Family Genetic Studies Research Articles

Genetic family studies and prospective evaluation for multisystem involvement are needed in LHON patients.

Genetic family studies and prospective evaluation for multisystem involvement are needed in LHON patients.

Prothrombin deficiency with recurrent subretinal hemorrhage.

Ocular hemorrhage has been recorded in congenital factor deficiencies like hemophilia A, but it has never been documented in prothrombin deficiency. Here, we describe an unusual case of sudden vision loss in the right eye caused by subretinal hemorrhage following a coughing episode in a 67-year-old woman. Notably, the patient underwent left eye enucleation 12 years previously under similar circumstances due to subretinal hemorrhage. During the interview, it was discovered that the patient had a history of prothrombin deficiency, which was subsequently confirmed through laboratory testing. Aside from recurrent ocular bleeding and 1 instance of bleeding following dental extraction in childhood, there is no other history of bleeding. Subsequent molecular studies revealed a homozygous missense mutation at G1499A (Arg500Gln), a variant previously identified as R457Q. Although the likelihood of prothrombin deficiency initiating subretinal hemorrhage is low, it is likely to worsen retinal hemorrhage and contribute to difficulty in controlling bleeding. A comprehensive coagulation workup is essential in patients with ocular hemorrhage. Determining factor II activity should be included in individuals exhibiting variably prolonged prothrombin time and activated partial thromboplastin time with correction in mixing studies. Additional investigations, such as genetic sequencing and family studies, are advised for those with isolated low prothrombin levels.

Shared aetiology underlying multiple sclerosis and other immune mediated inflammatory diseases: Swedish familial co-aggregation and large-scale genetic correlation analyses

BackgroundWhile multiple sclerosis (MS) affects less than 1 % of the general population, immune mediated inflammatory diseases (IMIDs) collectively influence 5–10 % of the population. Understanding familial co-aggregation of MS and other IMIDs carries important clinical and public health implications that will enable early detection and personalized treatment. ObjectiveTo estimate the familial association between MS and other IMIDs and to quantify their shared genetic basis. DesignRegister-based multi-generational nested case-control familial co-aggregation study and genetic correlation study. SettingSweden. Participants24,995 individuals with MS matched with 253,870 controls and 1,283,502 first-degree relatives (mothers, fathers, full siblings, and offspring) for familial co-aggregation analysis; population of European ancestry for genetic correlation analysis. MeasurementsLogistic regressions with adjustment for covariates were used to estimate the odds ratios (ORs) of developing MS in individuals with first-degree relatives diagnosed with IMIDs compared to those without such family history. Pairwise genome-wide genetic correlations were estimated with linkage-disequilibrium score regression. ResultsWe observed an OR for familial co-aggregation of MS of 1.09 (95 % confidence interval (95%CI) = 1.07−1.11) in families with IMIDs history compared to families without. The association remained broadly consistent after stratification by sex concordance of relative pairs and by kinships. 18 IMID subtypes showed a familial association with MS, 7 of which including other acute widespread myelin destruction, encephalitis or myelitis or encephalomyelitis, inflammatory bowel disease, autoimmune thyroid diseases, systemic lupus erythematosus, other inflammatory system diseases, and sarcoidosis withstood multiple correction. Genetic correlations further revealed a shared genetic basis between 7 IMID subtypes with MS. ConclusionWe demonstrated a modest familial co-aggregation of MS with several IMIDs, and such association is likely due to shared genetic factors.

Phenotype and Clinical Outcomes in Desmin-Related Arrhythmogenic Cardiomyopathy

BackgroundDesmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce. ObjectivesThis study sought to provide information on the clinical phenotype and outcomes of patients with ACM caused by pathogenic variants of the DES gene in a multicenter cohort. MethodsWe collected phenotypic and outcomes data from 16 families with DES-related ACM from 10 European centers. We assessed in vitro DES aggregates. Major cardiac events were compared to historical controls with lamin A/C truncating variant (LMNA-tv) and filament C truncating variant (FLNC-tv) ACM. ResultsOf 82 patients (54% males, median age: 36 years), 11 experienced sudden cardiac death (SCD) (n = 7) or heart failure death (HFd)/heart transplantation (HTx) (n = 4) before clinical evaluation. Among 68 survivors, 59 (86%) presented signs of cardiomyopathy, with left ventricular (LV) dominant (50%) or biventricular (34%) disease. Mean LV ejection fraction was 51% ± 13%; 36 of 53 had late gadolinium enhancement (ring-like pattern in 49%). During a median of 6.73 years (Q1-Q3: 3.55-9.52 years), the composite endpoint (sustained ventricular tachycardia, aborted SCD, implantable cardioverter-defibrillator therapy, SCD, HFd, and HTx) was achieved in 15 additional patients with HFd/HTx (n = 5) and SCD/aborted SCD/implantable cardioverter-defibrillator therapy/sustained ventricular tachycardia (n = 10). Male sex (P = 0.004), nonsustained ventricular tachycardia (P = 0.017) and LV ejection fraction ≤50% (P = 0.012) were associated with the composite endpoint. Males with DES variants had similar outcomes to historical FLNC-tv and LMNA-tv controls. However, females showed better outcomes than those with LMNA-tv. In vitro experiments showed the characteristic finding of DES aggregates in 7 of 12 variants. ConclusionsDES ACM is associated with poor outcomes which can be predicted with potentially successful treatments, underscoring the importance of familial evaluation and genetic studies to identify at risk individuals.

Familial genetic study in a patient with global maturational delay and central hypotonia

Familial genetic study in a patient with global maturational delay and central hypotonia

Caveolinopathy pesenting with excercise induced stiffness and transient muscle mounding

Rippling muscle disease (RMD) is caused by dominant mutations of the caveolin-3 gene (CAV3), and presents with overlapping limb-girdle muscle weakness, elevated creatine kinase (hyper- CKemia), RMD, and distal myopathy. We report a patient with a CAV3 mutation who presented with myalgia, exercise-induced muscle stiffness, hyperCKemia, and percussion-induced rapid muscle contraction and muscle mounding. A familial genetic study revealed the same mutation in two family members, with physical examinations showing that both of them had rippling muscles.

A Family Genetic Study of Obsessive Compulsive Disorder in Youth

Objective: To use a family genetic study to evaluate familial risk of obsessive compulsive disorder (OCD) and common comorbid illnesses in first-degree relatives of pediatric-onset probands with primary OCD. Method: One hundred and thirty youth with OCD and their 133 siblings and 241 parents and 49 pediatric controls were directly evaluated along multiple domains including psychopathology using structured diagnostic interviews and clinical corroboration. Results: Rates of anxiety, mood, disruptive behavior, and tic disorders were markedly elevated in the probands while rates in siblings were elevated at rates between the probands and controls. Twenty six percent of first-degree relatives had clinical OCD, 9% had chronic tics or Tourette’s disorder, and 21% met criteria for ADHD. Conclusion: Rates of familial transmission of OCD and common comorbid illnesses were significantly higher in our pediatric-onset probands than rates reported in the literature in relatives of those with adult-onset OCD.

Marine heatwaves impact mortality of triploid Pacific oysters.

Studies of heatwave impacts on marine organisms are needed to understand biological tolerance to heat stress. Such studies should include integrative analyses across different levels of biological organization, which often reveal that predictions are non‐linear (e.g., gene–protein–physiology–organism). Further insights into potential evolutionary responses of organisms to rapid environmental change can be gained from formal genetic studies of multigenerational pedigreed families.

Association of mitochondrial DNA variation with high myopia in a Han Chinese population

High myopia (HM), which is characterized by oxidative stress, is one of the leading causes of visual impairment and blindness across the world. Family and population genetic studies have uncovered nuclear-genome variants in proteins functioned in the mitochondria. However, whether mitochondrial DNA mutations are involved in HM remains unexplored. Here, we performed the first large-scale whole-mitochondrial genome study in 9613 HM cases and 9606 control subjects of Han Chinese ancestry for identifying HM-associated mitochondrial variants. The single-variant association analysis identified nine novel genetic variants associated with HM reaching the entire mitochondrial wide significance level, including rs370378529 in ND2 with an odds ratio (OR) of 5.25. Interestingly, eight out of nine variants were predominantly located in related sub-haplogroups, i.e. m.5261G > A in B4b1c, m.12280A > G in G2a4, m.7912G > A in D4a3b, m.94G > A in D4e1, m.14857 T > C in D4e3, m.14280A > G in D5a2, m.16272A > G in G2a4, m.8718A > G in M71 and F1a3, indicating that the sub-haplogroup background can increase the susceptible risk for high myopia. The polygenic risk score analysis of the target and validation cohorts indicated a high accuracy for predicting HM with mtDNA variants (AUC = 0.641). Cumulatively, our findings highlight the critical roles of mitochondrial variants in untangling the genetic etiology of HM.

Family-base rare variant association analysis in Saudi Arabian hydrocephalus subjects using whole exome sequencing.

Hydrocephalus is a highly heterogeneous multifactorial disease that arises from genetic and environmental factors. Familial genetic studies of hydrocephalus have elucidated four robustly associated hydrocephalus associated loci. This study aims to identify potential genetic causation in cases of hydrocephalus, with or without spina bifida and Dandy Walker Syndrome (DWS), using family-based rare variant association analysis of whole exome sequencing. We performed whole exome sequencing in 143 individuals across 48 families where at least one offspring was affected with hydrocephalus (N.=27), with hydrocephalus with spina bifida (N.=21) and with DWS (N.=3), using Illumina HiSeq 2500 instrument. No pathogenic or putative pathogenic single-nucleotide variants were evident in the four known hydrocephalus loci in our subjects. However, after examining 73 known hydrocephalus genes previously identified from literature, we identified three potentially impactful variants from the cohort. Using a gene panel comprising variants in known neural tube defects loci, we identified a total of 1024 potentially deleterious variants, of which 797 were missense variants and 191 were frameshift variants, 36 were stop gain/loss variants. A small portion of our family pedigree analyses yielded putative genetic signals which may be responsible for hydrocephaly elated phenotypes, however the low diagnostic yield may be due to lack of capture of genetic variants in the exonic regions i.e. structural variants may only be evident from whole genome sequencing. We identified three potentially impactful variants from our cohort in 73 known hydrocephalus genes previously identified in literature.

Genome-wide analysis of runs of homozygosity in Pakistani controls with no history of speech or language-related developmental phenotypes

Background Runs of homozygosity (ROHs) analysis of controls provide a convenient resource to minimize the association of false positive results of disease-associated ROHs and genetic variants for simple and complex disorders in individuals from the same population. Evidence for the value of ROHs to speech or language-related traits is restricted due to the absence of population-matched behaviourally defined controls and limited family-based studies. Aim This study aims to identify common ROHs in the Pakistani population, focussing on the total length and frequency of ROHs of variable sizes, shared ROHs, and their genomic distribution. Subjects and methods We performed homozygosity analysis (in PLINK) of 86 individuals (39 males, 47 females) with no history of speech or language-related phenotypes (controls) who had been genotyped with the Illumina Infinium QC Array-24. Results ROHs of 1-<4 megabases (Mb) were frequent in unrelated individuals. We observed ROHs over 20 Mb among six individuals. Over 30 percent of the identified ROHs were shared among several individuals, indicating consanguinity’s effect on the Pakistani population. Conclusion Our findings serve as a foundation for family-based genetic studies of consanguineous families with speech or language-related disorders to ultimately narrow the homozygosity regions of interest to identify pathogenic variants.

Family, twin and adoption studies of severe mental disorders in sub-Saharan Africa: a scoping review.

The traditional genetic epidemiological studies are necessary to improve accurate risk communication to service users and their families. This scoping review aimed to describe the volume and scope of existing research evidence on family, twin and adoption studies of severe mental disorders (SMDs) in SSA. This is with a view to identifying gaps in the literature and the adequacy of data for a systematic review and meta-analysis. Literature search was done for all original peer-reviewed research articles on the topic in SSA using PubMed and MEDLINE. Publications included were peer-reviewed original articles, irrespective of their quality, carried out in the region from the 1970s till 9th March, 2022, which were available in English or translated to English. Case reports, abstracts, and studies among populations living outside the region were excluded. A total of five studies that met the inclusion criteria across the 46 countries in the region were identified. Of the three thematic areas of focus, only family studies on SMDs had research work in SSA. These studies provided evidence of familial clustering of SMDs in SSA. There were no twin and adoption studies on SMDs in the region. However, the review noted the establishment of two twin registries in Guinea-Bissau and Nigeria. A huge gap exists in the area of twin and adoption studies on SMDs in SSA. The volume of research evidence on traditional family genetic studies of SMDs is grossly inadequate to consider a systematic review in SSA. We have suggested studies to remedy the situation.

Updates and perspectives on the genetic markers in Rheumatoid Arthritis

The research was carried out on a representative group of patients diagnosed with rheumatoid arthritis (RA). We studied the distribution of patients by sex, age group, and disease stage, and we also tried to identify a genetic marker. In this sense, the blood groups of all RA patients were determined. In the study group, the frequency of patients with blood group B was much increased (47%), compared to the frequency of patients with blood group B in the control group (12%). Calculating the relative risk Rr for the disease, of the patients with blood group B, we found that it was 6.5, which indicated a positive association between RA and the blood group B marker. As a result, individuals belonging to blood group B are much more susceptible to RA compared to those who belong to other blood groups. Another genetic aspect of the research was the familial genetic study of RA. Using the family investigation as a method of investigation, we found that the incidence of family cases of RA in the studied group was 13%. RA, being a condition with the polygenic hereditary transmission, it is difficult to calculate the risk of recurrence, however, we found that, in affected families, the genes with "risk" for RA are much more frequent than in families where they were not observed, in the direct or collateral ancestry, other subjects diagnosed with RA. These observations are of particular importance in the prophylaxis of this condition.

Recent advances in hidradenitis suppurativa: Role of race, genetics, and immunology.

Hidradenitis suppurativa (HS) is a multifactorial chronic skin disease characterized by inflammation around the hair follicles commonly affecting intertriginous areas. The underlying pathogenesis of HS and its molecular mechanisms are largely understudied. Genetic studies in families have identified variants within the γ-secretase complex associated with HS; however, no definitive genotype-phenotype correlations have been made. The lack of knowledge regarding the intersection of genetics, immunology and environmental risk factors is a major obstacle to improving treatment for patients with HS. This article provides an overview of the role of race, genetics, and immunology in HS to provide insight into the multiple factors influencing the pathophysiology of HS.

Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Epilepsy with myoclonic-atonic seizures, also known as Doose syndrome: Modification of the diagnostic criteria.

The aim of this review is to propose the updated diagnostic criteria of epilepsy with myoclonic-atonic seizures (EMAS), which is a recent subject of genetic studies. Although EMAS has been well known as Doose syndrome, it is often difficult to diagnose due to a lack of consensus regarding some of the inclusion criteria. Along with progress in molecular genetic study on the syndrome, it becomes important to recruit electroclinical homogeneous EMAS patients, hence the validity of the clinical criteria should be verified based on recent clinical researches. At present, the most updated ILAE diagnostic manual of EMAS includes: (1) normal development and cognition before the onset of epilepsy; (2) onset of epilepsy between 6 months and 6 years of age (peak: 2-4 years); (3) myoclonic-atonic seizures (MAS) are mandatory (4) presence of generalized spike-wave discharges at 2-3Hz without persistent focal spike discharges; and (5) exclusion of other myoclonic epilepsy syndromes. In the criteria, we should emphasize that the age at onset of MAS is between 2-5 years in (2), presence of myoclonic-atonic, atonic or myoclonic-flexor seizures (MASs) causing drop attacks associated with generalized spike-wave discharges is mandatory in (3), and epileptic spasms causing drop attacks must be excluded in (5). In the modified criteria, I propose that EMAS is redesignated as genetic generalized epilepsy with MASs, consistent with the familial genetic study conducted by Doose and the recent identification of candidate genes. It should also be noted that EMASs evolves to transient or long-lasting epileptic encephalopathy.

A Case of Budd-Chiari Syndrome Associated with Erythrocytosis and Homozygous MTHFR C677T Mutation

An erythrocytosis describes an increased erythrocyte, subclassified into relative due to hemoconcentration or absolute by an increase in erythrocyte mass, defined as an increase in hemoglobin concentration and/or hematocrit in the peripheral blood above the sex-specific normal range. Budd-Chiari Syndrome (BCS) is related to an obstruction of the hepatic venous flow leading to occlusion of hepatic veins and their tributaries. Genetic and environmental factors can interact for risk determination of venous thromboembolism. The risk associated with SNP 677C&gt;T and 1298A&gt;C of the methylenetetrahydrofolate reductase (MTHFR), 1691G&gt;A of the Factor V Leiden (FVL) and 20210G&gt;A of the prothrombin (FII) genes were investigated in many studies involving thrombosis. This case report describes the clinical, hematological and biochemistry data about a 48-year-old woman diagnosed with PV and a BCS associated, also carrying 677C&gt;T SNP in homozygosity. The patient started therapy with phlebotomy, hydroxyurea and oral anticoagulant. Currently, she presents a better clinical and laboratory condition with normalized values of hematological and platelet indices. This case report aims to contribute with evidence of related comorbidities and makes it possible to report that genetic factors are involved since the patient's mother had already been diagnosed with absolute erythrocytosis in 2016 at 78 years old. For this main result, we understand that it is clear that a family genetic study can reveal clinical modifying factors in these patients, as there are different clinical severities in the family. Furthermore, we believe in the need for a greater number of randomized clinical trials to add better evidence to complement an ideal therapeutic approach in these patients.

Research algorithm for the detection of genetic patterns and phenotypic variety of non-syndromic dental agenesis.

Introduction: Dental agenesis (DA), brings together the anodontia, oligodontia, hypodontia, characterized by a deficit in the development of a variable number of teeth. The objectives of the study were to illustrate the phenotypic variability of non-syndromic DA, to identify cases of DA with hereditary genetic transmission, and establish the mode of DA genetic pattern in these cases, together with the determination of DA prevalence in the population group study. Patients, Materials and Methods: The cross-sectional observational study was performed on a mixed population group, consisting of 861 Caucasian patients, between January 2018–December 2019. The clinical evaluation protocol of patients with DA, used to illustrate their phenotype, included the following stages: oral examination, photographic examination, and radiological examination. The evaluation protocol specific to the family genetic study of patients with DA, involved the following three stages: family survey, construction of the family tree and analysis of the pedigree structure. Results: The prevalence of DA in the population group was 2.78%. Regarding the phenotype, DA mainly affected the upper arch (50% of cases); bilateral DA had a significantly increased incidence (83.33% of cases) compared to unilateral form; in most cases (75%), a patient lacked one to two teeth, the lack of two teeth being the most common form (83.33% of cases); the upper lateral incisors were the teeth most frequently involved in DA (31.11% of the total missing teeth). Regarding the family genetic study, hereditary DA with autosomal dominant inheritance was present in 37.50% of cases. In the other cases (62.50%), isolated, sporadic forms of DA were registered, suggesting a spontaneous de novo mutation or a disorder of odontogenesis of a non-genetic nature. Conclusions: We consider that this study is of interest for current scientific research with applicability in dental medicine, by bringing actual information on the prevalence of non-syndromic DA in South-East Romania, the variety of phenotypic spectrum of DA for this geographic area, and the role of heredity in the DA genetic determinism in the studied population.

Genetic study of Italian families affected by small fibre neuropathy identified variants in predisposing pain phenotype

Peripheral Neuropathy (PN) affects 2.4% of people and almost 50% of general population is known to have pain-related symptoms. Genetic studies in painful PN (PPN) revealed that Voltage Gated Sodium Channels (VGSCs) genes are involved in pain amplification. Here we aimed to broaden the genetic aspect of PPN by using whole exome sequencing (WES).

P-045: Immunoglobulin V(D) J Recombination, Protein Ubiquitination, Cell Adhesion and Sonic Hedgehog Gene Variants are detected among familial Multiple Myeloma subjects following whole exome sequencing

<h3>Background</h3> Familial multiple myeloma(MM) cases have been associated with some rare, germline variants, mostly among epigenetic modification genes and needs to be validated in other populations. The aim of this study is to investigate formerly reported rare variants in our population and to search for additional ones. <h3>Methods</h3> Following the ethical committee approval, hematology centers in Turkey were informed for collaboration in this familial MM genetic association study. Inclusion criteria was defined as having one or more first, second or third degree relatives who have plasma cell diseases. After obtaining informed consents, patients' peripheral blood samples or DNAs from pathological samples were collected. NGS analysis have been performed on 33 samples from 23 families, targeting 14 variants in 6 genes, previously reported to be associated with familial presentation (EP300, CDKN2A, USP45, ARID1A, KDM1A, DIS314)(Pertesi et al., Leukemia, 2020). To widen the range of analysis, whole exome sequencing (WES) within 3 families (6 patients) of first degree relatives were carried out. The detected variants were checked against NCBI's dbSNP. Mutation Taster was utilized for probable disease associations. <h3>Results</h3> 30 MM families(63 patients) were included. Of the patients 69% were first, 4% were second and 27% were third degree relatives. Neither of the previously reported rare variants were detected among the subjects in the targeted sequencing. However, an heterozygote variant (rs3731249) close to the targeted region in CDKN2A was detected in 3 patients. WES detected new variants which were not observed earlier. Family 1:Missense variants in BRIP1 (function: DNA double strand break repair)(rs886053214, rs886053215) and ACD (function: maintain telomere length)(rs1306270247). All of which were predicted as polymorphism, in silico. Family 2:Missense variant in RAG2 (function:V(D)J recombination of Ig and T cell receptor) (rs765298019) predicted as disease causing. Family 3:Missense variant in RET (function: receptor tyrosine kinase)(rs1366681125) predicted as polymorphism. Missense variants in CBL (function: protein ubiquitination)(rs754194646), APC (function: cell adhesion)(rs760591046) and PTCH1 (function: sonic hedgehog) (rs772574714) were predicted as disease causing. All of the variants from the patients were detected as one-copy-alleles. The variant in RAG2 was reported to cause severe combined immunodeficiency and histiocytic medullary reticulosis in homozygous state. The PTCH1 variant is known to give rise to nevoid basal cell carcinoma syndrome. Germline mutations of CBL and APC are related to the juvenile myelomonocytic leukemia, familial AML and familial adenomatous polyposis respectively. <h3>Conclusion</h3> MM development is a multistep process. As of actual literature, MM susceptibility in familial cases involve various gene variants. Here we suggest the consideration of RAG2, CBL, APC, PTCH1 as additional loci for the progression to familial MM.