Amish Population Research Articles

Alterations of the Ganglion Cell Complex in Age-Related Macular Degeneration: An Amish Eye Study Analysis

To compare the ganglion cell complex (GCC) thickness in eyes with age-related macular degeneration (AMD) vs healthy controls in an elderly Amish population. Prospective cross-sectional study. This is a post hoc analysis of the family-based prospective study of Amish subjects. Study subjects underwent imaging with the Cirrus HD-OCT (Carl Zeiss Meditec Inc) using a macular cube protocol of 512 × 128 scans (128 horizontal B-scans, each comprising 512 A-scans) over a 6 mm × 6 mm region centered on the fovea. The ganglion cell analysis algorithm calculated the GCC thickness by segmenting the outer boundaries of the retinal nerve fiber layer (RNFL) and inner plexiform layer (IPL) in all B-scans of the volume, with the region between these boundaries representing the combined thickness of the ganglion cell layer (GCL) and the IPL. A number of parameters were used to evaluate the GCC thickness: the average GCC thickness, minimum (lowest GCC thickness at a single meridian crossing the elliptical annulus), and sectoral (within each of 6 sectoral areas: superior, superotemporal, superonasal, inferior, inferonasal, and inferotemporal). The stage of AMD was graded on color fundus photographs in accordance with the Beckman Initiative for Macular Research classification system. Of 1339 subjects enrolled in the Amish eye study, a total of 1294 eyes of 1294 subjects had all required imaging studies of sufficient quality and were included in the final analysis. Of these, 798 (62%) were female. Following age adjustment, the average GCC thickness was significantly (P < .001) thinner in AMD subjects (73.71 ± SD; 13.77 µm) compared to normals (77.97 ± 10.42 µm). An independent t test showed that the early AMD (75.03 ± 12.45 µm) and late AMD (61.64 ± 21.18 µm) groups (among which eyes with geographic atrophy [GA] had the lowest thickness, of 58.10 ± 20.27 µm) had a statistically significant lower GCC thickness compared to eyes without AMD. There was no significant differences in average GCC thickness between early AMD and intermediate AMD (76.36 ± 9.25 µm) eyes. The GCC thickness in AMD eyes is reduced compared to normal eyes; however, the relationship is complex, with the greatest reduction in late AMD eyes (particularly eyes with GA) but no difference between early and intermediate AMD eyes.

RMRP-related short stature: A report of six additional Japanese individuals with cartilage hair hypoplasia and literature review.

Biallelic pathogenic variants in RMRP, the gene encoding the RNA component of RNase mitochondrial RNA processing enzyme complex, have been reported in individuals with cartilage hair hypoplasia (CHH). CHH is prevalent in Finnish and Amish populations due to a founder pathogenic variant, n.71A > G. Based on the manifestations in the Finnish and Amish individuals, the hallmarks of CHH are prenatal-onset growth failure, metaphyseal dysplasia, hair hypoplasia, immunodeficiency, and other extraskeletal manifestations. Herein, we report six Japanese individuals with CHH from four families. All probands presented with moderate short stature with mild metaphyseal dysplasia or brachydactyly. One of them had hair hypoplasia and the other immunodeficiency. By contrast, the affected siblings of two families showed only mild short stature. We also reviewed all previously reported 13 Japanese individuals. No n.71A > G allele was detected. The proportions of Japanese versus Finnish individuals were 0% versus 70% for birth length < -2.0 SD, 84% versus 100% for metaphyseal dysplasia and 26% versus 88% for hair hypoplasia. Milder manifestations in the Japanese individuals may be related to the difference of genotypes. The mildest form of CHH phenotypes is mild short stature without overt skeletal alteration or extraskeletal manifestation and can be termed "RMRP-related short stature".

Detecting Protective Rare Variants for Alzheimer’s Disease from Whole‐Genome Sequencing in the Amish

AbstractBackgroundA shift in focus from risk to resilience for Alzheimer’s disease (AD) encourages efforts to uncover novel AD biological mechanisms. Rare variants identified through whole genome sequencing (WGS) may represent an important and understudied component of complex trait genetics. While population‐based studies are powered to discover associations with common genetic variants, founder populations are better powered for discovery of previously unknown rare alleles that have risen to higher frequency due to genetic drift.MethodWe examined WGS data from the Mid‐Western Amish population in a genome‐wide search for rare coding variants shared only among cognitively‐unimpaired (CU) individuals. The cognitive status of each individual was assigned via consensus review of medical history and neuropsychological testing. Allele frequencies were calculated across all samples and for CU and cognitively‐impaired (CI) groups separately. We defined rare variants as having an allele frequency &lt;0.05 across all samples. Variants with a minor allele count (MAC)&gt;10 in the CU group, and 0 in the CI group were annotated to determine likely loss of function.ResultAfter extensive QC, 1,048 samples were available to estimate overall allele frequency. Allele frequencies of rare variants (n = 11,854,817) within 634 CU (mean age = 81.53±6.10, 60% female) and within 184 CI (mean age = 84.77±6.60, 62% female) individuals were compared and 51,616 variants with MAC &gt;10 were found only in CU. There were 316 unique coding variants (288 missense, 4 inframe_insertion, 6 inframe_deletion, 11 frameshift, 4 stop_gained, 3 splice_donor) and 180 synonymous variants located within 425 unique genes. Among them, 7 missense variants and 7 synonymous variants had MAC &gt;20 and the remaining variants had MAC of 11‐20. The mean allele frequency of the 7 missense variants was 0.0038 in TOPMed compared to 0.0154 in our data. Two synonymous variants were located within proposed AD genes (NYAP1 and ZNF423). Additionally, several untranslated region or nonsense‐mediated decay transcript variants existed within 26 known AD gene regions, among which 8 of them are reported to harbor protective variants for AD.ConclusionNumerous rare variants potentially impacting gene function were found only in CU individuals, providing a rich resource for further investigation of genes that may provide protection from cognitive impairment.

Clonal Hematopoiesis in Cartilage-Hair Hypoplasia

Background: Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder characterized by short stature, hypotrichosis, combined immunodeficiency, and macrocytic anemia. CHH is caused by germline mutations in the RMRP gene encoding the RNA component of the mitochondrial RNA processing endoribonuclease. CHH is heavily enriched in the Finnish (1 in 23000 births) and the Amish (1 in 1340 births) populations. Transient macrocytic anemia is common in children with CHH, whereas severe hypoplastic macrocytic anemia is only present in 10% of pediatric CHH patients and can be treated with allogeneic hematopoietic stem cell transplantation (HSCT). The mechanism behind hypoplastic anemia in CHH is unknown: while erythroid differentiation from hematopoietic stem cells is impaired in vitro in CHH, immune dysregulation may also play a role in this phenotype. Clonal hematopoiesis is a common phenomenon of aging. Patients with inherited and immune-mediated bone marrow failure (BMF) show distinct spectra of clonal hematopoiesis mutations, reflecting context-specific selection of hematopoietic stem cell clones. However, the spectrum of clonal hematopoiesis is yet to be characterized in CHH. Methods: To assess the landscape of somatic alterations in hematopoietic cells in CHH, we performed whole exome sequencing (WES) on twelve bone marrow samples of four pediatric (age 4 to 13 years) and eight adult (age 20 to 52 years) unrelated subjects with CHH. Three children with CHH had severe hypoplastic anemia at the time of DNA sampling and three patients underwent HSCT during follow-up. Seven adults with CHH had normal blood counts and no severe immune phenotypes despite other clinical manifestations of CHH. Matched skin fibroblast samples were available for five CHH adults in the cohort for whom we performed tumor-normal variant calling. For the remaining cases, variant calling was based on tumor-only samples and stringent filtering to exclude germline variants. Additionally, we queried the FINRISK dataset, a Finnish cohort comprising WES and SNP microarray data from 10 129 participants, for the presence of CHH associated RMRP variants and evaluated their association with clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs). Results: The median WES coverage of the bone marrow samples was 445x (347-505). Eleven out of 12 patients were homozygous for the RMRP founder variant n.71A&amp;gt;G and one patient was compound heterozygous for two pathogenic RMRP variants. We observed no somatic reversion of the germline RMRP variants. Two pediatric patients had variants in the CHIP genes: CHH1 (age 13 years) with TP53 hotspot variant R175C (variant allele frequency, VAF 0.006) and CHH2 (age 4 years) with BCORL1 P1681Qfs*20 (VAF 0.025). One fifty-year-old patient had a DNMT3A splicing variant c.1555-1G&amp;gt;C (VAF 0.022), likely consistent with CHIP observed in older general population. To identify clonal hematopoiesis outside the classical CHIP genes, we performed conservative filtering of the remaining somatic variant calls, resulting in a list of 36 high-confidence coding variants (VAF &amp;gt;0.02). These variants were present in 10 out of 12 patients; no recurrent genetic alterations were observed. Finally, the analysis of the FINRISK dataset revealed eleven participants with RMRP disease-associated variants; each participant had one heterozygous RMRP variant. No enrichment of CHIP variants or mCAs were observed in carriers of RMRP variants. Conclusion: We observed TP53 and BCORL1 mutations in the bone marrow samples of pediatric patients with CHH. In comparison to other CHIP-associated conditions, BCORL1 variants are disproportionately represented in immune-mediated aplastic anemia, potentially suggestive of similar immune-mediated origin of hypoplastic anemia in CHH. TP53 mutations are abundant in inherited BMF syndromes; however and in contrast to classical inherited BMF syndromes, CHH is not associated with increased risk of myeloid malignancies. No enrichment of classical or non-classical clonal hematopoiesis mutations were observed in adults with clinical CHH diagnosis or in RMRP variant carriers in the population-level FINRISK cohort. This is consistent with transient selection pressure on hematopoietic stem cells in childhood CHH. To our knowledge, our study is the first attempt to characterize the spectrum of clonal hematopoiesis in CHH.

Missense variants in SORT1 are associated with LDL-C in an Amish population

Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL6/J mouse via CRISPR/Cas9 had decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C.

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish

Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants. Using this information, polygenic risk scores (PRSs) can be calculated to quantify an individual's relative disease risk due to genetic factors. The Amish are a founder population descended from German and Swiss Anabaptist immigrants. They experienced a genetic bottleneck after arrival in the United States, making their genetic architecture different from the broader European ancestry population. Prior work has demonstrated the lack of transferability of PRSs across populations. Here, we compared the performance of PRSs derived from genome-wide association studies (GWASs) of Amish individuals to those derived from a large European ancestry GWAS. Participants were screened for cognitive impairment with further evaluation for AD. Genotype data were imputed after collection via Illumina genotyping arrays. The Amish individuals were split into two groups based on the primary site of recruitment. For each group, GWAS was conducted with account for relatedness and adjustment for covariates. PRSs were then calculated using weights from the other Amish group. PRS models were evaluated with and without covariates. The Amish-derived PRSs distinguished between dementia status better than the European-derived PRS in our Amish populations and demonstrated performance improvements despite a smaller training sample size. This work highlighted considerations for AD PRS usage in populations that cannot be adequately described by basic race/ethnicity or ancestry classifications.

Vitamin D Deficiency Increases Vulnerability to Canagliflozin-induced Adverse Effects on 1,25-Dihydroxyvitamin D and PTH.

Canagliflozin has been reported to increase the risk of bone fracture-possibly mediated by decreasing 1,25-dihydroxyvitamin D (1,25(OH)2D) and increasing parathyroid hormone (PTH). This work investigated whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD3 supplementation is protective. This community-based, outpatient study had a paired design comparing individual participants before and after VitD3 supplementation. Eleven VitD-deficient (25-hydroxyvitamin D [25(OH)D] ≤ 20 ng/mL) individuals were recruited from the Amish population in Lancaster, Pennsylvania. Participants underwent 2 canagliflozin challenge protocols (300 mg daily for 5 days): the first before and the second after VitD3 supplementation. In the VitD3 supplementation protocol, participants received VitD3 supplementation (50 000 IU once or twice a week depending on body mass index for 4-6 weeks) to achieve 25(OH)D of 30 ng/mL or greater. Two coprimary end points were identified: effects of VitD3 supplementation on canagliflozin-induced changes in 1,25(OH)2D and PTH. Secondary end points included effects of VitD3 supplementation on baseline levels of VitD metabolites and PTH. VitD3 supplementation increased mean 25(OH)D from 16.5 ± 1.6 to 44.3 ± 5.5 ng/mL (P = .0006) and 24,25-dihydroxyvitamin D (24,25(OH)2D) from 1.0 ± 0.1 to 4.3 ± 0.6 ng/mL (P = .0002). Mean 1,25(OH)2D and PTH were unchanged. VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)2D (from -31.3%±4.7% to -9.3%±8.3%; P = .04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; P = .005). VitD deficiency rendered individuals more vulnerable to adverse effects of canagliflozin on biomarkers associated with bone health. VitD3 supplementation was protective against canagliflozin's short-term adverse effects on 1,25(OH)2D and PTH.

In-Depth Mass Spectrometry Analysis Reveals the Plasma Proteomic and N-Glycoproteomic Impact of an Amish-Enriched Cardioprotective Variant in B4GALT1

B4GALT1 encodes β-1,4-galactosyltransferase 1, an enzyme that plays a major role in glycan synthesis in the Golgi apparatus by catalyzing the addition of terminal galactose. Studies increasingly suggest that B4GALT1 may be involved in the regulation of lipid metabolism pathways. Recently, we discovered a single-site missense variant Asn352Ser (N352S) in the functional domain of B4GALT1 in an Amish population, which decreases the level of LDL-cholesterol (LDL-c) as well as the protein levels of ApoB, fibrinogen, and IgG in the blood. To systematically evaluate the effects of this missense variant on protein glycosylation, expression, and secretion, we developed a nano-LC-MS/MS-based platform combined with TMT-labeling for in-depth quantitative proteomic and glycoproteomic analyses in the plasma of individuals homozygous for the B4GALT1 missense variant N352S versus non-carriers (n = 5 per genotype). A total of 488 secreted proteins in the plasma were identified and quantified, 34 of which showed significant fold changes in protein levels between N352S homozygotes and non-carriers. We determined N-glycosylation profiles from 370 glycosylation sites in 151 glycoproteins and identified ten proteins most significantly associated with decreased galactosylation and sialyation in B4GALT1 N352S homozygotes. These results further support that B4GALT1 N352S alters the glycosylation profiles of a variety of critical target proteins, thus governing the functions of these proteins in multiple pathways, such as those involved in lipid metabolism, coagulation, and the immune response.

Multiple Intestinal Atresia with Combined Immunodeficiency, a New Gene Arises

We present here a single case report of a 2-day-old female born to a 29-year-old G4P3→4 Swartzentruber Amish mother at 35 weeks gestation that presented with abdominal distension and failure to pass meconium.Family history was positive for a cousin born with multiple intestinal atresia (MIA) and combined immunodeficiency (CID) who died in his first month of life. A primary immune deficiency targeted gene panel was done, covering TTC7A, in addition to 206 other genes, with no known mutations identified.An exploratory laparotomy was performed on DOL4 with MIA observed, as well as malrotation without volvulus. Repair of pyloric atresia and multiple small bowel resections and anastomosis were performed. She was kept NPO with TPN and NG suctioning of gastric contents for bowel rest.Immunologic profiling revealed low CD3+ cells (578/µL), very low CD8+ T cells (23/µL), low CD4+ T cells (485/µL), normal NK and B cell counts, low levels of serum IgM (< 10 mg/dL) with normal levels of IgG (likely maternal) and IgA. Mitogen stimulation testing was normal. Sanger sequencing showed a homozygous c.4867 T>G (p.Tyr1623Asp) mutation in PIK4A confirming the diagnosis of Gastrointestinal Defects and Immunodeficiency Syndrome 2 (GIDID2). Despite surgery, the patient continued to have large volume NG output without return of bowel function. Other treatment options, including long term TPN, potential small bowel and liver transplants, and HSCT were discussed, but the family elected for hospice given the poor prognosis. She passed away on DOL 28. PI4KIIIα, encoded by PI4KA, catalyzes the conversion of phosphatidyl inositol to phosphatidyl inositol-4-phosphate while using TTC7A as a scaffolding protein. This process is critical for development of enterocyte polarity and actomyosin contractility in multiple cell types. PI4KA mutations have only recently been implicated in causing MIA with CID and can be missed in many genetic screens. GIDID2 is a devastating disease in which intestinal surgery provides only an immediate mechanical fix, without improving mortality. Further research on the molecular mechanisms that govern GIDID2 is critically needed to identify new treatment modalities. Furthermore, awareness of PI4KA mutations in newborns with MIA with CID is critical, particularly in Amish populations.

Neurological insights on two siblings with GM3 synthase deficiency due to novel compound heterozygous ST3GAL5 variants

BackgroundST3GAL5 encodes GM3 synthase (ST3 beta-galactoside alpha-2,3-sialyltransferase 5; ST3GAL5), which synthesizes GM3 by transferring sialic acid to lactosylceramide. GM3, a sialic acid-containing glycosphingolipid known as ganglioside, is a precursor to the biosynthesis of various more complex gangliosides that are active in the brain. Biallelic variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD), a rare congenital disorder of glycosylation. GM3SD was first identified in the Amish population in 2004. CaseWe report two siblings diagnosed with GM3SD due to novel compound heterozygous ST3GAL5 variants. The novel ST3GAL5 variants, detected by whole-exome sequencing in the patients, were confirmed to be pathogenic by GM3 synthase assay. The clinical courses of these patients, which began in infancy with irritability and growth failure, followed by developmental delay and hearing loss, were consistent with previous case reports of GM3SD. The older sibling underwent deep brain stimulation for severe involuntary movements at the age of 9 years. The younger sibling suffered from acute encephalopathy at the age of 9 months and subsequently developed refractory epilepsy. DiscussionReports of GM3SD outside the Amish population are rare, and whole-exome sequencing may be required to diagnose GM3SD in non-Amish patients. Since an effective treatment for GM3SD has not yet been established, we might select deep brain stimulation as a symptomatic treatment for involuntary movements in GM3SD.

Attitudes toward the Amish Held by Nursing and Social Work Students at a Midwestern University

As Amish populations increase and move across North America, the likelihood grows that healthcare professionals will come into contact with them. No studies have been conducted to examine contact frequency with or attitudes of healthcare providers toward the Amish. The aims of this study were to examine attitudes toward the Amish among nursing and social work students attending a Christian liberal arts university in a Midwestern state, and, to determine the relationship between students’ cultural awareness, their knowledge of the Amish, their contact with the Amish, and their attitudes toward the Amish. The participants were anonymously surveyed using the Revised Attitudes toward the Amish questionnaire (RATA), the Multicultural Awareness Survey (MAS), a Brief Knowledge of Amish Culture questionnaire, and a demographics form which included questions about contact frequency. One hundred and forty-four students completed the survey (n = 106 nursing students; n= 40 social work students). Contact frequency was significantly correlated with knowledge of Amish culture (p &lt;.001). Students who were more aware of other cultures had a significantly more tolerant attitude toward the Amish (p &lt;.001). These university students had more tolerant attitudes toward the Amish when they had a higher level of multicultural awareness and more knowledge of the Amish culture itself. Educators may help students become more tolerant toward patients of other cultures by identifying strategies to increase students’ awareness of and knowledge about those other cultures. [Abstract by authors.]

Amish Population Pyramids: Demographic Patterns across Affiliations in the Holmes County, Ohio, Settlement

Research indicates demographic trends within the Amish community remain stable over time, even as Amish populations proliferate. However, most of the research on demographic trends fails to examine variation across affiliations. We use data from Ohio Amish Directory, Holmes County and Vicinity, 2010 to construct age-sex population pyramids for three different affiliations. Population pyramids render the growth, decline, and stability of populations visible. Andy Weaver (or Dan) and Old Order churches present expanding pyramids implying rapid growth, while New Order churches render a stationary pyramid indicating slower growth. Sociologists of religion consistently find that strict churches, cultivating separation from the outside world, tend to grow faster than those that foster accommodation with the outside world. We argue that the data presented in this article suggests a similar dynamic at work in Plain Anabaptist communities.

Natural history of propionic acidemia in the Amish population

Propionic acidemia (PA) in the Amish is caused by a homozygous pathogenic variant (c.1606A>G; p.Asn536Asp) in the PCCB gene. Amish patients can have borderline or normal newborn screening (NBS) results and symptoms can present at any time from early childhood to mid-adulthood. Early diagnosis and initiation of treatment for PA in the non-Amish population improves patient outcomes. Here, we present data from a retrospective chart review of Amish patients diagnosed with PA from three different medical centers in order to document its natural history in the Amish and determine the influence of treatment on outcomes in this population. A total of 38 patients with average current age 19.9 years (range 4y-45y), 57.9% males, were enrolled in the study. Fourteen patients (36.8%) were diagnosed with a positive newborn screening (NBS) while 24 patients (63.2%) had negative or inconclusive NBS or had no record of NBS in their charts. These 24 patients were diagnosed by screening after a family member was diagnosed with PA (14; 58.3%), following a hospitalization for metabolic acidosis (5; 20.8%), hospitalization for seizures (3; 12.5%) or via cord blood (2; 8.3%). The majority of patients were prescribed a protein restricted diet (32; 84.2%), including metabolic formula (29; 76.3%). Most were treated with carnitine (35; 92.1%), biotin (2; 76.3%) and/or Coenzyme Q10 (16; 42.1%). However, treatment adherence varied widely among patients, with 7 (24.1%) of the patients prescribed metabolic formula reportedly nonadherent. Cardiomyopathy was the most prevalent finding (22; 63.2%), followed by developmental delay/intellectual disability (15; 39.5%), long QT (14; 36.8%), seizures (12; 31.6%), failure to thrive (4; 10.5%), and basal ganglia strokes (3; 7.9%). No difference in outcome was obvious for those diagnosed by NBS and treated early with dietary and supplement management, especially for cardiomyopathy. However, this is a limited retrospective observational study. A prospective study with strict documentation of treatment adherence and universal screening for cardiomyopathy and long QT should be conducted to better study the impact of early detection and treatment. Additional treatment options such as liver transplantation and future therapies such as mRNA or gene therapy should be explored in this population.

Congenital Nephrotic Syndrome in the Amish and Mennonite Population of Central Pennsylvania

Congenital Nephrotic Syndrome in the Amish and Mennonite Population of Central Pennsylvania

The «Amish» NM_000256.3:c.3330+2T>G splice variant in MYBPC3 associated with hypertrophic cardiomyopathy is an ancient Swiss mutation

MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM). Several loss-of-function founder variants have been reported in MYBPC3 from various geographic regions, altogether suggestive of a modest or absent effect of these variants on reproductive fitness. One of them, a MYBPC3 splice variant, NM_000256.3:c.3330+2T > G, was first described in homozygous state in newborns presenting with a severe, recessive form of HCM among the Amish population and was later associated with adult-onset dominant HCM in heterozygous carriers. We here report this splice variant in heterozygous state in eight unrelated Swiss families with HCM, making it the most prevalent cardiomyopathy variant in western Switzerland. This variant was identified in patients using targeted (n = 5) or full-genome sequencing (n = 3). Given the prevalence of this variant in the Old Order Amish, Mennonites and Swiss populations, and given that both Amish and Mennonites founders originated from the Bern Canton in Switzerland, the MYBPC3, NM_000256.3:c.3330+2T > G variant appears to be of Swiss origin. Neighboring regions that hosted the first Amish settlements (Alsace, South Germany) should be on the lookout for that variant. The existence of MYBPC3 founder variants in different populations suggests that individuals with early-onset clinical disease may be the tip of the iceberg of a much larger number of asymptomatic carriers. Alternatively, reproductive fitness could even be slightly increased in some variant carriers to compensate for the reduction of fitness in the more severely affected ones, but this remains to be investigated.

Ellis-Van Creveld syndrome: a case report

Ellis-Van Creveled (EVC) syndrome, also called chondroectodermal dysplasia, is a rare genetic disorder with autosomal recessive type of inheritance with 25% risk of transmission to subsequent pregnancies. The syndrome is due to mutation of EVC1 and EVC2 genes on chromosome 4p16, characterized by acromesomalic dwarfism, bilateral postaxial polydactyly, ectodermal dysplasia affecting nails, teeth and congenital heart malformation. One third of the patients die at an early age or during infancy from cardio respiratory problems. The birth prevalence of EVC syndrome is 1/5000 live births in Amish population and 7/1,000,000 live birth in non-Amish population. There are a very few case reports in the literature. We reported a case of 14-year male presenting with typical features of this syndrome.

Genomewide Association Study of Retinal Traits in the Amish Reveals Loci Influencing Drusen Development and Link to Age-Related Macular Degeneration.

PurposeThe purpose of this study was to identify genetic risk loci for retinal traits, including drusen, in an Amish study population and compare these risk loci to known risk loci of age-related macular degeneration (AMD).MethodsParticipants were recruited from Amish communities in Ohio, Indiana, and Pennsylvania. Each participant underwent a basic health history, ophthalmologic examination, and genotyping. A genomewide association analysis (GWAS) was conducted for the presence and quantity of each of three retinal traits: geographic atrophy, drusen area, and drusen volume. The findings were compared to results from a prior large GWAS of predominantly European-ancestry individuals. Further, a genetic risk score for AMD was used to predict the presence and quantity of the retinal traits.ResultsAfter quality control, 1074 participants were included in analyses. Six single nucleotide polymorphisms (SNPs) met criteria for genomewide significance and 48 were suggestively associated across three retinal traits. The significant SNPs were not highly correlated with known risk SNPs for AMD. A genetic risk score for AMD provided significant predictive value of the retinal traits.ConclusionsWe identified potential novel genetic risk loci for AMD in a midwestern Amish study population. Additionally, we determined that there is a clear link between the genetic risk of AMD and drusen. Further study, including longitudinal data collection, may improve our ability to define this connection and improve understanding of the biological risk factors underlying drusen development.

Study of Regions of Homozygosity (ROH) Patterns to Evaluate the Use of Dogs’ Genome in Human Drug Development

Animals are used as preclinical models for human diseases in drug development. Dogs, especially, are used in preclinical research to support clinical safety evaluations during drug development. Comparisons of patterns of regions of homozygosity (ROH) and phenotypes between dogs and humans are not well known. We conducted a genome-wide homozygosity analysis (GWHA) on the human and dog genomes. We calculated ROH patterns across distinct human cohorts, including the Amish, the 1000 genomes, Vanda 1 k genomes, and the Alzheimer’s cohort. The Amish provided a large cohort of extended kinships, allowing for in-depth family-oriented analyses. The remaining human cohorts served as statistical references. We then calculated ROH across different dog breeds, with emphasis on the beagle—the preferred breed used in drug development. Out of five studied human cohorts, we reported the highest mean ROH in the Amish population. We calculated the extent of the genome covered by ROH (FROH) (human 3.2 Gb, dog 2.5 Gb). Overall, FROH differed significantly between the Amish and the 1000 genomes, and between the human and the beagle genomes. The mean FROHper 1 Mb was ~ 16 kb for Amish, ~ 0.6 kb for Vanda 1 k, and ~ 128 kb for beagles. This result demonstrated the highest degree of inbreeding in beagles, far above that of the Amish, one of the most inbred human populations. ROH can contribute to inbreeding depression if it contains deleterious variants that are fully or partially recessive. The differences in ROH characteristics between human and dog genomes question the applicability of dog models in preclinical research, especially when the goal is to gauge the subtle effects on the organism’s physiology produced by candidate therapeutic agents. Importantly, there are huge differences in a subset of ADME genes, specifically the cytochrome P450 family (CYPs), which constitute major enzymes involved in drug metabolism. We should use caution when generalizing from dog to human, even if human and beagle are relatively close species phylogenetically. Doi: 10.28991/HEF-SP2022-01-02 Full Text: PDF

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

SummaryAlzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States, and the proportion of deaths due to AD has been increasing since 2000, while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Although APOE ε4 remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. As a founder population that typically practices endogamy, variants that are rare in the general population may be of a higher frequency in the Amish population. Since the Amish have a slightly lower incidence and later age of onset of disease, they represent an excellent and unique population for research on protective genetic variants. We compared AD risk in the Amish and to a non-Amish population through APOE genotype, a non-APOE genetic risk score of genome-wide significant variants, and a non-APOE polygenic risk score considering all of the variants. Our results highlight the lesser relative impact of APOE and differing genetic architecture of AD risk in the Amish compared to a non-Amish, general European ancestry population.

Kentucky Anabaptists' Knowledge of Newborn Screening

The Plain Anabaptist population in Kentucky is growing, with the Amish population alone expected to double about every 20 years. Anabaptists in Kentucky are largely composed of Amish (both Old Order and New Order) and Old Order and Conservative Mennonites. All Anabaptists experience an increased incidence of recessive genetic disorders. Newborn screening (NBS) is a state-regulated program that identifies inherited and congenital disorders and conditions. The purpose of this study is to determine the knowledge of Kentucky Amish and Mennonite communities regarding NBS. A researcher-adapted questionnaire was mailed to Kentucky Amish and Mennonite households, and 292 respondents returned the questionnaire. The majority (85.2%) reported at least "a little" knowledge of NBS; however, only 6.8% reported "a lot" of knowledge. Respondents identified the midwife as the most common source of information related to NBS; however, 18% reported NBS was not offered by any provider. There was a statistically significant relationship between knowledge of NBS and children receiving NBS, indicating that knowledge of NBS increased participation in NBS. As the midwife is the most common source of NBS knowledge, an educational program for midwives as well as the Anabaptist communities throughout Kentucky is planned.