Rare Variation Research Articles

The "Deep Subarcuate Fossa" sign and three types of anomalous subarcuate loops encountered during vestibular schwannoma removal.

An anomalous subarcuate loop (SL) of the anteroinferior cerebellar artery (AICA) is a rare anatomic variation, which increases the complexity and risk of vestibular schwannoma (VS) removal. However, preoperative diagnosis of this anomaly remains difficult. The aim of this study was to report three types of anomalous SLs encountered during VS removal and to describe the "Deep Subarcuate Fossa (SF)" sign and its significance in the diagnosis and treatment of an osseous-penetrating SL. We prospectively observed 963 patients with newly/recently diagnosed VS who underwent surgical treatment performed by the senior author (P.Z.) from 2012 to 2021 and identified 16 patients with an anomalous SL. The SF was retrospectively measured on preoperative thin-slice temporal bone computed tomography in 963 patients. Three types of anomalous SLs were encountered during VS removal: the apex of the SL was embedded in the dorsal tumor capsule (type I, 1 case), the dura (type II, 8 cases), or the dura and bone (type III, 7 cases) surrounding the SF. The depth of the SF in 7 patients with a type III anomalous SL ranged from 2.3 to 7.0mm (3.56 ± 1.56mm), which was significantly larger than that in 845 patients without an osseous-penetrating SL (1.23 ± 0.43mm) (p = 0.008). When the depth of the SF exceeded 2mm, the sensitivity and precision of the diagnosis of a type III anomalous SL were 100% (7/7) and 31.8% (7/22), respectively. Three types of anomalous SLs may be encountered during VS removal, and AICA displacement is recommended before tumor removal. The "Deep SF" sign may indicate the existence of a type III anomalous SL and it can predict the depth of the AICA in the bone and guide the drilling of the bone around the vessel loop.

The impact of rare germline variants on human somatic mutation processes

Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.

Investigation of the Frequency of Coronary Artery Anomalies in MDCT Coronary Angiography and Comparison of Atherosclerotic Involvement between Anomaly Types.

Coronary artery anomalies (CAAs) are rare anatomical variations characterized by abnormal origin, course, or termination of the coronary arteries. This study aims to identify incidental CAAs in patients who underwent multidetector computed tomography coronary angiography (MDCTCA) to determine their incidence and to evaluate whether there is a difference between CAA types in terms of coronary atherosclerotic involvement. For this purpose, patients who underwent MDCTCA between December 2018 and January 2022 were retrospectively assessed. Of the 5200 MDCTCAs analyzed, CAAs were detected in 136 patients (2.61%). Of these 136 patients, 37 (27.2%) patients had an origin anomaly, 97 (71.3%) had a course anomaly, and 2 (1.5%) had a termination anomaly. There was no statistically significant difference between CAA types in terms of atherosclerotic involvement (p = 0.220). However, atherosclerotic involvement was high in vessels with anomalies when normal vessels with and without anomalies were compared (p = 0.005). Accurate detection of CAAs is vital for endovascular treatment or surgical intervention. MDCTCA is helpful both in the diagnosis of CAA and in the early detection and development of prevention strategies for coronary atherosclerosis.

Anastomosis between Median and Musculocutaneous Nerve: Presentation of a Very Rare Anatomical Variation in Comparison to Classical Divisions

The musculocutaneous nerve (MCN) is the terminal branch of the lateral cord of the brachial plexus, and emerges at the inferior border of pectoralis minor muscle. The nerve can interact with the median nerve (MN), adhering to the nerve and sharing fibers with it. During anatomical dissection of twelve cadavers, we have detected a rare variation of the anastomosis between MCN and MN. The knowledge of this anatomical variation could be of great relevance during surgical and clinical practices.

Abstract 688: Multi-stage exome sequencing study of 17,546 aggressive and non-aggressive prostate cancer cases

Abstract Rare pathogenic variants in DNA repair genes have been found to influence risk of aggressive prostate cancer. We conducted a large case-only exome sequencing study to further understand the role of rare coding variation in aggressive prostate cancer in a study of 9,185 aggressive (prostate cancer death, metastatic disease, T4, or both T3 and Gleason≥8) and 8,361 non-aggressive cases (T1/T2 and Gleason≤6) of European ancestry from 19 international studies. Stage 1 samples (N=5,545) had whole exome-sequencing, and stage 2 samples (N=12,001) had targeted exome sequencing for 1,459 genes selected based on stage 1 results and previous evidence. Logistic regression models were used to evaluate gene-based tests and the aggregate effect of multiple genes to investigate whether carrying pathogenic/likely pathogenic/deleterious (P/LP/D) variants (18,759 identified) was associated with risk of aggressive prostate cancer, prostate cancer death (N=6,033), or metastatic disease (N=1,730) compared to non-aggressive disease. Gene-based tests were meta-analyzed across stages 1 and 2. BRCA2, ATM, and NBN had the most statistically significant gene-based results: BRCA2 P/LP/D variant carriers had 4.3-fold higher odds of aggressive disease (95% CI=3.15-5.86, P=4x10-20), 4.7-fold higher odds of prostate cancer death (95% CI=3.41-6.59, P=2x10-20), and 5.7-fold higher odds of metastatic disease (95% CI=3.71-8.76, P=2x10-15); ATM P/LP/D variant carriers had 2.2-fold higher odds of aggressive disease (95% CI=1.58-2.99, P=2x10-6), 2.2-fold higher odds of prostate cancer death (95% CI=1.52-3.05, P=2x10-5), and 3.0-fold higher odds of metastatic disease (95% CI=1.93-4.61, P=9x10-7); and NBN P/LP/D variant carriers had 5.9-fold higher odds of metastatic disease (95% CI=2.56-13.84, P=3x10-5). Among potentially novel genes with strong but not exome-wide significant statistical evidence were MMP19, involved in reproduction and metastasis, with carriers having 2.8-fold higher odds of prostate cancer death (95% CI=1.53-5.05, P=8x10-4); PKD2L2, involved in fertility, with carriers having 3.5-fold higher odds of prostate cancer death (95% CI=1.76-7.04, P=5x10-4); and SMPD1, involved in converting sphingomyelin to ceramide, with carriers having 5.3-fold higher odds of metastatic disease (95% CI=1.85-14.98, P=0.002). At least one P/LP/D variant within a subset of 24 previously curated candidate prostate cancer DNA repair genes was carried by 12.8% of aggressive cases (OR=1.48, 95% CI=1.34-1.64, P=3x10-14), 12.6% of cases who died due to prostate cancer (OR=1.47, 95% CI=1.31-1.65, P=3x10-11), and 15.1% of metastatic cases (OR=2.16, 95% CI=1.57-2.16, P=5x10-14) compared to 9.4% of non-aggressive cases. These findings support the importance of rare genetic variation in aggressive prostate cancer risk and may have important implications for prostate cancer risk stratification and screening. Citation Format: Burcu F. Darst, Ed Saunders, Tokhir Dadaev, Xin Sheng, Peggy Wan, Loreall Pooler, Lucy Y. Xia, Stephen Chanock, Sonja I. Berndt, Susan M. Gapstur, Victoria Stevens, Demetrius Albanes, Stephanie J. Weinstein, Vincent Gnanapragasam, Graham G. Giles, Tu Nguyen-Dumont, Roger L. Milne, Mark M. Pomerantz, Julie A. Schmidt, Ruth C. Travis, Timothy J. Key, Konrad H. Stopsack, Lorelei A. Mucci, William J. Catalona, Beth Marosy, Kurt N. Hetrick, Kimberly F. Doheny, Robert J. MacInnis, Melissa C. Southey, Rosalind A. Eeles, Fredrik Wiklund, Zsofia Kote-Jarai, David V. Conti, Christopher A. Haiman. Multi-stage exome sequencing study of 17,546 aggressive and non-aggressive prostate cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 688.

Association of Common and Rare Genetic Variation in the 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene and Cataract Risk.

BackgroundResults from animal models and observational studies have raised concerns regarding the potential cataractogenic effects of statin treatment. We investigated whether common and rare genetic variants in HMGCR are associated with cataract risk, to gauge the likely long‐term effects of statin treatment on lenticular opacities.Methods and ResultsWe used genotyping data and exome sequencing data of unrelated European individuals in the UK Biobank to test the association between genetically proxied inhibition of HMGCR and cataract risk. First, we constructed an HMGCR genetic score consisting of 5 common variants weighted by their association with low‐density lipoprotein cholesterol. Second, we analyzed exome sequencing data to identify carriers of predicted loss‐of‐function mutations in HMGCR. Common and rare variants in aggregate were then tested for association with cataract and cataract surgery. In an analysis of >402 000 individuals, a 38.7 mg/dL (1 mmol/L) reduction in low‐density lipoprotein C by the HMGCR genetic score was associated with higher risk for cataract (odds ratio, 1.14 [95% CI, 1.00–1.39], P=0.045) and cataract surgery (odds ratio, 1.25 [95% CI, 1.06–1.48], P=0.009). Among 169 172 individuals with HMGCR sequencing data, we identified 32 participants (0.02%), who carried a rare HMGCR predicted loss‐of‐function variant. Compared with noncarriers, heterozygous carriers of HMGCR predicted loss‐of‐function had a higher risk of developing cataract (odds ratio, 4.54 [95% CI, 1.96–10.53], P=0.001) and cataract surgery (odds ratio, 5.27 [95% CI, 2.27–12.25], P=5.37×10−4). In exploratory analyses, we found no significant association between genetically proxied inhibition of PCSK9, NPC1L1, or circulating low‐density lipoprotein cholesterol levels (P>0.05 for all) and cataract risk.ConclusionsWe found that genetically proxied inhibition of the HMGCR gene mimicking long‐term statin treatment associated with higher risk of cataract. Clinical trials with longer follow‐up are needed to confirm these findings.

Double Cystic Ducts With The Single Gallbladder

Background: Cystic duct is forming one of the boundaries of triangle of cholecystectomy. The variations in cystic duct anatomy are of considerable importance during surgical excision of the gallbladder. A double cystic duct is very rare and poses a challenge for surgeons during cholecystectomy operation. If duplication of cystic ducts is present, it is associated with a double gallbladder 80% of the time. Presence of duplication of cystic duct associated with a single gallbladder is a extremely rare variant. Most of the times this variation is not picked up on routine preoperative investigations of patients planned for a laparoscopic cholecystectomy and often present as an unusual ‘surprise’ during surgery and creates a challenge to the surgeons. If they fail to identify this very rare variation they may create iatrogenic injury to these cystic ducts, which leads to bile leakage and other complications. Aim of the study: To find out the incidence of variations in the number of cystic duct in cadavers. Materials and Methods: Present study was done in 50 adult cadavers in the Department of Anatomy, Government Tiruvannamalai medical college, Tamil nadu. Meticulous dissection was done in the hepatobiliary system of these cadavers, and the variations in the number of cystic duct were noted. Observations: Presence of double cystic ducts were seen in three cadavers. Conclusion: If an anomaly of the biliary ductal system is not identified before or during surgery, it may turn out to be a bile duct injury which leads to bile leak. Hence Surgeons should keep in mind about the possibility of this rare variant double cystic ducts with a single gallbladder while performing cholecystectomy surgery. KEY WORDS: Cystic duct, Gallbladder, Cholecystectomy.

Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

To better understand the genetics of hearing loss, we performed a genome-wide association meta-analysis with 125,749 cases and 469,497 controls across five cohorts. We identified 53/c loci affecting hearing loss risk, including common coding variants in COL9A3 and TMPRSS3. Through exome sequencing of 108,415 cases and 329,581 controls, we observed rare coding associations with 11 Mendelian hearing loss genes, including additive effects in known hearing loss genes GJB2 (Gly12fs; odds ratio [OR] = 1.21, P = 4.2 × 10−11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10−17). We also identified hearing loss associations with rare coding variants in FSCN2 (OR = 1.14, P = 1.9 × 10−15) and KLHDC7B (OR = 2.14, P = 5.2 × 10−30). Our results suggest a shared etiology between Mendelian and common hearing loss in adults. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common disorders where both common and rare variation contribute to risk.

Rare and population-specific functional variation across pig lines

BackgroundIt is expected that functional, mainly missense and loss-of-function (LOF), and regulatory variants are responsible for most phenotypic differences between breeds and genetic lines of livestock species that have undergone diverse selection histories. However, there is still limited knowledge about the existing missense and LOF variation in commercial livestock populations, in particular regarding population-specific variation and how it can affect applications such as across-breed genomic prediction.MethodsWe re-sequenced the whole genome of 7848 individuals from nine commercial pig lines (average sequencing coverage: 4.1×) and imputed whole-genome genotypes for 440,610 pedigree-related individuals. The called variants were categorized according to predicted functional annotation (from LOF to intergenic) and prevalence level (number of lines in which the variant segregated; from private to widespread). Variants in each category were examined in terms of their distribution along the genome, alternative allele frequency, per-site Wright’s fixation index (FST), individual load, and association to production traits.ResultsOf the 46 million called variants, 28% were private (called in only one line) and 21% were widespread (called in all nine lines). Genomic regions with a low recombination rate were enriched with private variants. Low-prevalence variants (called in one or a few lines only) were enriched for lower allele frequencies, lower FST, and putatively functional and regulatory roles (including LOF and deleterious missense variants). On average, individuals carried fewer private deleterious missense alleles than expected compared to alleles with other predicted consequences. Only a small subset of the low-prevalence variants had intermediate allele frequencies and explained small fractions of phenotypic variance (up to 3.2%) of production traits. The significant low-prevalence variants had higher per-site FST than the non-significant ones. These associated low-prevalence variants were tagged by other more widespread variants in high linkage disequilibrium, including intergenic variants.ConclusionsMost low-prevalence variants have low minor allele frequencies and only a small subset of low-prevalence variants contributed detectable fractions of phenotypic variance of production traits. Accounting for low-prevalence variants is therefore unlikely to noticeably benefit across-breed analyses, such as the prediction of genomic breeding values in a population using reference populations of a different genetic background.

The risks of RELN polymorphisms and its expression in the development of otosclerosis.

Otosclerosis (OTSC) is the primary form of conductive hearing loss characterized by abnormal bone remodelling within the otic capsule of the human middle ear. A genetic association of the RELN SNP rs3914132 with OTSC has been identified in European population. Previously, we showed a trend towards association of this polymorphism with OTSC and identified a rare variant rs74503667 in a familial case. Here, we genotyped these variants in an Indian cohort composed of 254 OTSC cases and 262 controls. We detected a significant association of rs3914132 with OTSC (OR = 0.569, 95%CI = 0.386–0.838, p = 0.0041). To confirm this finding, we completed a meta-analysis which revealed a significant association of the rs3914132 polymorphism with OTSC (Z = 6.707, p<0.0001) across different ethnic populations. Linkage analysis found the evidence of linkage at RELN locus (LOD score 2.1059) in the OTSC family which has shown the transmission of rare variant rs74503667 in the affected individuals. To understand the role of RELN and its receptors in the development of OTSC, we went further to perform a functional analysis of RELN/reelin. Here we detected a reduced RELN (p = 0.0068) and VLDLR (p = 0.0348) mRNA levels in the otosclerotic stapes tissues. Furthermore, a reduced reelin protein expression by immunohistochemistry was confirmed in the otosclerotic tissues. Electrophoretic mobility shift assays for rs3914132 and rs74503667 variants revealed an altered binding of transcription factors in the mutated sequences which indicates the regulatory role of these variations in the RELN gene regulation. Subsequently, we showed by scanning electron microscopy a change in stapes bone morphology of otosclerotic patients. In conclusion, this study evidenced that the rare variation rs74503667 and the common polymorphism rs3914132 in the RELN gene and its reduced expressions that were associated with OTSC.

Integrative analysis prioritised oxytocin-related biomarkers associated with the aetiology of autism spectrum disorder.

SummaryBackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. The common variants of specific oxytocin-related genes (OTRGs), particularly OXTR, are associated with the aetiology of ASD. The contribution of rare genetic variations in OTRGs to ASD aetiology remains unclear.MethodsWe catalogued publicly available de novo mutations (DNMs) [from 6,511 patients with ASD and 3,391 controls], rare inherited variants (RIVs) [from 1,786 patients with ASD and 1,786 controls], and both de novo copy number variations (dnCNVs) and inherited CNVs (ihCNVs) [from 15,581 patients with ASD and 6,017 controls] in 963 curated OTRGs to explore their contribution to ASD pathology, respectively. Finally, a combined model was designed to prioritise the contribution of each gene to ASD aetiology by integrating DNMs and CNVs.FindingsThe rare genetic variations of OTRGs were significantly associated with ASD aetiology, in the order of dnCNVs > ihCNVs > DNMs. Furthermore, 172 OTRGs and their connected 286 ASD core genes were prioritised to positively contribute to ASD aetiology, including top-ranked MAPK3. Probands carrying rare disruptive variations in these genes were estimated to account for 10∼11% of all ASD probands.InterpretationOur findings suggest that rare disruptive variations in 172 OTRGs and their connected 286 ASD core genes are associated with ASD aetiology and may be potential biomarkers predicting the effects of oxytocin treatment.FundingGuangdong Key Project, National Natural Science Foundation of China, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province.

POS-017 A POPULATION PERSPECTIVE OF NEPHRITIC FACTORS AS SYSTEMIC DRIVERS OF COMPLEMENT DYSREGULATION IN C3 GLOMERULOPATHY

POS-017 A POPULATION PERSPECTIVE OF NEPHRITIC FACTORS AS SYSTEMIC DRIVERS OF COMPLEMENT DYSREGULATION IN C3 GLOMERULOPATHY

Population dynamics and genetic connectivity in recent chimpanzee history

SummaryKnowledge on the population history of endangered species is critical for conservation, but whole-genome data on chimpanzees (Pan troglodytes) is geographically sparse. Here, we produced the first non-invasive geolocalized catalog of genomic diversity by capturing chromosome 21 from 828 non-invasive samples collected at 48 sampling sites across Africa. The four recognized subspecies show clear genetic differentiation correlating with known barriers, while previously undescribed genetic exchange suggests that these have been permeable on a local scale. We obtained a detailed reconstruction of population stratification and fine-scale patterns of isolation, migration, and connectivity, including a comprehensive picture of admixture with bonobos (Pan paniscus). Unlike humans, chimpanzees did not experience extended episodes of long-distance migrations, which might have limited cultural transmission. Finally, based on local rare variation, we implement a fine-grained geolocalization approach demonstrating improved precision in determining the origin of confiscated chimpanzees.

Fenestration of the vertebrobasilar junction detected with multidetector computed tomography angiography.

The complex embryonic origin of the vertebrobasilar system may result in a wide range of anatomical variations. It has been hypothesized that the formation of fenestrations are likely to occur due to the failure of regression of the bridging arteries that connect the longitudinal neural arteries during embryogenesis. Fenestration of the vertebrobasilar system is a rare anatomical variation that involves a luminal division of the artery, that has a single origin into two separate and parallel channels which are rejoined distally. Fenestrations are important anatomical variants in patients undergoing endovascular and invasive intracranial interventions. Vascular fenestration has been associated with aneurysms, arteriovenous malformations, neuralgia, and vertebrobasilar ischaemia. We report on 3 cases of fenestration at the vertebrobasilar junction in 1 female and 2 male patients, respectively, using multidetector computed tomography angiography. The length of the fenestrated segment of the artery measured 4.41 mm, 3.90 mm, and 5.90 mm, respectively in the patients. Our report is clinically important as the presence of this anatomical variation may influence the management of cervical and intracranial pathologies. Increased awareness of the prevalence of anatomic variations contributes to the advancement of noninvasive imaging capabilities.

Anatomical variations of the hepatic artery: a closer view of rare unclassified variants

Defining the hepatic artery anatomy is of great importance for both surgeons and radiologists. Michel classification was designed to classify hepatic artery variations. Nevertheless, there are variations that do not fit into this classification. In this study, we aim to define the incidence of all variations in a healthy liver donor by reviewing their computed tomography (CT) scan with special emphasis on variations that do not fit in any of the Michel classes. A retrospective analysis of CT scan of donors and potential liver donors who were evaluated by triphasic CT scan. The CT scans were reviewed independently by a radiologist and two transplant surgeons. Cases that did not fit in any of the Michel classes were classified as class 0. Out of 241 donors, 210 were classified within the Michel classification, of which 60.9% were class I and 9.1% class II. Thirty-one (12.9%) donors classified as class 0. Of which, nine, three, two and three had replaced right hepatic artery from pancreaticoduodenal artery, gastroduodenal artery, aorta and coeliac artery, respectively. Two and six donors had accessory right hepatic artery from pancreaticoduodenal artery and gastroduodenal artery, respectively. Segment 4 artery originated from left and right hepatic artery in 56.8% and 31.9%, respectively. A great caution should be taken when evaluating the hepatic artery anatomy, clinicians should anticipate and be familiar with the rare unclassified variations of the hepatic artery.

The Genetics of Autoimmune Myositis.

The idiopathic inflammatory myopathies (IIM) are rare, heterogeneous systemic autoimmune disorders, characterized by inflammation of skeletal muscle and multi-organ involvement. Studies to identify genetic risk factors and dysregulated gene expression in IIM aim to increase our understanding of disease pathogenesis. Genome-wide association studies have confirmed the HLA region as the most strongly associated region in IIM, with different associations between clinically-defined subgroups. Associated genes are involved in both the innate and adaptive immune response, while identification of variants reported in other autoimmune disorders suggests shared biological pathways. Targeted imputation analysis has identified key associated amino acid residues within HLA molecules that may influence antigen recognition. These amino acids increase risk for specific clinical phenotypes and autoantibody subgroups, and suggest that serology-defined subgroups may be more homogeneous. Recent data support the contribution of rare genetic variation to disease susceptibility in IIM, including mitochondrial DNA variation in sporadic inclusion body myositis and somatic mutations and loss of heterozygosity in cancer-associated myositis. Gene expression studies in skeletal muscle, blood and skin from individuals with IIM has confirmed the role of interferon signalling and other dysregulated pathways, and identified cell-type specific signatures. These dysregulated genes differentiate IIM subgroups and identify potential biomarkers. Here, we review recent genetic studies in IIM, and how these inform our understanding of disease pathogenesis and provide mechanistic insights into biological pathways.

Association of soluble epoxide hydrolase 2 gene with the risk of non-syndromic cleft lip with or without cleft palate in western Han Chinese population.

This study aimed to explore the associations between soluble epoxide hydrolase 2 gene (EPHX2) variants and non-syndromic cleft lip with or without cleft palate (NSCL/P) in Chinese Han population. We recruited 159 NSCL/P cases from Chinese Han population and carried out targeted resequencing using the whole genome sequencing data of 542 healthy Chinese individuals from Novegene internal database as controls. We classified EPHX2 variants as common or rare according to their minor allele frequency and performed an association analysis for common variations and a burden analysis for rare variations. The lowest P-value in NSCL/P was observed at rs57699806 (P=0.000 13, OR=2.849 and 95% CI: 1.691-4.800), followed by rs4732723 (P=0.006 50, OR=0.662 and 95%CI: 0.491-0.892), rs7829267 (P=0.009 20, OR=1.496 and 95%CI: 1.117-2.005), rs721619 (P=0.011 00, OR=1.474 and 95%CI: 1.098-1.980), and rs7816586 (P=0.040 00, OR=1.310 and 95%CI: 1.015-1.691). The odds ratios suggested the C allele at rs4732723 as a protective factor for NSCL/P and the reference alleles at other single nucleotide polymorphisms (SNPs) as the risk factors for NSCL/P. Burden analysis showed no statistical significance (P>0.05). Through targeted resequencing, this study identified five SNPs named rs57699806, rs4732723, rs7829267, rs721619, and rs7816586 around the region of EPHX2 gene associated with NSCL/P in Chinese Han population. Four SNPs of rs57699806, rs4732723, rs7829267, and rs7816586 were first identified.

Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach

BackgroundAs genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly penetrant, medically actionable genes. A curated list of genes has been recommended by the American College of Medical Genetics and Genomics (ACMG) for return of incidental findings. However, the pleiotropic effects of these genes are not fully known. Such effects could complicate genetic counseling when returning incidental findings. In particular, there has been no systematic evaluation of psychiatric manifestations associated with rare variation in these genes.ResultsHere, we leveraged a targeted sequence panel and real-world electronic health records from the eMERGE network to assess the burden of rare variation in the ACMG-56 genes and two psychiatric-associated genes (CACNA1C and TCF4) across common mental health conditions in 15,181 individuals of European descent. As a positive control, we showed that this approach replicated the established association between rare mutations in LDLR and hypercholesterolemia with no visible inflation from population stratification. However, we did not identify any genes significantly enriched with rare deleterious variants that confer risk for common psychiatric disorders after correction for multiple testing. Suggestive associations were observed between depression and rare coding variation in PTEN (P = 1.5 × 10–4), LDLR (P = 3.6 × 10–4), and CACNA1S (P = 5.8 × 10–4). We also observed nominal associations between rare variants in KCNQ1 and substance use disorders (P = 2.4 × 10–4), and APOB and tobacco use disorder (P = 1.1 × 10–3).ConclusionsOur results do not support an association between psychiatric disorders and incidental findings in medically actionable gene mutations, but power was limited with the available sample sizes. Given the phenotypic and genetic complexity of psychiatric phenotypes, future work will require a much larger sequencing dataset to determine whether incidental findings in these genes have implications for risk of psychopathology.

Rare and Common Genetic Variation Underlying the Risk of Hypertrophic Cardiomyopathy in a National Biobank

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis. To assess the contributions of rare and common genetic variation to risk of HCM in the general population. This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022. Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors. Risk of HCM. The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87). Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.

Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.

Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole-exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the National Heart, Lung and Blood Institute's Exome Sequencing Project. Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in fibrinogen gamma chain (FGG) (with fibrinogen, P = 9.1×10-13), coagulation factor VII (F7) (with factor VII, P = 1.3×10-72; seven novel variants) and VWF (with factor VIII and vWF; P = 3.2×10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; P = 4.2×10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to AAs (rs3211938) in CD36 molecule (CD36). This variant has previously been linked to dyslipidemia but not with the levels of a hemostatic factor. These efforts represent the largest integration of whole-exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.