regulations that require private health insurance plans to cover the services needed by children born with cleft lip and/or cleft palate (CL/P). The goal is to better understand how states are reducing the barriers children with CL/P face when seeking recommended health care services. DESIGN: We identified all state laws and regulations mandating insurance coverage of services for children with CL/P by private insurance carriers from 1999 through 2017 using Westlaw legal database. We categorized laws and regulations into ten services: facial surgery (facial, corrective, reconstructive), oral surgery, orthodontics, dental care, habilitation/rehabilitation/speech therapy, prosthetic treatment, audiology, nutrition counseling, genetic testing, and psychological counseling. We also captured broad mandates indicating coverage for all necessary treatments. RESULTS: There was a trend toward increased coverage of services for CL/P over time. In 1999, 27 states and Washington, DC did not have relevant laws or regulations. By 2017, there were 19 states without laws or regulations mandating services. The most common mandated service was facial surgery followed by habilitation/rehabilitation/speech therapy, orthodontics, dental care, and oral surgery. Nutrition, audiology, genetic testing and psychological counseling were rarely included in mandated services. CONCLUSIONS: States vary widely in their requirements for coverage of services needed by children with CL/P in private health insurance plans. There has been an increase in mandates over the past two decades to cover services, although significant variation continues to exist across states.

Genome-wide interaction studies identify sex-specific risk alleles for nonsyndromic orofacial clefts.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 -5 ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 -5 ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.