Family Cohort Research Articles

Differences in public's perception of air quality and acceptability of a clean air zone: A mixed-methods cross sectional study

BackgroundAir pollution is a major cause of morbidity and mortality. Clean Air Zones (CAZs) which restrict the entry of polluting vehicles in targeted areas have been identified as potentially effective in improving health and reducing air pollution; however, their implementation can be controversial. MethodsA cross-sectional survey was completed by 1949 respondents who lived or worked in Bradford, a multi-cultural deprived city in England, between April and December 2021. Of these, 1137 were recruited from the longitudinal Born in Bradford (BiB) family cohort (families with children born in the city during 2007–2011) and 812 were from the general public. Bradford is the seventh largest metropolitan district in England and Wales with a population of over half a million mainly white British and Pakistani origin. The BiB families cohort and the general public respondents were used for descriptive analysis of perception of air quality and acceptability of CAZ, then the relationship between participants responses with demographic characteristics were investigated using the BiB families cohort. Outcomes included perceptions of air quality and acceptability of the CAZ supplemented by free-text questions. Thematic analysis was used to code free-text data. Descriptive analyses were performed on the entire sample. Latent class analysis was used to characterise participants was performed in the BiB dataset for whom detailed existing socio-demographic data were available. ResultsThe majority of participants (67%) considered improving air quality in Bradford as extremely important; 70% supported implementation of the CAZ. Three latent classes were identified within the BiB sample: deprived white British families (25%), more affluent white British families (32%) and deprived Pakistani-origin families (43%). Deprived white British (OR = 0.54, 95% CI: 0.34 to 0.84) and more affluent white British families (OR = 0.53, 95% CI: 0.36 to 0.79) were less likely to say the air quality was good/excellent when compared with deprived Pakistani-origin families. Affluent White British families were more likely to support the CAZ compared with deprived white British families (OR = 2.24; 95% CI: 1.55. to 3.25) and deprived Pakistani-origin families (OR = 2.06, 95% CI: 1.50 to 2.85). Qualitative analysis suggested that a perceived lack of cohesion in the policy and concerns about financial impacts drove negative attitudes. ConclusionFamilies in Bradford were generally supportive of the planned CAZ and efforts to reduce pollution; however, support was weaker in more deprived communities. Pakistani-origin communities living in deprived areas perceived air quality as better than other groups. Tailored approaches to communicate about the proposed benefits of policies such as CAZ prior to implementation may be an important way to increase acceptability amongst vulnerable groups.

Layer myocardial strain is the most heritable echocardiographic trait.

Myocardial deformation assessed by strain analysis represents a significant advancement in our assessment of cardiac mechanics. However, whether this variable is genetically heritable or whether all/most of its variability is related to environmental factors is currently unknown.We sought to determine the heritability of echocardiographically determined cardiac mechanics indices in a population setting. A total of 1357 initially healthy subjects (women 51.6%; 48.2 ± 14.1 years) were included in this study from 20 years follow-up after the 4th visit of the longitudinal familial STANISLAS cohort (Lorraine, France). Data were acquired using state-of-the-art cardiac ultrasound equipment, using acquisition and measurement protocols recommended by the EACVI/ASE/Industry Task Force. Layer-specific global longitudinal strain (GLS) and global circumferential strain (GCS) (full-wall, subendocardial and subepicardial) and conventional structural and functional cardiac parameters and their potential heritability were assessed using restricted maximum likelihood analysis, with genetic relatedness matrix calculated from genome-wide association data. Indices of longitudinal/circumferential myocardial function and left ventricular (LV) ejection fraction had low heritability (ranging from 10 to 20%). Diastolic and standard LV function parameters had moderate heritability (ranging from 20 to 30%) except for end-systolic and end-diastolic volumes (respectively 30 and 45%). In contrast, GLSEndo/GLSEpi ratio had a high level of heritability (65%). Except for GLSendo/GLSepi ratio, a large percentage of variance remained unexplained (greater than 50%). In our population cohort, GLSendo/GLSepi ratio had a high level of heritability whereas other classical and mechanical LV function parameters did not. Given the increasing recognition of GLSendo/GLSepi ratio as an early/sensitive imaging biomarker of systolic dysfunction, our results suggest the possible existence of individual genetic predispositions to myocardial decline.

Performance of the ACMG-AMP criteria in a large familial renal glucosuria cohort with identified SLC5A2 sequence variants.

Familial Renal Glucosuria (FRG) is a co-dominantly inherited trait characterized by orthoglycaemic glucosuria. From 2003 to 2015 we have reported several cohorts validating SLC5A2 (16p11.2), encoding SGLT2 (Na+/glucose cotransporter family member 2), as the gene responsible for FRG. The aim of this work was to validate the variants identified in our extended FRG cohort of published, as well more recent unreported cases, according to the ACMG-AMP 2015 criteria. Forty-six variants were evaluated, including 16 novel alleles first described in this study. All are rare, ultra-rare or absent from population databases and most are missense changes. According to the ACMG-AMP standards, only 74% of the variants were classified as P/LP. The lack of descriptions of unrelated patients with similar variants or failing to test additional affected family members, averted a conclusion for pathogenicity in the alleles that scored VUS, highlighting the importance of both family testing and variant reporting. Finally, the cryo-EM structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state improved the ACMG-AMP pathogenicity score by identifying critical/functional protein domains.

Automated simulation for household road traffic noise exposure: Application and field evaluation in a high-density city

Road traffic noise is a major nuisance and a risk factor of poor health for urban dwellers. A household's exposure to road traffic noise, especially in a high-density city, can be easily modified by the surrounding built environment, i.e., roads, traffic, buildings, and the topography. This leads to high variation in noise exposure between neighboring households. Existing simulation-based studies were limited in accounting for the variation of noise exposure at the household level, which restricted their applications in public health research involving large numbers of participants. This paper describes a novel simulation-based workflow to assess household traffic noise exposure, which consists of 1) a source model to assess road traffic noise levels, 2) a propagation model to simulate noise propagation in complex three-dimensional urban areas, 3) an automation algorithm to process large quantity of simulation runs and data. The workflow has been evaluated using field studies conducted in Sham Shui Po District, Hong Kong, with reasonably good agreements between simulated and measured data. It was then used to assess road traffic noise exposure for a sample of 6158 households enrolled in the FAMILY Cohort, representing Hong Kong's population dwelling in the dense urban areas. Results showed that 83% of sampled households have been exposed to excessive road traffic noise above the World Health Organization (WHO) standard, or 30% above the local standard. The estimated burden of disease is over 45,000 disability-adjusted life-years (DALYs) from both high annoyance and sleep disturbance for households in Hong Kong. The study has contributed to the methodologies and datasets in evaluating noise exposure in high-density cities, which can further support urban noise mitigation policies and planning and population-based health studies in the next steps.

Longitudinal Associations Between Vitamin D Status and Cardiometabolic Risk Markers Among Children and Adolescents.

Vitamin D status has previously been associated with cardiometabolic risk markers in children and adolescents. In particular, it has been suggested that children with obesity are more prone to vitamin D deficiency and unfavorable metabolic outcomes compared with healthy-weight children. To conduct a longitudinal study assessing this association in children and stratify by body mass index (BMI) category. Children from the pan-European IDEFICS/I.Family cohort with at least one measurement of serum 25-hydroxyvitamin D [25(OH)D] at cohort entry or follow-up (n = 2171) were included in this study. Linear mixed-effect models were used to assess the association between serum 25(OH)D as an independent variable and z-scores of cardiometabolic risk markers (waist circumference, systolic [SBP] and diastolic blood pressure [DBP], high- [HDL] and low-density lipoprotein, non-HDL, triglycerides [TRG], apolipoprotein A1 [ApoA1] and ApoB, fasting glucose [FG], homeostatic model assessment for insulin resistance [HOMA-IR], and metabolic syndrome score) as dependent variables. After adjustment for age, sex, study region, smoking and alcohol status, sports club membership, screen time, BMI, parental education, and month of blood collection, 25(OH)D levels were inversely associated with SBP, DBP, FG, HOMA-IR, and TRG. The HOMA-IR z-score decreased by 0.07 units per 5 ng/mL increase in 25(OH)D. The 25(OH)D level was consistently associated with HOMA-IR irrespective of sex or BMI category. Low serum 25(OH)D concentrations are associated with unfavorable levels of cardiometabolic markers in children and adolescents. Interventions to improve vitamin D levels in children with a poor status early in life may help to reduce cardiometabolic risk.

ResQ Family: Respiratory Syncytial Virus (RSV) Infection in Infants and Quality of Life of Families-Study Protocol of a Multi-Country Family Cohort Study.

(1) Respiratory syncytial virus (RSV) infection in infants not only affects the child itself, but also their families. Nevertheless, information on the overall impact is scarce. A comprehensive caregiver-specific approach covering essential (health) dimensions and relevant stakeholders was initiated under the ResQ Family study conducted in Germany, France, Italy and Sweden. The primary objective is to investigate the health-related quality of life of parents and/or caregivers of children (<24 months) hospitalised for RSV. (2) Each participant completes an online questionnaire disseminated via social media and printed material in hospitals. Using the PedsQLTM FIM as well as further self-designed questions, parent and patient characteristics as well as potential stressors and preventive factors are recorded at baseline and after six weeks. Multivariate regression models with health-related quality of life as main outcome parameter will be conducted. (3) The study is currently in the recruitment process. A full analysis will be performed once the data collection phase is complete. First results are to be expected in late 2023. (4) Publishing the results in the form of scientific papers but also non-scientific (information) material will help us raise awareness for RSV and the importance of prevention among healthcare professionals, patient representatives and decision-makers.

Recessive CHRM5 variant as a potential cause of neurogenic bladder.

Neurogenic bladder is caused by disruption of neuronal pathways regulating bladder relaxation and contraction. In severe cases, neurogenic bladder can lead to vesicoureteral reflux, hydroureter, and chronic kidney disease. These complications overlap with manifestations of congenital anomalies of the kidney and urinary tract (CAKUT). To identify novel monogenic causes of neurogenic bladder, we applied exome sequencing (ES) to our cohort of families with CAKUT. By ES, we have identified a homozygous missense variant (p.Gln184Arg) in CHRM5 (cholinergic receptor, muscarinic, 5) in a patient with neurogenic bladder and secondary complications of CAKUT. CHRM5 codes for a seven transmembrane-spanning G-protein-coupled muscarinic acetylcholine receptor. CHRM5 is shown to be expressed in murine and human bladder walls and is reported to cause bladder overactivity in Chrm5 knockout mice. We investigated CHRM5 as a potential novel candidate gene for neurogenic bladder with secondary complications of CAKUT. CHRM5 is similar to the cholinergic bladder neuron receptor CHRNA3, which Mann et al. published as the first monogenic cause of neurogenic bladder. However, functional in vitro studies did not reveal evidence to strengthen the status as a candidate gene. Discovering additional families with CHRM5 variants could help to further assess the genes' candidate status.

Maternal adverse childhood experiences, child mental health, and the mediating effect of maternal depression: A cross-sectional, population-based study in rural, southwestern Uganda.

This study aimed to examine the intergenerational effects of maternal adverse childhood experiences (ACEs) and child mental health outcomes in rural Uganda, as well as the potentially mediating role of maternal depression in this pathway. Additionally, we sought to test the extent to which maternal social group membership attenuated the mediating effect of maternal depression on child mental health. Data come from a population-based cohort of families living in the Nyakabare Parish, a rural district in southwestern Uganda. Between 2016 and 2018, mothers completed surveys about childhood adversity, depressive symptoms, social group membership, and their children's mental health. Survey data were analyzed using causal mediation and moderated-mediation analysis. Among 218 mother-child pairs, 61 mothers (28%) and 47 children (22%) showed symptoms meeting cutoffs for clinically significant psychological distress. In multivariable linear regression models, maternal ACEs had a statistically significant association with severity of child conduct problems, peer problems, and total child difficulty scores. Maternal depression mediated the relationship between maternal ACEs and conduct problems, peer problems, and total difficulty, but this mediating effect was not moderated by maternal group membership. Maternal depression may act as a potential mechanism linking maternal childhood adversity with poor child mental health in the next generation. Within a context of elevated rates of psychiatric morbidity, high prevalence of childhood adversity, and limited healthcare and economic infrastructures across Uganda, these results emphasize the prioritization of social services and mental health resources for rural Ugandan families.

Cohort profile of FALCON: a prospective nationwide cohort of families with minor children who have lost a parent in Denmark in 2019–2021

Difficulties in recruiting newly bereaved families and following them over time present a major barrier in grief research following the death of a spouse/parent. We established FALCON—the first prospective nationwide cohort of families with children below age 18 years whose parent died in Denmark between April 2019 and July 2021. Data from parents and children were collected within 2 months of death with ongoing follow-up assessments up to 18 months post-death. A total of 992 families were invited. The final cohort consisted of 250 families (250 widowed parents, 134 adolescents, 120 children aged 6–12 years and 63 children aged 0–5 years). In this paper, we describe the rationale for the cohort’s creation, the challenges of researching grief in families, the methods used and future plans to utilize this unique family-level dataset.

The genetics of autism spectrum disorder in an East African familial cohort

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions affecting communication and social interaction in 2.3% of children. Studies that demonstrated its complex genetic architecture have been mainly performed in populations of European ancestry. We investigate the genetics of ASD in an East African cohort (129 individuals) from a population with higher prevalence (5%). Whole-genome sequencing identified 2.13 million private variants in the cohort and potentially pathogenic variants in known ASD genes (including CACNA1C, CHD7, FMR1, and TCF7L2). Admixture analysis demonstrated that the cohort comprises two ancestral populations, African and Eurasian. Admixture mapping discovered 10 regions that confer ASD risk on the African haplotypes, containing several known ASD genes. The increased ASD prevalence in this population suggests decreased heterogeneity in the underlying genetic etiology, enabling risk allele identification. Our approach emphasizes the power of African genetic variation and admixture analysis to inform the architecture of complex disorders.

Novel pathogenic CERKL variant in Iranian familial with inherited retinal dystrophies: genotype-phenotype correlation.

Inherited retinal dystrophies (IRDs) include a large chronic heterogeneity genetic disease. While many disease-causing pathogenic variants were involved in the progression of IRD, the Ceramide Kinase Like (CERKL) gene variant in Iranian patients is not well characterized. In this study, a consanguineous Iranian family with three generations was recruited whom presented with the clinical diagnosis of autosomal recessive IRD. By targeted next-generation sequencing (TGS) and Sanger sequencing, the proband was found to have a novel, pathological homozygous deletion variant c.560_568del (p.187_190del) of the CERKL gene (NM_001030311.2) that co-segregated with the disease in all affected family members. The Cerkl is highly expressed in the later four developmental retinal stages, playing a vital role in retina degeneration. Therefore, the identification of a novel, homozygous deletion CERKL variant c.560_568del (p.187_190del) in an IRD familial cohort descent provides insights into the molecular pathogenesis of IRD and facilitates genetic counseling and disease prediction.

Spinocerebellar Ataxia 36 is a Frequent Cause of Hereditary Ataxia in Eastern Spain.

Autosomal dominant spinocerebellar ataxia 36 (SCA36) is caused by hexanucleotide repeat expansion in the NOP56 gene. To assess frequency, clinical and genetic features of SCA36 in Eastern Spain. NOP56 expansion was tested in a cohort of undiagnosed cerebellar ataxia families (n = 84). Clinical characterization and haplotype studies were performed. SCA36 was identified in 37 individuals from 16 unrelated families. It represented 5.4% of hereditary ataxia patients. The majority were originally from the same region and displayed a shared haplotype. Mean age at onset was 52.5 years. Non-ataxic features included: hypoacusis (67.9%), pyramidal signs (46.4%), lingual fasciculations/atrophy (25%), dystonia (17.8%), and parkinsonism with evidence of dopaminergic denervation (10.7%). SCA36 is a frequent cause of hereditary ataxia in Eastern Spain, and is associated with a strong founder effect. SCA36 analysis should be considered prior to other studies, especially in AD presentations. Parkinsonism reported here broadens SCA36 clinical spectrum.

Identification of fecal microbiome signatures associated with familial longevity and candidate metabolites for healthy aging.

Gut microbiota associated with longevity plays an important role in the adaptation to damaging stimuli accumulated during the aging process. The mechanism by which the longevity-associated microbiota protects the senescent host remains unclear, while the metabolites of the gut bacteria are of particular interest. Here, an integrated analysis of untargeted metabolomics and 16S rRNA gene sequencing was used to characterize the metabolite and microbiota profiles of long-lived individuals (aged ≥90 years) in comparison to old-elderly (aged 75-89 years), young-elderly (aged 60-74 years), and young to middle-aged (aged ≤59 years) individuals. This novel study constructed both metabolite and microbiota trajectories across aging in populations from Jiaoling county (the seventh longevity town of the world) in China. We found that the long-lived group exhibited remarkably differential metabolomic signatures, highlighting the existence of metabolic heterogeneity with aging. Importantly, we also discovered that long-lived individuals from the familial longevity cohort harbored a microbiome distinguished from that of the general population. Specifically, we identified that the levels of a candidate metabolite, pinane thromboxane A2 (PTA2), which is positively associated with aging, were consistently higher in individuals with familial longevity and their younger descendants than in those of the general population. Furtherly, functional analysis revealed that PTA2 potentiated the efficiency of microglial phagocytosis of β-amyloid 40 and enhanced an anti-inflammatory phenotype, indicating a protective role of PTA2 toward host health. Collectively, our results improve the understanding of the role of the gut microbiome in longevity and may facilitate the development of strategies for healthy aging.

Curation Of Genes Associated with Primary Antibody Deficiencies Using A ClinGen Framework

The Antibody Deficiencies Gene Curation Expert Panel (AD-GCEP, Table 1**) was convened in 2020 as part of the Clinical Genome Resource (ClinGen), an NIH funded program to build a genomic knowledge base publicly available for laboratories, clinicians, and scientists. The objective of the AD-GCEP was to curate genes associated with inborn errors of immunity (IEIs) that cause antibody deficiencies with or without quantitative B-cell defects and other phenotypic manifestations. Using a gene-disease validity scoring system established by ClinGen, the gene curation provides guidelines for definitive, strong, moderate, limited, or disputed classification depending on the reported evidence. We selected 55 genes from Table 3 of the International Union of Immunological Societies (IUIS 2022) classification of IEIs. As of November 2022, 46 of these have been curated (Table 2). Several of these genes are associated with multiple disease entities, for which the ClinGen lumping-splitting criteria were applied. Through curation, the GCEP has identified 53 gene-disease relationships. Twenty-six (49%) were definitive classifications with abundant genetic and experimental evidence. Only three genes reached a strong classification (5.7%): RAC2 deficiency, FNIP1-associated syndrome, and SPI1 deficiency. In contrast, insufficient evidence led to moderate classifications for eight (15.1%) and limited classifications for thirteen (24.5%) gene-disease relationships. Of note, two gene-disease relationships (3.7%) were disputed: BTK-isolated growth hormone deficiency (GHD) type III, and common variable immunodeficiency associated with INO80 variants (CVID1). The single family cohort reported with the BTK variant and GHD was later shown to have another molecular etiology, while the INO80 variants had a population frequency too high to be regarded as disease-causing. An additional ten genes need to be curated to complete the current list of antibody defects. Additionally, the AD-GCEP has collaborated with other GCEPs to curate related genes such as MOGS, ATP6AP1, CD40L, KMT2A, MSH6, GATA2, PMS2, BLK and BRWD1, which cause antibody deficiency as one component of a more extensive phenotype series. Information about these genes is provided in Table 3. In summary, the work of this GCEP represents the first comprehensive gene curation for antibody deficiencies.Table 1Members of the Antibody Deficiency (AD) GCEPMemberRoleRoshini S. Abraham, PhD, D (ABMLI)Co-Chair, ExpertStuart Tangye, PhD.Co-Chair, ExpertForum Raval, Ph.D.Co-Chair ExpertAlejandro Nieto, Ph.DCoordinatorKathleen E. Sullivan, MD, PhDExpertAnna Sediva, MDExpertKejian Zhang, MDExpertStephen Jolles, MDExpertPJ Maglione, MD, PhDExpertCapucine Picard, MD, PhDExpertCraig Platt, MD, PhDExpertAnita Chandra, PhDExpertKlaus Warnatz, MDExpertAdrian Harry Lesmana, MDExpertShruthi Mohan, PhDBiocuratorJustyne Ross, PhDBiocuratorMichelle Paczosa, PhDBiocuratorRasha Soliman, MD, MSBiocuratorOlga Sarmento, PhDBiocuratorErmal Aliu, MDBiocuratorTable 2Classification of genes curated by the Antibody Deficiencies GCEP (AD-GCEP)GeneDiseaseMOIClassificationAICDAHyper-IgM syndrome type 2 (AID deficiency)ARDefinitiveATMAtaxia telangiectasia (AT)ARDefinitiveBLNKAgammaglobulinemia 4, autosomal recessive (BLNK-associated agammaglobulinemia)ARDefinitiveBTKBruton-type agammaglobulinemia (X-linked agammaglobulinemia)XLRDefinitiveBTKIsolated growth hormone deficiency type IIIXLRDisputedCARD11BENTA (B cell expansion with NFκB and T cell anergy) diseaseADDefinitiveCARD11Severe combined immunodeficiency due to CARD11 deficiencyARDefinitiveCARD11Immunodeficiency 11b with atopic dermatitis (CARD11 + atopic dermatitis)ADDefinitiveCD19Immunodeficiency, common variable, 3 (CD19 deficiency)ARDefinitiveCD79AAgammaglobulinemia 3, autosomal recessive (Ig-alpha deficiency)ARDefinitiveCD79BAgammaglobulinemia 6, autosomal recessive (Ig-beta deficiency)ARDefinitiveCR2Immunodeficiency, common variable, 7 (CD21 deficiency)ARDefinitiveCTLA4Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (CHAI)ADDefinitiveIGHMAutosomal recessive agammaglobulinemia 1 (Mu-heavy chain deficiency)ARDefinitiveIKZF1Pancytopenia due to IKZF1mutations; IKAROS deficiencyADDefinitiveIKZF1Autoimmune disease, IKAROS defectADModerateLRBACombined immunodeficiency due to LRBA deficiency; LATAIEARDefinitiveNFKB1Immunodeficiency, common variable, 12 (NFkB1 deficiency)ADDefinitiveNFKB2Immunodeficiency, common variable, 10 (NFkB2 deficiency, DAVID syndrome)ADDefinitivePIK3CDImmunodeficiency 14b, autosomal recessiveARDefinitivePIK3CDImmunodeficiency 14 (APDS type 1; activated p110-delta syndrome, PASLI disease)ADDefinitivePIK3R1Immunodeficiency 36 (APDS type 2; gain-of-function disease in PI3K regulatory subunits)ADDefinitivePIK3R1Agammaglobulinemia 7, autosomal recessive (p85alpha subunit defect)ARLimitedTNFRSF13BImmunodeficiency, common variable, 2 (TACI deficiency)ARDefinitiveCD40Hyper-IgM syndrome type 3 (MONDO:0011735), CD40 deficiencyARDefinitiveTCF3Autosomal agammaglobulinemia (MONDO:0011096)/(agammaglobulinemia 8B)/AD (agammaglobulinemia 8A)ARDefinitiveTRNT1SIFD (sideroblastic anemia, B cell immunodeficiency, periodic fevers and developmental delay) retinitis pigmentosa with erythrocytic microcytosisARDefinitiveICOSCommon variable immunodeficiency, ICOS deficiencyARDefinitiveIL21RImmunodeficiency 56, IL-21R deficiencyARDefinitiveFNIP1FNIP1-associated syndrome, FNIP1 deficiencyARStrongSPI1Agammaglobulinemia 10, PU.1 deficiencyADStrongIGLL1Agammaglobulinemia 2, autosomal recessive, Ig light chain deficiency (lambda-like)ARModerateRAC2Immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF)ADStrongRAC2Immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF)ARModerateRAC2Neutrophil immunodeficiency syndrome, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF)ADModerateSEC61A1SEC61A1 deficiency, plasma cell deficiencyADModerateSLC39A7Agammaglobulinemia 9, ZIP7 deficiencyARModerateTOP2BB-cell immunodeficiency, distal limb anomalies, and urogenital malformations, Hoffman syndromeADModerateUNGHyper-IgM syndrome type 5, UNG deficiencyARModerateARHGEF1Immunodeficiency 62, ARHGEF1 deficiencyARLimitedCD81Immunodeficiency, common variable, 6, CD81 deficiencyARLimitedCTNNBL1Common variable immunodeficiency, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopeniasARLimitedIGKCRecurrent infections associated with rare immunoglobulin isotypes deficiency, Ig kappa light chain deficiencyARLimitedIRF2BP2Immunodeficiency, common variable, 14, IRF2BP2 deficiencyADLimitedMS4A1Immunodeficiency, common variable, 5, CD20 deficiencyARLimitedPOU2AF1Agammaglobulinemia, Bob1 deficiencyARLimitedSH3KBP1Immunodeficiency 61, CIN85 deficiencyXLRLimitedTNFRSF13CImmunodeficiency, common variable, 4, BAFF-R deficiencyARLimitedTNFSF12Common variable immunodeficiency, TWEAK deficiencyADLimitedTNFSF13Common variable immunodeficiency, APRIL deficiencyARLimitedIL21Common variable immunodeficiency 11, IL-21 deficiencyARLimitedINO80immunodeficiency, common variable, 1, INO80 deficiencyARDisputedAR: autosomal recessive; AD: autosomal dominant; XLR: X-linked recessiveTable 3Genes associated with antibody deficiencies curated in collaboration with other GCEPsGeneDiseaseInheritanceCollaborating GCEPClassificationMOGSMOGS-congenital disorder of glycosylationARGeneral Inborn Errors of Metabolism GCEPDefinitiveATP6AP1Congenital disorder of glycosylation type IIXLRGeneral Inborn Errors of Metabolism GCEPLimitedCD40LX-linked Hyper IgM syndromeXLRSCID-CIDDefinitiveKMT2AWiedemann-Steiner syndromeADSyndromic Disorders GCEPDefinitiveMSH6mismatch repair cancer syndrome 1ARHereditary Cancer GCEPDefinitiveGATA2Mono-MAC syndrome, Familial myeloid leukemia, DCML deficiency, GATA2 haploinsufficiencyADHereditary CancerDefinitivePMS2Mismatch repair cancer syndrome 1ARHereditary CancerDefinitiveBLKMonogenic diabetesADMonogenic DiabetesRefutedBRWD1Primary Ciliary Dyskinesia (PCD)ARMotile CiliopathyRefutedBRWD1Agammaglobulinemia, B cell deficiencyADTransferred to AD-GCEPLimited

High-resolution structural variants catalogue in a large-scale whole genome sequenced bovine family cohort data

BackgroundStructural variants (SVs) are chromosomal segments that differ between genomes, such as deletions, duplications, insertions, inversions and translocations. The genomics revolution enabled the discovery of sub-microscopic SVs via array and whole-genome sequencing (WGS) data, paving the way to unravel the functional impact of SVs. Recent human expression QTL mapping studies demonstrated that SVs play a disproportionally large role in altering gene expression, underlining the importance of including SVs in genetic analyses. Therefore, this study aimed to generate and explore a high-quality bovine SV catalogue exploiting a unique cattle family cohort data (total 266 samples, forming 127 trios).ResultsWe curated 13,731 SVs segregating in the population, consisting of 12,201 deletions, 1,509 duplications, and 21 multi-allelic CNVs (> 50-bp). Of these, we validated a subset of copy number variants (CNVs) utilising a direct genotyping approach in an independent cohort, indicating that at least 62% of the CNVs are true variants, segregating in the population. Among gene-disrupting SVs, we prioritised two likely high impact duplications, encompassing ORM1 and POPDC3 genes, respectively. Liver expression QTL mapping results revealed that these duplications are likely causing altered gene expression, confirming the functional importance of SVs. Although most of the accurately genotyped CNVs are tagged by single nucleotide polymorphisms (SNPs) ascertained in WGS data, most CNVs were not captured by individual SNPs obtained from a 50K genotyping array.ConclusionWe generated a high-quality SV catalogue exploiting unique whole genome sequenced bovine family cohort data. Two high impact duplications upregulating the ORM1 and POPDC3 are putative candidates for postpartum feed intake and hoof health traits, thus warranting further investigation. Generally, CNVs were in low LD with SNPs on the 50K array. Hence, it remains crucial to incorporate CNVs via means other than tagging SNPs, such as investigation of tagging haplotypes, direct imputation of CNVs, or direct genotyping as done in the current study. The SV catalogue and the custom genotyping array generated in the current study will serve as valuable resources accelerating utilisation of full spectrum of genetic variants in bovine genomes.

Prepregnancy BMI, gestational weight gain, and susceptibility to autism-related traits: the EARLI and HOME studies.

Excessive gestational weight gain (GWG) has been associated with autism spectrum disorder (ASD). This study sought to examine whether familial susceptibility for autism, intensity of ASD-related behaviors, or prepregnancy BMI influences the association of GWG with ASD-related behaviors. Using data from the Early Autism Risk Longitudinal Investigation (EARLI) study (n=136), a familial enriched cohort of mothers who had a previous child with ASD, and the Health Outcomes and Measures of the Environment (HOME) study (n=253), a general population cohort, gestational age and prepregnancy BMI category-specific GWG z scores were calculated. Caregivers completed the Social Responsiveness Scale (SRS) to assess the presence and severity of ASD-related traits in children aged 3 to 8 years. Using quantile regression, the association between GWG z scores and ASD-related behaviors in children was estimated. In HOME, among mothers who had overweight or obesity prepregnancy BMI values, GWG z scores and SRS scores were positively associated in children with more ASD-related traits (higher SRS scores), but not in children with fewer ASD-related traits. Similar patterns were observed in EARLI among mothers with prepregnancy obesity. GWG may be associated with autism-related behaviors among children who have a greater predisposition to these behaviors and who have mothers with prepregnancy overweight or obesity.

A Familial Cohort of Adult-Onset Alexander Disease (P12-3.016)

<h3>Objective:</h3> To describe a familial cohort of adult-onset Alexander Disease. <h3>Background:</h3> Leukodystrophies are a group of rare, hereditary disorders characterized by abnormal myelination. Each leukodystrophy is caused by abnormalities in one or more genes leading to abnormal production of myelin (hypomyelination) or destruction (demyelination). Leukodystrophies are also classified by the region of the brain or in some cases peripheral nerves that are affected. Alexander Disease is a leukodystrophy characterized by a confluent pattern of demyelination. It is caused by autosomal dominant gain-of-function mutation in the <i>GFAP (glial fibrillary acidic protein)</i> gene. <i>GFAP</i> serves an intermediate filament protein of mature astrocytes; incorrect formation of the protein can lead to astrocyte cytoskeletal collapse and abnormal protein aggregation. Clinically, this can lead to innumerable neurologic manifestations in the affected individual. Alexander Disease predominantly affects neonates, infants, children and rarely adults. We describe a familial cohort of adult-onset Alexander Disease associated with a c.758C&gt;G (p.A253G) mutation of GFAP. This mutation has previously been described in neonates. In this case series we describe the clinical and radiologic features of three sisters with adult-onset symptoms. The first patient is a 53-year-old female who presented with progressive myelopathy and later developed bulbar symptoms. Her 51-year-old sister developed progressive, bilateral leg weakness and gait disturbance. She progressed to have profound cognitive dysfunction. The MRI features include T2 hyperintensities with atrophy in the midbrain and upper cervical spine with peripheral rim brainstem and periventricular garlands. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> N/A <h3>Conclusions:</h3> These cases describe the clinical and radiologic features of a familial cohort of adult-onset Alexander disease in a mutation previously described only in childhood onset. This also illustrates the importance of considering a diagnosis of Alexander Disease in adult patients and the necessity of genetic analysis of patients and their family members. <b>Disclosure:</b> Dr. Wolf has nothing to disclose. Dr. Gettings has nothing to disclose. Dr. Goodrich has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono.

Birth weight and subclinical cardiovascular and renal damage in a population-based study (the STANISLAS cohort study).

Although preterm-born and low-birth-weight individuals have an increased risk of cardiovascular diseases in adulthood, little is known regarding early cardiovascular and renal damage (CVRD) or hypertension in adulthood. Our study investigated the association of birth weight with early CVRD markers as well as the heritability of birth weight in an initially healthy family-based cohort. This study was based on 1028 individuals from the familial longitudinal STANISLAS cohort (399 parents/629 children) initiated in 1993-1995, with a fourth examination conducted in 2011-2016. Analyses performed at the fourth visit included pulse-wave velocity, central pressure, ambulatory blood pressure, hypertension status, diastolic dysfunction/distensibility, left ventricular mass indexed (LVMI), carotid intima-media thickness and kidney damage. The family structure of the cohort allowed birth weight heritability estimation. Mean (±SD) birth weight was 3.3 ± 0.6 kg. Heritability was moderate (42-44%). At the fourth visit, individuals were 37 years old (32.0-57.0), 56% were women and 13% had antihypertensive treatment. Birth weight was strongly and negatively associated with hypertension [odds ratio (OR) 95% confidence interval (CI) 0.61 (0.45-0.84)]. A nonlinear association was found with LVMI, participants with a birth weight greater than 3 kg having a higher LVMI. A positive association ( β 95% CI 5.09 (1.8-8.38)] was also observed between birth weight and distensibility for adults with normal BMI. No associations were found with other CVRD. In this middle-aged population, birth weight was strongly and negatively associated with hypertension, and positively associated with distensibility in adults with normal BMI and with LVMI for higher birth weights. No associations were found with other CVRD markers.

An investigation into the relationship between community engagement and maternal mental health in Calgary, Alberta using the All Our Families cohort.

Existing literature shows that increased community engagement is associated with decreased depressive symptoms. To our knowledge, no existing studies have investigated the relationship between community engagement and adverse mental health among mothers in a Canadian context, nor has this relationship been studied over time. The current study aims to address these gaps by modelling the association between community engagement and anxiety and depression longitudinally using a cohort of prenatal and postnatal mothers living in Calgary, Alberta. We used data from the All our Families (AOF) study, a prospective cohort study of expectant and new mothers in Calgary, Alberta from 2008 to 2017 across seven timepoints. We used three-level latent growth curves to model the relationship between individual-level community engagement and maternal depression and anxiety scores, while adjusting for both individual and neighborhood-level characteristics. The study sample consisted of 2129 mothers across 174 neighborhoods in Calgary. Adjusted latent growth curve models demonstrated that community engagement was associated with lower depression (b = -0.28, 95% CI -0.33, -0.23) and anxiety (b = -0.07, 95% CI -0.12, -0.02) scores among mothers over time. Adjusted results show that community engagement has a protective effect against depression and anxiety amongst mothers. The results of this study are in line with existing evidence suggesting that social cohesion, civic participation, and community engagement are protective against adverse mental health outcomes.

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations.

Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.