Supergenes are not necessary to explain the maintenance of complex alternative phenotypes.

Evolutionary biology aims to explain the diversity seen in nature. Evolutionary theory provides frameworks to understand how simple polymorphisms or continuous variation are maintained, but phenotypes inherited as discrete suites of quantitative traits are difficult to fit into this framework. Supergenes have been proposed as a solution to this problem-if causal genes are co-located, they can be inherited as if a single gene, thus bridging the gap between simple polymorphisms and continuous traits. We develop models to ask: how are critical supergenes for maintaining phenotypic diversity? In our simplest model, without explicit genetic architectures, three alternative reproductive morphs are maintained in many of the parameter combinations we evaluated. For these same parameter values, models with demographic stochasticity, recombination and mutation (but without explicit genetic architecture) maintained only two of these three morphs, with stochasticity determining which morphs persisted. With explicit genetic architectures, regardless of whether causal loci were co-located in a supergene or distributed randomly, this stochasticity in which morphs are maintained was reduced. Even when phenotypic variation was lost, genetic diversity was maintained. Altogether, categorical traits with polygenic bases exhibited similar evolutionary dynamics to those determined by supergenes. Our work suggests that supergenes are not the only answer to the puzzle of how discrete polygenic phenotypic variation is maintained.

Sexual Selection on Non-Ornamental Traits Is Underpinned by Evidence of Genetic Constraints on Sex-Biased Expression in Dusky Pipefish.

Species lacking distinct secondary sex characteristics, such as differences in size or morphology, are often thought to experience lower levels of sex-specific selection in comparison to highly sexually dimorphic organisms. However, monomorphism in classic visible traits could be a result of genetic or physiological constraints that prevent the sexes from reaching divergent fitness optima. Additionally, biochemical and molecular work have revealed a variety of less easily observed phenotypes that nonetheless exhibit profound dimorphism. Sex-specific selection could act on these more subtle, less visible, traits. We investigate sex-specific selection in the polygynandrous dusky pipefish (Syngnathus floridae), which lacks distinct secondary sexual characteristics such as size, colour and morphological dimorphism. Using experimental breeding populations, we revealed that although males and females have similar opportunities for sexual selection, only males experience significant sexual selection pressures on body size. We also investigated patterns of sex-biased and sex-specific gene expression in gonads, livers and gills, and tested whether genes with highly divergent expression patterns between the sexes are more likely to be tissue-specific, and therefore relieved of genetic constraints. Sex bias in gene expression was widespread, although the reproductive organs had the most sex-biased and sex-specific genes. Sex-specific selection on gene expression in gills was primarily related to immune response, whereas the liver and gonads had a wide variety of cellular processes, as well as reproductive proteins, showing sex-biased expression. These sex-biased genes showed higher organ-specificity in their expression patterns, suggesting that pleiotropic constraints might have historically impacted the evolution of sex-specific expression patterns. Altogether, we find evidence for ongoing and historical sex-specific selection in the dusky pipefish.

Cortical Block Grafting Successfully Augments Alveolar Cleft Sites for Dental Implant Placement.

BACKGROUND: Supplemental bone grafting is regularly required before dental implant placement in patients with cleft lip and palate (CLP). PURPOSE: The study purpose was to measure and compare implant osseointegration and changes in graft dimensions following lateral incisor onlay cortical bone grafting in CLP and non-CLP patients. STUDY DESIGN, SETTING, SAMPLE: Retrospective cohort study composed of patients who presented to Boston Children's Hospital and underwent autogenous onlay cortical block bone grafting at lateral incisor sites from 2015 through 2023. Patients were excluded if the cone beam computed tomography (CBCT) quality was insufficient for accurate measurements. PREDICTOR VARIABLE: The predictor variable was CLP status coded as CLP or non-CLP. MAIN OUTCOME VARIABLE: The primary outcome variable was successful implant osseointegration confirmed by a torque of 35 N/cm or more after 3 months of implant healing. Secondary outcomes were change in bone width between preoperative and postoperative CBCT scans at lateral incisor sites and the need for additional bone augmentation prior to or during implant placement. COVARIATES: Covariates were age, sex, cleft location, and time from bone graft to postoperative CBCT and implant placement. ANALYSES: Data analyses were performed using t-tests, Fisher's exact tests, Mann-Whitney U tests, and Pearson's correlation. P < .05 was considered statistically significant. RESULTS: A total of 22 subjects (16 with CLP) were evaluated. The mean age at the time of graft was 19.3 ± 2.4 years with 52.6% males. Implants were osseointegrated at 20 of 22 lateral incisor sites (1 CLP failure, 1 non-CLP failure). There was significant change in bone width after grafting for patients with CLP (P < .001). Patients with CLP experienced a 3.32 (± 1.80) mm and 2.99 (± 1.61) mm increase in bone width at 2 different levels. Patients with CLP achieved greater boney changes near the alveolar crest than noncleft patients (P = .008) but the change was not significantly different more apically (P = .86). One subject with CLP required additional grafting during implant placement. CONCLUSION AND RELEVANCE: Cortical block onlay bone grafting is a predictable technique to augment lateral incisor sites in patients with CLP for placement of a dental implant.

Does Anesthesiologist Experience Influence Early Postoperative Outcomes Following Orthognathic Surgery?

BACKGROUND: Anesthesia provider experience impacts nausea and vomiting in other surgical specialties but its influence within orthognathic surgery remains unclear. PURPOSE: The study purpose was to evaluate whether anesthesiologist experience with orthognathic surgery impacts postoperative outcomes, including nausea, emesis, narcotic use, and perioperative adverse events, for patients undergoing orthognathic surgery. STUDY DESIGN, SETTING, SAMPLE: This is a retrospective cohort study of subjects aged 12 to 35 years old who underwent orthognathic surgery, including Le Fort 1 osteotomy ± bilateral sagittal split osteotomy, at Boston Children's Hospital from August 2018 to January 2022. Subjects were excluded if they had incomplete medical records, a syndromic diagnosis, or a hospital stay of greater than 2 days. PREDICTOR VARIABLE: The predictor variable was attending anesthesia provider experience with orthognathic surgery. Providers were classified as experienced or inexperienced, with experienced providers defined as having anesthetized ≥10 orthognathic operations during the study period. MAIN OUTCOME VARIABLES: The primary outcome variable was postoperative nausea. Secondary outcome variables were emesis, narcotic use in the hospital, and perioperative adverse events within 30 days of their operation. COVARIATES: Study covariates included age, sex, race, comorbidities (body mass index, history of psychiatric illness, cleft lip and/or palate, chronic pain, postoperative nausea/vomiting, gastrointestinal conditions), enhanced recovery after surgery protocol enrollment, and intraoperative factors (operation performed, anesthesia/procedure times, estimated blood loss, intravenous fluid and narcotic administration, and anesthesiologist's years in practice). ANALYSES: χ2 and unpaired t-tests were used to compare primary predictor and covariates against outcome variables. A P-value <.05 was considered significant. RESULTS: There were 118 subjects included in the study after 4 were excluded (51.7% female, mean age 19.1 ± 3.30 years). There were 71 operations performed by 5 experienced anesthesiologists (mean cases/provider 15.4 ± 5.95) and 47 cases by 22 different inexperienced providers (mean cases/provider 1.91 ± 1.16). The nausea rate was 52.1% for experienced providers and 53.2% for inexperienced providers (P = .909). There were no statistically significant associations between anesthesiologist experience and any outcome variable (P > .341). CONCLUSIONS AND RELEVANCE: Anesthesia providers' experience with orthognathic surgery did not significantly influence postoperative nausea, emesis, narcotic use, or perioperative adverse events.

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Bringing precision medicine to the management of pregnancy in women with glucokinase-MODY: a study of diagnostic accuracy and feasibility of non-invasive prenatal testing.

AIMS/HYPOTHESIS: In pregnancies where the mother has glucokinase-MODY (GCK-MODY), fetal growth is determined by fetal genotype. When the fetus inherits a maternal pathogenic GCK variant, normal fetal growth is anticipated, and insulin treatment of maternal hyperglycaemia is not recommended. At present, fetal genotype is estimated from measurement of fetal abdominal circumference on ultrasound. Non-invasive prenatal testing of fetal GCK genotype (NIPT-GCK) using cell-free DNA in maternal blood has recently been developed. We aimed to compare the diagnostic accuracy of NIPT-GCK with that of ultrasound, and determine the feasibility of using NIPT-GCK to guide pregnancy management. METHODS: We studied an international cohort of pregnant women with hyperglycaemia due to GCK-MODY. We compared the diagnostic accuracy of NIPT-GCK with that of measurement of fetal abdominal circumference at 28 weeks' gestation (n=38) using a directly genotyped offspring sample as the reference standard. In a feasibility study, we assessed the time to result given to clinicians in 43 consecutive pregnancies affected by GCK-MODY between July 2019 and September 2021. RESULTS: In terms of diagnostic accuracy, NIPT-GCK was more sensitive and specific than ultrasound in predicting fetal genotype (sensitivity 100% and specificity 96% for NIPT-GCK vs sensitivity 53% and specificity 61% for fetal abdominal circumference 75th percentile). In terms of feasibility, a valid NIPT-GCK fetal genotype (≥95% probability) was reported in all 38 pregnancies with an amenable variant and repeated samples when needed. The median time to report was 5 weeks (IQR 3-8 weeks). For the 25 samples received before 20 weeks' gestation, results were reported at a median gestational age of 20 weeks (IQR 18-24), with 23/25 (92%) reported before 28 weeks. CONCLUSIONS/INTERPRETATION: Non-invasive prenatal testing of fetal genotype in GCK-MODY pregnancies is highly accurate and is capable of providing a result before the last trimester for most patients. This means that non-invasive prenatal testing of fetal genotype is the optimal approach to management of GCK-MODY pregnancies.

FOXP3 TSDR Measurement Could Assist Variant Classification and Diagnosis of IPEX Syndrome.

Pathogenic FOXP3 variants cause immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a progressive autoimmune disease resulting from disruption of the regulatory T cell (Treg) compartment. Assigning pathogenicity to novel variants in FOXP3 is challenging due to the heterogeneous phenotype and variable immunological abnormalities. The number of cells with demethylation at the Treg cell-specific demethylated region (TSDR) is an independent biomarker of IPEX. We aimed to investigate if diagnosing IPEX at presentation with isolated diabetes could allow for effective monitoring of disease progression and assess whether TSDR analysis can aid FOXP3 variant classification and predict disease course. We describe a large genetically diagnosed IPEX cohort (n = 65) and 13 individuals with other monogenic autoimmunity subtypes in whom we quantified the proportion of cells with FOXP3 TSDR demethylation, normalized to the number with CD4 demethylation (%TSDR/CD4) and compare them to 29 unaffected controls. IPEX patients presenting with isolated diabetes (50/65, 77%) often later developed enteropathy (20/50, 40%) with a median interval of 23.5 weeks. %TSDR/CD4 was a good discriminator of IPEX vs. unaffected controls (ROC-AUC 0.81, median 13.6% vs. 8.5%, p < 0.0001) with higher levels of demethylation associated with more severe disease. Patients with other monogenic autoimmunity had a similar %TSDR/CD4 to controls (median 8.7%, p = 1.0). Identifying increased %TSDR/CD4 in patients with novel FOXP3 mutations presenting with isolated diabetes facilitates diagnosis and could offer an opportunity to monitor patients and begin immune modulatory treatment before onset of severe enteropathy.

Neonatal and early-onset diabetes in Ukraine: Atypical features and mortality.

AIMS: The aim of this study is to elucidate the aetiology and clinical features of neonatal and early-onset diabetes in a large database for pediatric diabetes patients in Ukraine. METHODS: We established a Pediatric Diabetes Register to identify patients diagnosed with diabetes before 9 months of age. Genetic testing was undertaken for 66 patients from 65 unrelated families with diabetes diagnosed within the first 6 months of life (neonatal diabetes, n = 36) or between 6 and 9 months (early-onset diabetes, n = 30). RESULTS: We determined the genetic aetiology in 86.1% of patients (31/36) diagnosed before 6 months and in 20% (6/30) diagnosed between 6 and 9 months. Fourteen individuals (37.8% of those with a genetic cause identified) had activating heterozygous variants in ABCC8 or KCNJ11. An additional 10 individuals had pathogenic variants in the INS or GCK genes, while 4 had 6q24 transient neonatal diabetes. Rare genetic subtypes (including pathogenic variants in EIF2AK3, GLIS3, INSR, PDX1, LRBA, RFX6 and FOXP3) were identified in nine probands (24.3% of solved cases), 6 of whom died. In total, eight individuals died between infancy and childhood, all of them were diagnosed before 6 months and had received a genetic diagnosis. CONCLUSIONS: In the last decade, the increased availability of comprehensive genetic testing has resulted in increased recognition of the contribution of rare genetic subtypes within pediatric diabetes cohorts. In our study, we identified a high mortality rate among these patients.

SavvyCNV: Genome-wide CNV calling from off-target reads.

Identifying copy number variants (CNVs) can provide diagnoses to patients and provide important biological insights into human health and disease. Current exome and targeted sequencing approaches cannot detect clinically and biologically-relevant CNVs outside their target area. We present SavvyCNV, a tool which uses off-target read data from exome and targeted sequencing data to call germline CNVs genome-wide. Up to 70% of sequencing reads from exome and targeted sequencing fall outside the targeted regions. We have developed a new tool, SavvyCNV, to exploit this 'free data' to call CNVs across the genome. We benchmarked SavvyCNV against five state-of-the-art CNV callers using truth sets generated from genome sequencing data and Multiplex Ligation-dependent Probe Amplification assays. SavvyCNV called CNVs with high precision and recall, outperforming the five other tools at calling CNVs genome-wide, using off-target or on-target reads from targeted panel and exome sequencing. We then applied SavvyCNV to clinical samples sequenced using a targeted panel and were able to call previously undetected clinically-relevant CNVs, highlighting the utility of this tool within the diagnostic setting. SavvyCNV outperforms existing tools for calling CNVs from off-target reads. It can call CNVs genome-wide from targeted panel and exome data, increasing the utility and diagnostic yield of these tests. SavvyCNV is freely available at https://github.com/rdemolgen/SavvySuite.

Is Preoperative Urine Human Chorionic Gonadotropin (hCG) Testing Necessary for Pediatric Patients Before Oral and Maxillofacial Surgery Procedures With Sedation?

PURPOSE: Human chorionic gonadotropin (hCG) testing is performed prior to surgical procedures to ensure patient and fetal safety. The purpose of this study was to evaluate the utility of routine pregnancy testing prior to elective outpatient oral and maxillofacial surgery procedures being performed with intravenous sedation (IVS). METHODS: A retrospective cohort study was implemented assessing hCG testing in postmenarche females who underwent elective outpatient oral surgery procedures scheduled with IVS at a tertiary care institution. Medical records were used to identify eligible subjects aged 12 to 45 years. The primary predictor variable was age, and the primary outcome variable was urine hCG test result. Age was divided into groups to reflect early adolescence (12 to 14 years), mid-adolescence (15 to 17 years), late adolescence/early adulthood (18 to 24 years) and adulthood (25+ years). Secondary outcome variables included inability to void for hCG testing, change in anesthetic, case cancellation or rescheduling and were measured over a 2 year period. Descriptive statistics were performed. Relative risk (RR) and Cochran-Armitage test for trend were calculated to determine the statistical significance of age on inability to void. RESULTS: The sample consisted of 5,006 females, with a median age (IQR, range) of 18.0 (3.6, 12.0 to 43.6) years. There was one positive urine hCG result providing a preoperative pregnancy rate of 0.02%. Fourteen of 1,195 subjects (1.2%) over a 2 year period were unable to provide a urine hCG sample. There was a statistically significant trend in inability to void as age groups got older (P = .001). Patients aged 12 to 17 years had an increased risk of being unable to void compared to patients 18 years and older (RR: 14.30, 95% CI: 1.88 to 108.99, P = .01). The total cost of testing over the 11 year observation period was $9,019.59. CONCLUSIONS: The risk of surgical cancellations and delayed care due to patients' inability to void preoperatively plus a lack of any positive preoperative urine hCG findings in patients under 18 years of age in this study, call into question the necessity of routine preoperative hCG screening in pediatric patients presenting for IVS for elective outpatient oral and maxillofacial procedures.

Prognosis of Maxillary Central Incisors in Patients with Bilateral Cleft Lip/Palate.

Evaluate periodontal bone support of maxillary central incisors (MCI) in patients with bilateral complete cleft lip and palate (BCCLP). Determine if syndromic diagnosis, age at time of alveolar bone graft (ABG), presence of maxillary lateral incisor (MLI), history of dentofacial orthopedics, maxillary expansion, and pre-maxillary osteotomy are associated with the periodontal bone support of MCI.Retrospective radiographic study.Tertiary care children's hospital.One hundred seventy-nine patients with BCCLP (22 syndromic) who had post-operative ABG cone beam computed tomography (CBCT) scans taken between 2002-2018.Crown to root (C/R) ratio of MCI measured on CBCT scans.The C/R ratio in 65% of MCI indicated periodontally compromised teeth. Presence of a MLI improved bone support on adjacent MCI when compared to those missing a MLI (51.4% vs 28.4%, P = .010). There was no significant difference in C/R ratios for syndromic diagnosis, age at ABG, history of dentofacial orthopedics, maxillary expansion, and pre-maxillary osteotomy.The majority of MCI in patients with BCCLP are periodontally compromised but bone support is improved when cleft adjacent lateral incisors are present.

Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes.

AIMS/HYPOTHESIS: A key unanswered question in type 1 diabetes is whether beta cells initiate their own destruction or are victims of an aberrant immune response (beta cell suicide or homicide?). To investigate this, we assessed islet autoantibodies in individuals with congenital beta cell defects causing neonatal diabetes mellitus (NDM). METHODS: We measured autoantibodies to GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) in 242 individuals with NDM (median age diagnosed 1.8 months [IQR 0.39-2.9 months]; median age collected 4.6 months [IQR 1.8-27.6 months]; median diabetes duration 2 months [IQR 0.6-23 months]), including 75 whose NDM resulted from severe beta cell endoplasmic reticulum (ER) stress. As a control cohort we also tested samples from 69 diabetes-free individuals (median age collected 9.9 months [IQR 9.0-48.6 months]) for autoantibodies. RESULTS: We found low prevalence of islet autoantibodies in individuals with monogenic NDM; 13/242 (5.4% [95% CI 2.9, 9.0%]) had detectable GADA, IA-2A and/or ZnT8A. This was similar to the proportion in the control participants who did not have diabetes (1/69 positive [1.4%, 95% CI 0.03, 7.8%], p=0.3). Importantly, monogenic individuals with beta cell ER stress had a similar rate of GADA/IA-2A/ZnT8A positivity to non-ER stress aetiologies (2.7% [95% CI 0.3, 9.3%] vs 6.6% [95% CI 3.3, 11.5%] p=0.4). We observed no association between islet autoimmunity and genetic risk, age at testing (including 30 individuals >10 years at testing) or diabetes duration (p>0.4 for all). CONCLUSIONS/INTERPRETATION: Our data support the hypothesis that beta cell stress/dysfunction alone does not lead to the production of islet autoantibodies, even in the context of high-risk HLA types. This suggests that additional factors are required to trigger an autoimmune response towards beta cells.

Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics.

AIMS/HYPOTHESIS: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. METHODS: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). RESULTS: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. CONCLUSIONS/INTERPRETATION: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.

A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.

A biallelic loss-of-function PDIA6 variant in a second patient with polycystic kidney disease, infancy-onset diabetes, and microcephaly.

We report a second patient with intrauterine growth retardation, congenital polycystic kidney disease, infancy-onset diabetes, microcephaly, and liver fibrosis caused by a homozygous PDIA6 loss-of-function variant. Our study further defines the genetic and clinical features of this rare syndromic form of infancy-onset diabetes.

Increased referrals for congenital hyperinsulinism genetic testing in children with trisomy 21 reflects the high burden of non-genetic risk factors in this group.

BACKGROUND: Hyperinsulinism results from inappropriate insulin secretion during hypoglycaemia. Down syndrome is causally linked to a number of endocrine disorders including Type 1 diabetes and neonatal diabetes. We noted a high number of individuals with Down syndrome referred for hyperinsulinism genetic testing, and therefore aimed to investigate whether the prevalence of Down syndrome was increased in our hyperinsulinism cohort compared to the population. METHODS: We identified individuals with Down syndrome referred for hyperinsulinism genetic testing to the Exeter Genomics Laboratory between 2008 and 2020. We sequenced the known hyperinsulinism genes in all individuals and investigated their clinical features. RESULTS: We identified 11 individuals with Down syndrome in a cohort of 2011 patients referred for genetic testing for hyperinsulinism. This represents an increased prevalence compared to the population (2.5/2011 expected vs. 11/2011 observed, p = 6.8 × 10-5 ). A pathogenic ABCC8 mutation was identified in one of the 11 individuals. Of the remaining 10 individuals, five had non-genetic risk factors for hyperinsulinism resulting from the Down syndrome phenotype: intrauterine growth restriction, prematurity, gastric/oesophageal surgery, and asparaginase treatment for leukaemia. For five individuals no risk factors for hypoglycaemia were reported although two of these individuals had transient hyperinsulinism and one was lost to follow-up. CONCLUSIONS: Down syndrome is more common in patients with hyperinsulinism than in the population. This is likely due to an increased burden of non-genetic risk factors resulting from the Down syndrome phenotype. Down syndrome should not preclude genetic testing as coincidental monogenic hyperinsulinism and Down syndrome is possible.

Do Race and Ethnicity Affect the Age When Third Molars are Extracted?

PURPOSE: Socioeconomic and racial statuses are barriers to dental and medical healthcare in America leading to poor health outcomes. Delayed management of third molars may increase the risk of complications. There have been no large-scale studies examining the role race and ethnicity have on timing of third molar extraction. The purpose of this study is to explore the associations of race and ethnicity on age of third molar extractions and complications. MATERIALS AND METHODS: This retrospective cohort study composed of patients who underwent third molar extraction at Boston Children's Hospital from April 2011 to March 2021. Patients self-identified race as White, Black/African American, Asian, Native American/Pacific Islander, other, and prefer not to answer. Patients identified ethnicity as Hispanic or non-Hispanic. Subjects with incomplete medical records were excluded. Primary predictor variables were race and ethnicity. The primary outcome variable was the age of third molar extractions and the secondary outcome variable was postoperative complications. Descriptive, univariate, and multivariate statistics were conducted. P < .05 was considered statistically significant. Covariates included gender, insurance type, interpreter requirements, and preoperative symptoms. RESULTS: This study included 3,933 patients after exclusion criteria were applied. The mean age was 18.6 ± 2.49 years. When third molars were removed, White patients were older than the non-White population (18.8 vs 18.2 years, P < .001). Black or African American patients were younger than all other races (18.1 vs 18.7 years, P < .001). Hispanics were younger compared to non-Hispanics (18.1 vs 18.7 years, P < .001). Patients with preoperative symptoms removed their wisdom teeth at an older age compared to those who were asymptomatic (19.0 vs 18.5 years, P < .001). Black patients experienced more preoperative symptoms than other races (46.2% vs 29.2%, P < .001). White patients experienced the most postoperative complications (7.7% vs 5.0%, P = .003), while Black or African American patients experienced less postoperative complications (2.7% vs 7.5%, P < .001). CONCLUSION: This study provides no evidence that patients from historically under-represented racial and ethnic groups had inadequate access for removal of their third molars. Patients from these communities experienced a lower rate of complications after third molar extractions confirming quality of care was not compromised for these patients.

Two decades since the fetal insulin hypothesis: what have we learned from genetics?

In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.

The population genomics of repeated freshwater colonizations by Gulf pipefish.

How organisms adapt to the novel challenges imposed by the colonization of a new habitat has long been a central question in evolutionary biology. When multiple populations of the same species independently adapt to similar environmental challenges, the question becomes whether the populations have arrived at their adaptations through the same genetic mechanisms. In recent years, genetic techniques have been used to tackle these questions by investigating the genome-level changes underlying local adaptation. Here, we present a genomic analysis of colonization of freshwater habitats by a primarily marine fish, the Gulf pipefish (Syngnathus scovelli). We sample pipefish from four geographically distinct freshwater locations and use double-digest restriction site associated DNA sequencing to compare them to 12 previously studied saltwater populations. The two most geographically distant and isolated freshwater populations are the most genetically distinct, although demographic analysis suggests that these populations are experiencing ongoing migration with their saltwater neighbours. Additionally, outlier regions were found genome-wide, showing parallelism across ecotype pairs. We conclude that these multiple freshwater colonizations involve similar genomic regions, despite the large geographical distances and different underlying mechanisms. These similar patterns are probably facilitated by the interacting effects of intrinsic barriers, gene flow among populations and ecological selection in the Gulf pipefish.

Octreotide-LAR is a Useful Alternative for the Management of Diazoxide-Responsive Congenital Hyperinsulinism.

The data on the congenital hyperinsulinism (CHI) in Asian Indian patients is limited. Diazoxide is often unavailable in India, which poses challenge in managing CHI. The study was aimed to present our experience with CHI with a special focus on the effectiveness and cost-effectiveness of octreotide long-acting release (OCT-LAR) among diazoxide-responsive CHI. The data of 14 index cases with CHI registered at our center were retrospectively analyzed. The diagnosis of CHI was based on elevated serum insulin (3.4-32.5 µIU/ml) and C-peptide (0.58-1.98 ng/ml) at the time of symptomatic hypoglycemia (BG≤41 mg/dl). Fourteen patients (13 males) presented at a median (range) age of 3 (1-270) days, seizures being the most common mode of presentation (78.6%). Ten patients were diazoxide-responsive, two were partially responsive, while two were unresponsive. Genetics was available for eight patients; ABCC8 (n=3, 1 novel) and HADH (n=2, both novel) were the most commonly mutated genes. OCT-LAR was offered to eight patients including four with diazoxide-responsive disease and was universally effective. We propose a cost-effective approach to use OCT-LAR in the management of CHI, which may also make it more cost-effective than diazoxide for diazoxide-responsive disease. Five of the 11 (45.5%) patients had evidence of neurological impairment; notably, two patients with HADH mutations had intellectual disability despite diazoxide-responsiveness. We report three novel mutations in CHI-associated genes. We demonstrate the effectiveness of and propose a cost-effective approach to use OCT-LAR in diazoxide-responsive CHI. Mutations in HADH may be associated with abnormal neurodevelopmental outcomes despite diazoxide-responsiveness.