Monogenic Variants Research Articles

Mutation screening of eight genes and comparison of the clinical data in a Chinese cohort with congenital hypothyroidism.

Congenital hypothyroidism (CH) is a common neonatal endocrine disorder, characterized by irreversible intellectual disability and short stature if left untreated. It can be divided into thyroid dysgenesis (TD), including athyreosis, ectopy and hypoplasia, and dyshormonogenesis (DH), also referring to gland in situ (GIS), in which patients have eutopic thyroids with normal size or goiter. This study aims to analyze the clinical and genetic data of 375 Chinese CH patients without DUOX2 and thyroid transcription factor (TTF) variants, and to explore the mutation frequencies of the eight genes and the inheritance pattern of CH. Targeted next generation sequencing (NGS) and statistical analysis were performed for mutation screening on eight CH-related genes and the comparison of clinical data in a cohort of 606 Chinese CH patients from Henan Province. A total of 104 variants were detected in genes required for thyroid formation (TSHR, GLIS3, BOREALIN, NTN1, JAG1 and TUBB1) and thyroid hormone synthesis (TG and TPO) in 83 subjects. Monogenic variants were the most prevalent with a percentage of 75.00% (78/104) followed by oligogenic variants (25.00%, 26/104). No differences were found in various clinical data between patients with and without variants. However, it should be noted that only initial L-T4 dose was statistically different between patients with monogenic variants and oligogenic variants. Our results suggested that apart from Mendelian monogenic inheritance, oligogenic inheritance of CH could not be excluded and also involves other factors, such as penetrance, epigenetic mechanisms and environmental factors.

A Review on Response to Device-Aided Therapies Used in Monogenic Parkinsonism and GBA Variants Carriers: A Need for Guidelines and Comparative Studies.

Parkinson’s disease (PD) is in some cases predisposed-or-caused by genetic variants, contributing to the expression of different phenotypes. Regardless of etiology, as the disease progresses, motor fluctuations and/or levodopa-induced dyskinesias limit the benefit of pharmacotherapy. Device-aided therapies are good alternatives in advanced disease, including deep brain stimulation (DBS), levodopa-carbidopa intestinal gel, and continuous subcutaneous infusion of apomorphine. Candidate selection and timing are critical for the success of such therapies. Genetic screening in DBS cohorts has shown a higher proportion of mutation carriers than in general cohorts, suggesting that genetic factors may influence candidacy for advanced therapies. The response of monogenic PD to device therapies is not well established, and the contribution of genetic information to decision-making is still a matter of debate. The limited evidence regarding gene-dependent response to device-aided therapies is reviewed here. An accurate understanding of the adequacy and responses of different mutation carriers to device-aided therapies requires the development of specific studies with long-term monitoring.

Interpreting the spectrum of gamma-secretase complex missense variation in the context of hidradenitis suppurativa-An in-silico study.

Hidradenitis suppurativa (HS) is a disease of the pilosebaceous unit characterized by recurrent nodules, abscesses and draining tunnels with a predilection to intertriginous skin. The pathophysiology of HS is complex. However, it is known that inflammation and hyperkeratinization at the hair follicle play crucial roles in disease manifestation. Genetic and environmental factors are considered the main drivers of these two pathophysiological processes. Despite a considerable proportion of patients having a positive family history of disease, only a minority of patients suffering from HS have been found to harbor monogenic variants which segregate to affected kindreds. Most of these variants are in the ɣ secretase complex (GSC) protein-coding genes. In this manuscript, we set out to characterize the burden of missense pathogenic variants in healthy reference population using large scale genomic dataset thereby providing a standard for comparing genomic variation in GSC protein-coding genes in the HS patient cohort.

Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis.

Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histologic variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathologic findings were obtained from referring clinicians. We analyzed the associations of histologic variants with clinical characteristics, kidney survival, and gene variant detection rates. The distribution of histologic variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), and ACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; P<0.001). We revealed the distributions of histologic variants of genetic FSGS and nongenetic FSGS in a large patient population. Detailed data concerning gene variants and pathologic findings are important for understanding the etiology of FSGS.

Clinical Implementation of Combined Monogenic and Polygenic Risk Disclosure for Coronary Artery Disease

BackgroundState-of-the-art genetic risk interpretation for a common complex disease such as coronary artery disease (CAD) requires assessment for both monogenic variants—such as those related to familial hypercholesterolemia—as well as the cumulative impact of many common variants, as quantified by a polygenic score. ObjectivesThe objective of the study was to describe a combined monogenic and polygenic CAD risk assessment program and examine its impact on patient understanding and changes to clinical management. MethodsStudy participants attended an initial visit in a preventive genomics clinic and a disclosure visit to discuss results and recommendations, primarily via telemedicine. Digital postdisclosure surveys and chart review evaluated the impact of disclosure. ResultsThere were 60 participants (mean age 51 years, 37% women, 72% with no known CAD), including 30 (50%) referred by their cardiologists and 30 (50%) self-referred. Two (3%) participants had a monogenic variant pathogenic for familial hypercholesterolemia, and 19 (32%) had a high polygenic score in the top quintile of the population distribution. In a postdisclosure survey, both the genetic test report (in 80% of participants) and the discussion with the clinician (in 89% of participants) were ranked as very or extremely helpful in understanding the result. Of the 42 participants without CAD, 17 or 40% had a change in management, including statin initiation, statin intensification, or coronary imaging. ConclusionsCombined monogenic and polygenic assessments for CAD risk provided by preventive genomics clinics are beneficial for patients and result in changes in management in a significant portion of patients.

Use of perampanel in children with refractory epilepsy of genetic aetiology

Pathogenic mutations in refractory childhood epilepsy are being increasingly discovered. In this study, we analysed the efficacy and tolerability of perampanel as treatment for genetically-related refractory childhood epilepsy. This prospective study, conducted in China, included 50 patients with refractory epilepsy of genetic aetiology, who were treated with adjunctive perampanel therapy. Perampanel treatment was considered effective when the seizure frequency was reduced by >50%. Perampanel treatment was evaluated over at least nine months, from January 2020. A total of 184 paediatric patients with refractory epilepsy received addon perampanel therapy, and of these, 128 received treatment for ≥nine months and underwent genetic analysis. Fifty children were identified with pathogenic or likely pathogenic variants. A total of 24 different causative monogenic mutations were found, and the most common causative monogenic variants were observed in the SCN1A gene (n = 15). The mean maximal dose of perampanel was 3.4±1.2 mg/day in responders. The response rates to perampanel in children with genetically-related refractory epilepsy (n=50) were 68.0%, 58.0%, and 46.0% at three, six and nine months post-initiation, respectively. Adverse events were reported in 23 patients (46.0%) with genetic aetiology. Somnolence, ataxia, and irritability were the most common adverse events. The response rates to perampanel in children with pathogenic or likely pathogenic variants associated with Dravet syndrome, tuberous sclerosis, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, Rett syndrome, and dentatorubral-pallidoluysian atrophy were high. A low maintenance dose of perampanel may be effective and well-tolerated as adjunctive treatment in children with refractory epilepsy of genetic aetiology.

Metabolic and Genetic Evaluation in Children with Nephrolithiasis.

To evaluate metabolic and genetic abnormalities in children with nephrolithiasis attending a referral center in North India. The patients aged 1-18 y old with nephrolithiasis underwent biochemical evaluation and whole-exome sequencing. The authors evaluated for monogenic variants in 56 genes and compared allele frequency of 39 reported polymorphisms between patients and 1739 controls from the GenomeAsia 100K database. Fifty-four patients, aged 9.1 ± 3.7 y were included. Stones were bilateral in 42.6%, familial in 33.3%, and recurrent in 25.9%. The most common metabolic abnormalities were hypercalciuria (35.2%), hyperoxaluria (24.1%), or both (11.1%), while xanthinuria (n = 3), cystinuria (n = 1), and hyperuricosuria (n = 1) were rare. Exome sequencing identified an etiology in 6 (11.1%) patients with pathogenic/likely pathogenic causative variants. Three variants in MOCOS and one in ATP7B were pathogenic; likely pathogenic variants included MOCOS (n = 2), AGXT, and SLC7A9 (n = 1, each). Causality was not attributed to two SLC34A1 likely pathogenic variants, due to lack of matching phenotype and dominant family history. Compared to controls, allele frequency of the polymorphism TRPV5 rs4252402 was significantly higher in familial stone disease (allele frequency 0.47 versus 0.53; OR 3.2, p = 0.0001). The chief metabolic abnormalities were hypercalciuria and hyperoxaluria. A monogenic etiology was identified in 11% with pathogenic or likely pathogenic variants using a gene panel for nephrolithiasis. Heterozygous missense variants in the sodium-phosphate cotransporter SLC34A1 were common and required evaluation for attributing pathogenicity. Rare polymorphisms in TRPV5 might increase the risk of familial stones. These findings suggest that a combination of metabolic and genetic evaluation is useful for determining the etiology of nephrolithiasis.

Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India.

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD-relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment.

O-147 Genomic analyses in 101,127 UK women show that previously reported monogenic genes are not common causes of premature ovarian insufficiency

Abstract Study question What is the penetrance of variants in previously reported genes for premature ovarian insufficiency (POI) in the general population? Summary answer Heterozygous genetic variants in previously reported monogenic genes are not a common, highly penetrant cause of POI. What is known already Premature ovarian insufficiency (POI), defined as menopause before 40, has been associated with variants in over 70 genes. However, the evidence to support the causality of individual genetic variants varies between studies. As genomic data becomes more accessible, it is essential to ascertain the penetrance of variants in the absence of family history information. We identified 75 genes associated with POI from the literature, including family segregation studies, consanguineous pedigrees and cohort analyses of whole-exome/targeted sequencing data. Functional evaluation was also available for many of the genes. Study design, size, duration We used data from 101,127 females of European ancestry in the UK Biobank, to study the role of previously reported monogenic causal genes on ovarian function. We tested the association of 301 previously reported variants with POI and ANM, plus more than 2.5 million rare variants which were annotated and had not been implicated in POI previously. Genomic variants were tested individually and also combined into a gene burden test. Participants/materials, setting, methods Age at natural menopause (ANM) was derived from self-reported questionnaire data from the age at last menstrual period, excluding those with surgical menopause or taking hormone replacement therapy. POI cases were classified as women with ANM under 40 years (N = 2,213). Linked primary care records were used to identify a clinical cohort of POI cases, including primary amenorrhea (N = 113). Main results and the role of chance All of the previously reported individual variants we identified in our POI cases were also detected in the control group. Moreover, the gene burden tests were not associated with POI or ANM as a quantitative trait. Our results indicate that autosomal dominant causes of POI are rare; a single predicted loss-of-function (LOF) or non-synonymous genetic variant in one of the previously reported genes is generally not pathogenic. Limitations, reasons for caution The penetrance of monogenic disease-causing variants is likely to be lower in population-based cohorts such as UK Biobank than in clinically-ascertained cohorts. Wider implications of the findings Heterozygous LOF or non-synonymous variants in previously reported POI genes should be interpreted with caution and are unlikely to cause POI. The findings have implications for clinicians diagnosing causes of POI. Trial registration number Not applicable

Monogenic inflammatory bowel disease-genetic variants, functional mechanisms and personalised medicine in clinical practice.

Over 100 genes are associated with monogenic forms of inflammatory bowel disease(IBD). These genes affect the epithelial barrier function, innate and adaptive immunity in the intestine, and immune tolerance. We provide an overview of newly discovered monogenic IBD genes and illustrate how a recently proposed taxonomy model can integrate phenotypes and shared pathways. We discuss how functional understanding of genetic disorders and clinical genomics supports personalised medicine for patients with monogenic IBD.

Gene Therapy: Novel Approaches to Targeting Monogenic Epilepsies.

Genetic epilepsies are a spectrum of disorders characterized by spontaneous and recurrent seizures that can arise from an array of inherited or de novo genetic variants and disrupt normal brain development or neuronal connectivity and function. Genetically determined epilepsies, many of which are due to monogenic pathogenic variants, can result in early mortality and may present in isolation or be accompanied by neurodevelopmental disability. Despite the availability of more than 20 antiseizure medications, many patients with epilepsy fail to achieve seizure control with current therapies. Patients with refractory epilepsy—particularly of childhood onset—experience increased risk for severe disability and premature death. Further, available medications inadequately address the comorbid developmental disability. The advent of next-generation gene sequencing has uncovered genetic etiologies and revolutionized diagnostic practices for many epilepsies. Advances in the field of gene therapy also present the opportunity to address the underlying mechanism of monogenic epilepsies, many of which have only recently been described due to advances in precision medicine and biology. To bring precision medicine and genetic therapies closer to clinical applications, experimental animal models are needed that replicate human disease and reflect the complexities of these disorders. Additionally, identifying and characterizing clinical phenotypes, natural disease course, and meaningful outcome measures from epileptic and neurodevelopmental perspectives are necessary to evaluate therapies in clinical studies. Here, we discuss the range of genetically determined epilepsies, the existing challenges to effective clinical management, and the potential role gene therapy may play in transforming treatment options available for these conditions.

Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population

SummaryMany rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DDs) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes by using whole-exome-sequencing data from ∼200,000 individuals and rare copy-number variants overlapping known DD loci by using SNP-array data from ∼500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores, and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, had a higher BMI, and had significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and higher deprivation index. Our findings suggest that many genes routinely tested within pediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong sub-clinical phenotypes in the general adult population.

Atopy as Immune Dysregulation: Offender Genes and Targets

Allergic diseases are a heterogeneous group of disorders resulting from exaggerated type 2 inflammation. Although typically viewed as polygenic multifactorial disorders caused by the interaction of several genes with the environment, we have come to appreciate that allergic diseases can also be caused by monogenic variants affecting the immune system and the skin epithelial barrier. Through a myriad of genetic association studies and high-throughput sequencing tools, many monogenic and polygenic culprits of allergic diseases have been described. Identifying the genetic causes of atopy has shaped our understanding of how these conditions occur and how they may be treated and even prevented. Precision diagnostic tools and therapies that address the specific molecular pathways implicated in allergic inflammation provide exciting opportunities to improve our care for patients across the field of allergy and immunology. Here, we highlight offender genes implicated in polygenic and monogenic allergic diseases and list targeted therapeutic approaches that address these disrupted pathways.

A Novel Targeted Amplicon Next-Generation Sequencing Gene Panel for the Diagnosis of Common Variable Immunodeficiency Has a High Diagnostic Yield: Results from the Perth CVID Cohort Study

With the advent of next-generation sequencing (NGS), monogenic forms of common variable immunodeficiency (CVID) have been increasingly described. Our study aimed to identify disease-causing variants in a Western Australian CVID cohort using a novel targeted NGS panel. Targeted amplicon NGS was performed on 22 unrelated subjects who met the formal European Society for Immunodeficiencies-Pan-American Group for Immunodeficiency diagnostic criteria for CVID and had at least one of the following additional criteria: disease onset at age <18 years, autoimmunity, low memory B lymphocytes, family history, and/or history of lymphoproliferation. Candidate variants were assessed by in silico predictions of deleteriousness, comparison to the literature, and classified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology criteria. All detected genetic variants were verified independently by an external laboratory, and additional functional studies were performed if required. Pathogenic or likely pathogenic variants were detected in 6 of 22 (27%) patients. Monoallelic variants of uncertain significance were also identified in a further 4 of 22 patients (18%). Pathogenic variants, likely pathogenic variants, or variants of uncertain significance were found in TNFRSF13B, TNFRSF13C, ICOS, AICDA, IL21R, NFKB2, and CD40LG, including novel variants and variants with unexpected inheritance pattern. Targeted amplicon NGS is an effective tool to identify monogenic disease-causing variants in CVID, and is comparable or superior to other NGS methods. Moreover, targeted amplicon NGS identified patients who may benefit from targeted therapeutic strategies and had important implications for family members.

Genetic diagnosis of common fetal renal abnormalities detected on prenatal ultrasound

This retrospective study aimed to investigate the correlations between phenotypes of fetal renal abnormalities on prenatal ultrasound and genetic aetiologies detected using chromosomal microarray analysis (CMA) and whole-exome sequencing (WES). Fetuses with renal abnormalities were subjected to CMA and were further analysed by WES when CMA-negative. The detection rates for chromosomal abnormalities and monogenic variants among different types of isolated renal abnormalities and those with extrarenal abnormalities (non-isolated cases) were determined and compared. CMA detected chromosomal abnormalities in 78 of 577 fetuses (13.52%). WES detected monogenic variants in 31 of 160 fetuses (19.38%) that had non-diagnostic CMA results. In cases of isolated hyperechogenic kidney, polycystic kidney disease, and multicystic dysplastic kidney, the detection rates of copy number variants (CNVs) by CMA and monogenic variants by WES were not significantly different (p>0.05). However, monogenic variants were more frequently detected than CNVs when kidney abnormalities were accompanied by reduced amniotic fluid (p<0.05). Other renal abnormalities identified on prenatal ultrasound had different detection rates. Our findings contribute to the overall knowledge of genetic variants associated with prenatally identified renal anomalies and may aid in decision making regarding prenatal genetic testing options for affected pregnancies.

FC034: Genomic Approach of the Undetermined Kidney Disease

Abstract BACKGROUND AND AIMS Chronic kidney disease (CKD) is considered as a public health problem. Almost 20%–25% of patients with end-stage kidney disease have been reported with an undetermined kidney disease (UKD) in large national registry. Recent data have shown that the number of monogenic disease-causing variants among patients with CKD is about 20%–30%. Monogenic disease-causing variants are underdiagnosed. We performed whole exome sequencing on patients in our centre with UKD. METHOD All patients gave their written informed consent for genetic testing. Whole exome sequencing by next-generation sequencing was proposed in routine care practice to patient with UKD between January 2019 and December 2021. High and reproducible coverage achieved by our sequencing approach enabled copy-number variation (CNV) analysis. All patients with inconclusive biopsy results were included. Only one patient from the same pedigree was included. We excluded patients with a typical presentation of ADPKD, familial IgA nephropathy, patients with typical presentation of Gitelman or Bartter syndrome or established genetic diagnosis in the family. RESULTS A total of 211 adult patients were included (120 males) with a median age of 48 years (range 37–62 years). Of these, 50 patients were treated with haemodialysis, 34 patients had a kidney transplantation. A total of 156 had self-declared Caucasian. Consanguinity was reported by 12 patients and suspected in 11 patients. Family history of kidney disease was present in 108 patients with both first and second degree affected in 38 patients. Kidney biopsy were inconclusive in 62 patients. Kidney biopsy was impossible in 57 incidents patients with CKD during the study period. A WES was performed first to avoid kidney biopsy in nine patients. A negative genetic testing prior to the WES with gene panel has been performed in 31 patients. We detected 27 monogenic renal disorders in 73 patients with either pathogenic or likely pathogenic variants and 5 copy number variants among 211 patients (37%). The glomerular disease represent the first yielded diagnostic subgroup in which Alport diseases (COL4A3/4/5) represent the dominant diagnostic (COL4A4 n = 18; COL4A3 n = 12; COL4A5 n = 7; TTC21B n = 3; APOL1 = 2; INF2 n = 2; PAX2 n = 2; TRPC6 n = 2; TREX1 n = 1; COQ8B n = 1; NPHS1 n = 1). Tubulointerstitial diseases is the second yielded diagnostic subgroup (UMOD n = 7; NPHP1 n = 2; NPHP3 n = 1; CCL5 n = 1; HNF1B n = 1; CNM4 n = 1; KCNJ1 n = 1). Cystic disease and CAKUT is the third yielded diagnostic subgroup (PKHD1 n = 3; DNAJB11 n = 2; VHL n = 1; PKD1 n = 1; GREB1L n = 1; PBX1 n = 1). In addition, we find two patients with pathogenic complement variation (CFH et C3), one patient with TTR amyloidosis and one patient with familial renal glucosuria (SLC5A2). Six of the nine patients with WES first to avoid renal biopsy, have positive diagnostic (five Alport disease and one APOL1 nephropathy). Interestingly, one of these nine patients had a WES for nephrotic syndrome during type-I diabetes and a dialysis sister with undetermined glomerular disease and consanguineous parents, which detected a known variation in TTC21B gene (P209L) at a heterozygote state that did not explain the nephrotic syndrome. We performed Sanger sequencing for her sister and revealed the same variation at a homozygous state and explain her renal phenotype. Among 57 patients with impossible kidney biopsy, the WES was positive for 18 patients. The diagnostic yield of WES was higher in consanguineous patients (P = 0.04) and familial history of kidney disease (P &amp;lt; 0.0001). The diagnostic yielded reach 60.5% when the patient had family history of renal disease in both first and second degree of the pedigree. CONCLUSION WES identified a molecular diagnosis in almost 40% of patients with UKD in our centre. An exome first may have a high diagnostic yielded and avoid an invasive procedure like kidney biopsy or when it is impossible. WES must be included as a standard of care for patients with UKD.

Genotype-Phenotype Correlation in Progressive Supranuclear Palsy Syndromes: Clinical and Radiological Similarities and Specificities.

The progressive supranuclear palsy (PSP) syndrome encompasses different entities. PSP disease of sporadic origin is the most frequent presentation, but different genetic mutations can lead either to monogenic variants of PSP disease, or to other conditions with a different pathophysiology that eventually may result in PSP phenotype. PSP syndrome of monogenic origin is poorly understood due to the low prevalence and variable expressivity of some mutations. Through this review, we describe how early age of onset, family history of early dementia, parkinsonism, dystonia, or motor neuron disease among other clinical features, as well as some neuroimaging signatures, may be the important clues to suspect PSP syndrome of monogenic origin. In addition, a diagnostic algorithm is proposed that may be useful to guide the genetic diagnosis once there is clinical suspicion of a monogenic PSP syndrome.

Polygenic risk score as a possible tool for identifying familial monogenic causes of complex diseases

PurposeThe study aimed to evaluate whether polygenic risk scores could be helpful in addition to family history for triaging individuals to undergo deep-depth diagnostic sequencing for identifying monogenic causes of complex diseases. MethodsAmong 44,550 exome-sequenced European ancestry UK Biobank participants, we identified individuals with a clinically reported or computationally predicted monogenic pathogenic variant for breast cancer, bowel cancer, heart disease, diabetes, or Alzheimer disease. We derived polygenic risk scores for these diseases. We tested whether a polygenic risk score could identify rare pathogenic variant heterozygotes among individuals with a parental disease history. ResultsMonogenic causes of complex diseases were more prevalent among individuals with a parental disease history than in the rest of the population. Polygenic risk scores showed moderate discriminative power to identify familial monogenic causes. For instance, we showed that prescreening the patients with a polygenic risk score for type 2 diabetes can prioritize individuals to undergo diagnostic sequencing for monogenic diabetes variants and reduce needs for such sequencing by up to 37%. ConclusionAmong individuals with a family history of complex diseases, those with a low polygenic risk score are more likely to have monogenic causes of the disease and could be prioritized to undergo genetic testing.

Monogenic and Polygenic Contributions to QTc Prolongation in the Population.

Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population. We performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/decile of PRS=1.4 ms [95% CI, 1.3 to 1.5]; P=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

Identification of deleterious variants in patients with male infertility due to idiopathic non-obstructive azoospermia

BackgroundNon-obstructive azoospermia (NOA) is the most severe type of male infertility, affecting 1% of men worldwide. Most of its etiologies remain idiopathic. Although genetic studies have identified dozens of NOA genes, monogenic mutations can also account for a small proportion of idiopathic NOA cases. Hence, this genetic study was conducted to explore the causes of monogenic variants of NOA in a cohort of Chinese patients.MethodsFollowing the screening using chromosomal karyotyping, Y chromosome microdeletion analyses, and sex hormone assessments, subsequent whole-exome sequencing analysis was performed in 55 unrelated idiopathic NOA patients with male infertility to explore potential deleterious variants associated with spermatogenesis. We also performed Sanger sequencing to demonstrate the variants. Testicular biopsy or microsurgical testicular sperm extraction was also performed to confirm the diagnosis of NOA and identify spermatozoa. Hematoxylin and eosin staining was performed to assess the histopathology of spermatogenesis.ResultsAbnormal testicular pathological phenotypes included Sertoli cell-only syndrome, maturation arrest, and hypospermatogenesis. Using bioinformatics analysis, we detected novel variants in two recessive genes, FANCA (NM_000135, c.3263C > T, c.1729C > G) and SYCE1 (NM_001143763, c.689_690del); one X-linked gene, TEX11 (NM_031276, c.466A > G, c.559_560del); and two dominant genes, DMRT1 (NM_021951, c.425C > T, c.340G > A) and PLK4 (NM_001190799, c.2785A > G), in eight patients, which corresponded to 14.55% (8/55) of the patients.ConclusionThis study presented some novel variants of known pathogenic genes for NOA. Further, it expanded the variant spectrum of NOA patients, which might advance clinical genetic counseling in the future.