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Background: Congenital heart disease (CHD) is the most common congenital anomaly. Up to 33% have an identifiable genetic etiology. Improved medical and surgical management of CHD has translated into longer life expectancy and a rapidly growing population of adults living with CHD. The adult CHD (ACHD) population did not have access during childhood to the genetic technologies available today and therefore have not had a robust genetic evaluation that is currently recommended for infants with CHD. Given this potential benefit; the aims of this study were to determine how ACHD cardiologists offer genetics services to patients and identify the indications that influence decision-making for genetics care. Methods: We performed a descriptive cross-sectional study of ACHD cardiologists. A study-developed questionnaire was distributed via emailed REDCap link. The recruitment email was sent to 104 potential respondents. The survey was open from 06/2022 to 01/2023. Results: Thirty-five cardiologists participated in the study (response rate of 34%). Most cardiologists identified as white (77%) and male (66%). Cardiologists were more likely to refer patients to genetics (91%) than to order testing themselves (57%). Of the testing ordered, chromosomal testing (55%) was ordered more than gene sequencing (14%). Most cardiologists would refer a patient with a conotruncal lesion (interrupted aortic arch) over other indications for a genetics evaluation. There were more reported barriers to ordering genetic testing (66%) compared to referring to genetics for a genetics evaluation (23%). Cardiologists were more confident recognizing features suggestive of a genetic syndrome than ordering the correct test (p = 0.001). Regarding associations between clinical factors and current practices, more years in practice trended towards less referrals and testing. Evaluating a greater number of patients (p = 0.11) and greater confidence recognizing syndromic features (p = 0.12) and ordering the correct test (p = 0.09) were all associated with ordering more testing. Conclusion: Testing for microdeletion syndromes is being offered and completed in the ACHD population, however testing for single-gene disorders associated with CHD is being under-utilized. Developing guidelines for genetic testing in adults with CHD could increase access to genetic services, impact medical management, reduce uncertainty regarding prognosis, and inform recurrence risk estimates. [ABSTRACT FROM AUTHOR]

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease of the spine and sacroiliac joints. This review discusses recent advances across multiple scientific fields that promise to transform axSpA management. Traditionally, axSpA was considered an immune-mediated disease driven by human leukocyte antigen B27 (HLA-B27), interleukin (IL)-23/IL-17 signaling, biomechanics, and dysbiosis. Diagnosis relies on clinical features, laboratory tests, and imaging, particularly magnetic resonance imaging (MRI) nowadays. Management includes exercise, lifestyle changes, non-steroidal anti-inflammatory drugs and if this is not sufficient to achieve disease control also biological and targeted-synthetic disease modifying anti-rheumatic drugs. Beyond long-recognized genetic risks like HLA-B27, high-throughput sequencing has revealed intricate gene-environment interactions influencing dysbiosis, immune dysfunction, and aberrant bone remodeling. Elucidating these mechanisms promises screening approaches to enable early intervention. Advanced imaging is revolutionizing the assessment of axSpA's hallmark: sacroiliac bone-marrow edema indicating inflammation. Novel magnetic resonance imaging (MRI) techniques sensitively quantify disease activity, while machine learning automates complex analysis to improve diagnostic accuracy and monitoring. Hybrid imaging like synthetic MRI/computed tomography (CT) visualizes structural damage with new clarity. Meanwhile, microbiome analysis has uncovered gut ecosystem alterations that may initiate joint inflammation through HLA-B27 misfolding or immune subversion. Correcting dysbiosis represents an enticing treatment target. Moving forward, emerging techniques must augment patient care. Incorporating patient perspectives will be key to ensure innovations like genetics, microbiome, and imaging biomarkers translate into improved mobility, reduced pain, and increased quality of life. By integrating cutting-edge, multidisciplinary science with patients' lived experience, researchers can unlock the full potential of new technologies to deliver transformative outcomes. The future is bright for precision diagnosis, tightly controlled treatment, and even prevention of axSpA. [ABSTRACT FROM AUTHOR]

Introduction/objectives: Familial Mediterranean Fever (FMF) is a genetic disorder of the innate immunity characterized by chronic inflammatory state. The diagnosis is mainly based on clinical criteria and supported by genotyping, especially in atypical phenotypes. The primary objective was to depict the Familial Mediterranean Fever (FMF) genotype of Greek patients and investigate the contribution of Next Generation Sequencing (NGS) beyond the contemporary techniques [(Polymerase Chain Reaction (PCR)/hybridization and Non-Isotopic RNase Cleavage Assay (NIRCA). The secondary objective was to unravel any associations between the mutated genes with the disease course and response to treatment. Methods: In this single center, retrospective study 31 patients with clinical diagnosis with FMF, but non-conclusive genetic analysis with PCR/hybridization and NIRCA, underwent NGS genotyping. Results: PCR/NIRCA detected ≥ 1 mutation in 25/31 patients, most frequently M694V (29%), while NGS in 26/31 (83.9%), most frequently R202Q (61.3%). NGS genetically confirmed the clinical diagnosis (heterozygosity to compound or complex genotype) in 19 (61.3%) patients of our cohort. R202Q was significantly more prevalent by NGS than by contemporary techniques (61.3 vs 12.9%, p = 0.0002) and was associated with FMF. Rare mutations were detected by NGS in 19.2% patients. Conclusion: NGS clarifies the genetic profile of patients with atypical phenotypes and supports therapeutic management decisions. NGS unveiled the frequent involvement of R202Q in the pathogenesis of our FMF patients. [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis. FMF is caused by mutations in the MEFV gene, encoding pyrin protein. Pyrin functions in innate immunity and triggers inflammation via inflammatory mediators' production and acts as the primary regulatory component of the inflammasome. On the other hand, various miRNAs play crucial roles in the pathogenesis of different types of cancers and immune-related and neurodegenerative diseases. However, their association with FMF is still unclear. Therefore, in this study, we assessed the roles of selected thirteen miRNAs associated with immune functions. We recruited genetically diagnosed 28 FMF patients and 28 healthy individuals. The expression profiling of the miRNAs was determined by qRT-PCR and normalized to SNORD61. Our analysis revealed that miR-34a-5p, miR-142-3p, miR-216a-5p, miR-340-5p, miR-429, and miR-582-5p were upregulated, whereas miR-107, miR-569, and miR-1304-5p were downregulated in the FMF patients. Among them, miR-107 was found to be the most remarkable in M694V homozygous mutants compared to other homozygous mutants. During clinical follow-up of the patients with M694V mutation, which is closely related to amyloidosis, evaluation of mir-107 expression might be crucial and suggestive. Our results showed that miRNAs might serve a function in the pathogenesis of FMF. Further studies may provide novel and effective diagnostic and therapeutic agents that target examined miRNAs. Targeting miRNAs in FMF seems to be promising and may yield a new generation of rational therapeutics and diagnostic or monitoring tools enabling FMF treatment. [ABSTRACT FROM AUTHOR]

An 86-year-old Caucasian man had prior episodes of fever (up to 38 °C), mild abdominal pain, tachycardia, and malaise in the last 3 months, lasting 2–3 days. He never suffered from abdominal or chest pain, rash, or arthralgia. Major causes of fever were excluded (pulmonary, urinary, abdomen, skin infections, neoplasms, and major rheumatologic disorders). The patient was native of Altamura with a family history of familial Mediterranean fever (FMF). The genetic testing confirmed the presence of MEFV gene variants c.442G>C (E148Q) on exon 2 and c.2282G>A (R761H) on exon 10, all in heterozygosity. Mildly elevated serum transaminases suggested an ongoing form of FMF hepatitis on nonalcoholic liver steatosis. The patient started colchicine 1 mg/day that induced symptom control and normalization of inflammatory markers, hyperbilirubinemia, and markers of cholestasis. Symptoms of FMF can appear at any age in life and our patient represents a very late-onset clinical case. The Apulian region has a consistent clustering of MEFV variants and FMF families with affected individuals in multiple consecutive generations. Families show unique clinical features and rare signs of secondary amyloidosis without kidney damage. Genetic and environmental bases of this phenotypic variant are under scrutiny. Colchicine lifetime remains the mainstay of treatment in FMF patients. Key Points: • Familial Mediterranean fever (FMF) is the most frequent hereditary monogenic recurrent fever syndrome, and symptoms can appear at any age in life. • Late-onset FMF approaches 30% in late adulthood, but in general, onset of FMF after the age of 40 (late onset FMF) is rare, usually associated with M694V heterozygosity. • In a local cluster of FMF families (Altamura, Puglia, Southern Italy), we report a very late-onset FMF (variants E148Q, R761H) in an 86-year-old patient with a positive family history of FMF in two generations of descendants. • While lifetime colchicine remains the mainstay of treatment in FMF patients, prospective studies need to identify the characteristics of several phenotypic variants accounting for (very)-late onset FMF. [ABSTRACT FROM AUTHOR]

Objective FMF is an inherited autoinflammatory syndrome, characterized by attacks of painful periodic fever caused by diffuse serositis and risk of secondary amyloidosis due to IL-1β-mediated inflammation. The disease appears to be transmitted through autosomal recessive mutations in the MEFV gene encoding the pyrin protein Although more than 300 variants have been reported worldwide so far, their association with symptom severity, the relative frequencies in different populations and the disease penetrance are far from being completely understood. We investigated genotype–phenotype correlations in two large nuclear families and verified whether commonly used web-based tools can usefully predict variant pathogenicity in FMF. Methods Peripheral blood samples were obtained from 15 patients of two families who had been diagnosed with FMF according to international criteria. The entire MEFV coding region was sequenced in all subjects, and 179 MEFV variants were surveyed with five different pathogenicity predictors. Results The inheritance of FMF could not be explained by traditional autosomal recessivity in both families. In silico tools demonstrated a significant association of variants' pathogenicity with their position along the coding sequence but not with variants' frequency. Conclusion By describing two large families with paradigmatic complexity of FMF genetics, we conclude that established concepts in assessing the causative role of variants identified in mutation screening cannot be easily translated into appropriate genetic counselling in FMF. Furthermore, we demonstrate that variants frequently associated with severe disease are not predicted to significantly impact protein function using in silico algorithms. [ABSTRACT FROM AUTHOR]

Ex situ germplasm collections seek to conserve maximum genetic diversity in a small number of samples. Geographic and environmental information have long been treated as surrogate measures of genetic diversity, proposed to be useful for increasing allelic diversity of collections. We examine the effect of maximizing geographic and environmental diversity on the retention of distinct haplotype blocks in germplasm subsets, using three species with extensive genomewide genotypic data. We show that maximizing diversity in the surrogate measures produces subsets with uneven representation of haplotypic diversity across the genome. Some regions are well-conserved, exhibiting high haplotypic diversity, while others are poorly-conserved and contain significantly less haplotypic diversity than would be obtained via random sampling. In two of three species, poorly-conserved genomic regions were enriched in regulatory genes which, as a class, contribute to phenotypic variation. The specific genes affected varied by species but, overall, haplotypic diversity was poorly-conserved at genes controlling ~ 10% of major molecular functions and biological processes. While this study was limited to three exemplar species, we find little evidence to support continued use of geographic or environmental surrogates for ex situ conservation activities attempting to capture maximum genomewide allelic diversity. Although geographic and environmental diversity have proven to be reliable predictors of allele frequency differences and ecotypic differentiation across species ranges, they appear to be poor predictors of allelic diversity per se, offering little opportunity to enrich collections for haplotypic diversity overall, and ample opportunity to bias the conservation of important functional genetic variation. We propose a bioinformatic bridge between haplotypic diversity and the potential phenotypic diversity residing in collections using the Gene Ontology. [ABSTRACT FROM AUTHOR]

Abstract: Studies on natural variation are an important tool to unravel the genetic basis of quantitative traits in plants. Despite the significant roles of phytohormones in plant development, including root architecture, hardly any studies have been done to investigate natural variation in endogenous hormone levels in plants. Therefore, in the present study a range of hormones were quantified in root extracts of thirteen Arabidopsis thaliana accessions using a ultra performance liquid chromatography triple quadrupole mass spectrometer. Root system architecture of the set of accessions was quantified, using a new parameter (mature root unit) for complex root systems, and correlated with the phytohormone data. Significant variations in phytohormone levels among the accessions were detected, but were remarkably small, namely less than three‐fold difference between extremes. For cytokinins, relatively larger variations were found for ribosides and glucosides, as compared to the free bases. For root phenotyping, length‐related traits—lateral root length and total root length—showed larger variations than lateral root number‐related ones. For root architecture, antagonistic interactions between hormones, for example, indole‐3‐acetic acid to trans‐zeatin were detected in correlation analysis. These findings provide conclusive evidence for the presence of natural variation in phytohormone levels in Arabidopsis roots, suggesting that quantitative genetic analyses are feasible. [ABSTRACT FROM AUTHOR]

Evidence accumulated over recent years has shown that genetic neurological channelopathies can cause many different neurological diseases. Presentations relating to the brain, spinal cord, peripheral nerve or muscle mean that channelopathies can impact on almost any area of neurological practice. Typically, neurological channelopathies are inherited in an autosomal dominant fashion and cause paroxysmal disturbances of neurological function, although the impairment of function can become fixed with time. These disorders are individually rare, but an accurate diagnosis is important as it has genetic counselling and often treatment implications. Furthermore, the study of less common ion channel mutation-related diseases has increased our understanding of pathomechanisms that is relevant to common neurological diseases such as migraine and epilepsy. Here, we review the molecular genetic and clinical features of inherited neurological channelopathies. [ABSTRACT FROM AUTHOR]

Plants dynamically cope with the variability of mineral nutrient distribution in soil by constantly modulating nutrient uptake and shaping root-system architecture. The changes in root morphology in response to major essential elements are largely documented, but little is known about how the root system responds to magnesium (Mg) availability. Thirty-six natural accessions of the model species Arabidopsis thaliana were subjected to an in vitro screen for identifying variation in root system architecture in response to Mg availability. Response of root morphology was observed on 2-dimensional agar plates. Low Mg supply repressed the elongation of the lateral roots more than of the primary root. However, some accessions exhibited higher number and length of lateral roots than the reference Columbia-0. Across all accessions, the root morphological traits did not correlate with tissue Mg concentrations. Interestingly, shoot calcium and root phosphorus concentrations were positively correlated with the number and length of lateral roots, whereas root iron concentration was negatively correlated with the primary root length. The diversity of root phenotypes identified in this report is a useful resource to study the genetic component determining root morphology in response to Mg availability. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system. The clinical features of this disorder are recurrent seizures, difference in age onset, type, and frequency, leading to motor, sensory, cognitive, psychic, or autonomic disturbances. Since the discovery of the first monogenic gene mutation in 1995, it is proposed that genetic factor plays an important role in the mechanism of epilepsy. Genes discovered in idiopathic epilepsies encode for ion channel or neurotransmitter receptor proteins, whereas syndromes with epilepsy as a main feature are caused by genes that are involved in functions such as cortical development, mitochondrial function, and cell metabolism. The identification of these monogenic epilepsy-causing genes provides new insight into the pathogenesis of epilepsies. Although most of the identified gene mutations present a monogenic inheritance, most of idiopathic epilepsies are complex genetic diseases exhibiting a polygenic or oligogenic inheritance. This article reviews recent genetic and molecular progresses in exploring the pathogenesis of epilepsy, with special emphasis on monogenic epilepsy-causing genes, including voltage-gated channels (Na, K, Ca, Cl, and HCN), ligand-gated channels (nicotinic acetylcholine and GABA receptors), non-ion channel genes as well as the mitochondrial DNA genes. These progresses have improved our understanding of the complex neurological disorder. [ABSTRACT FROM AUTHOR]

Purpose To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum ( EAS) in order to understand the genetic architecture of this group of disorders. Methods Patients with epileptic encephalopathy with continuous spike-and-wave during sleep ( ECSWS), Landau- Kleffner syndrome ( LKS), atypical benign partial epilepsy ( ABPE), and intermediate epilepsy-aphasia disorders ( IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes ( BECTS) using the same methodology. Key Findings Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31) . Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. Significance The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum. [ABSTRACT FROM AUTHOR]

Autosomal dominant nocturnal frontal lobe epilepsy is a familial partial epilepsy syndrome and the first human idiopathic epilepsy known to be related to specific gene defects. Clinically available molecular genetic testing reveals mutations in three genes, CHRNA4, CHRNB2 and CHRNA2. Mutations in CHRNA4 have been found in families from different countries; the Ser280Phe in an Australian, Spanish, Norwegian and Scottish families, and the Ser284Leu in a Japanese, Korean, Polish and Lebanese families. Clear evidence for founder effect was not reported among them, including a haplotype study carried out on the Australian and Norwegian families. Japanese and Koreans, because of their geographical closeness and historical interactions, show greater genetic similarities than do the populations of other countries where the mutation is found. Haplotype analysis in the two previously reported families showed, however, independent occurrence of the Ser284Leu mutation. The affected nucleotide was highly conserved and associated with a CpG hypermutable site, while other CHRNA4 mutations were not in mutation hot spots. Association with a CpG site accounts for independent occurrence of the Ser284Leu mutation. [ABSTRACT FROM AUTHOR]

Epilepsy is a frequent neurologic disease in childhood, characterized by recurrent seizures and sometimes with major effects on social, behavioral, and cognitive development. Childhood focal epilepsies particularly are age-related diseases mainly occurring during developmental critical periods. A complex interplay between brain development and maturation processes and susceptibility genes may contribute to the development of various childhood epileptic syndromes associated with language and cognitive deficits. Indeed, the Landau-Kleffner syndrome (LKS), the continuous spike-and-waves during sleep syndrome (CSWS), and the benign childhood epilepsy with centrotemporal spikes (BCECTS) or benign rolandic epilepsy, are different entities that are considered as part of a single continuous spectrum of disorders. Genetic predisposition with simple to complex modes of inheritance has long been suspected for this wide group of childhood focal epilepsies. Recent reports on the involvement of the SRPX2 and ELP4 genes with possible roles in cell motility, migration, and adhesion have provided first insights into the complex molecular bases of childhood focal epilepsies. [ABSTRACT FROM AUTHOR]

Bilateral frontoparietal polymicrogyria (BFPP) has been reported in sporadic patients and in recessive pedigrees. Eleven mutations in GPR56, a gene encoding an evolutionarily dynamic G-protein–coupled receptor, have been identified in 29 patients from 18 families. The clinical features of BFPP include severe mental retardation, motor and language impairment, and epilepsy. No detailed description of the epilepsy is available for the patients reported to date. We report three consanguineous families in which four affected individuals with BFPP and GPR56 mutations had Lennox-Gastaut syndrome. Family studies, brain magnetic resonance imaging (MRI), electroencephalography (EEG)-video recordings, and mutation analysis. In Family 1, with one affected proband, we found an R565W change in the second extracellular loop of GPR56, involving a highly conserved aminoacidic residue. In Family 2, with one affected proband, we found an R79X change affecting the protein N-terminus and predicted to cause a premature truncation with loss of the G-protein–coupled receptor proteolytic site. In family 3, with two affected siblings, we found an R33P substitution in the protein N-terminus, involving a highly conserved aminoacidic residue. Epilepsy, present in all four patients, had started between ages 1 and 8 years, with infantile spasms in one patient and with de novo Lennox-Gastaut syndrome in the remaining three. All patients had Lennox-Gastaut syndrome when last observed, at ages 13 to 32 years. Several genes, when mutated, can cause malformations of cortical development that have been associated with the Lennox-Gastaut syndrome. BFPP caused by GPR56 mutations represents an additional , although rare, genetically determined cause of Lennox-Gastaut syndrome. [ABSTRACT FROM AUTHOR]

The relationship between paroxysmal movement disorders (PD: paroxysmal dyskinesia) and epilepsy continues to present a challenging problem. Attacks of PD and epileptic seizures have several characteristics in common: both are paroxysmal in nature with a tendency to spontaneous remission, and a subset of PD responds well to anticonvulsants. In 1997, description of the ICCA (infantile convulsions and choreoathetosis) syndrome and linkage to chromosome 16p12-q12 provided the first genetic evidence for common mechanisms shared by benign infantile seizures and PD. The chromosome 16 ICCA locus is by far the most frequently involved in such associations as well as in pure forms of benign infantile seizures. The ICCA region at the pericentromeric area of chromosome 16 shows complicated genomic architecture and the ICCA gene still remains unknown. Genetic studies focusing on PD with or without epilepsy have led to the identification of other genes linked to chromosomes 2q35 and 10q22. Alterations of ion channel and ion pump subunits could provide a simple, albeit probably non-unique, explanation for the pathophysiology of the link between epilepsy and PD. The aim of this review is to update genetic aspects of infantile epileptic seizures and PD and their association in the context of ICCA and ICCA related syndromes. [ABSTRACT FROM AUTHOR]

We report a three generation pedigree with 11 of 22 affected with a variant form of rolandic epilepsy, speech impairment, oromotor apraxia, and cognitive deficit. The core features comprised nocturnal rolandic seizures, interictal centrotemporal spike waves with early age of onset and late age of offset. The transmission of the phenotype was consistent with autosomal dominant inheritance, with variable expressivity but no evidence of anticipation. We found evidence that the seizure and speech traits may be dissociated. No abnormalities were found by cytogenetic analysis. Linkage analysis excluded loci at 11p, 15q, 16p12, and Xq22 for related phenotypes, suggesting genetic heterogeneity. [ABSTRACT FROM AUTHOR]

Haplotype analysis of 376 Familial Mediterranean Fever (FMF) patients and 100 controls from Lebanon was performed using 4 microsatellite loci to study founder effects for the five most frequent mutations within the MEFV gene (M694V, M694I, V726A, M680I and E148Q). Each of these mutations was associated with a particular haplotype that was less frequent among controls, confirming that they have probably arisen from unique mutation events and that the carrier chromosomes derived from a common ancestor. The estimated ages of the most recent common ancestor for each of the 5 mutations, using the ESTIAGE program, were 7000, 8500, 15000, 23000 and 30000 years for M694V, M694I, V726A, M680I and E148Q, respectively. Varying the mutation rate at one of the markers led to younger age estimates, but the mutation E148Q remained the oldest one. Comparison of haplotype distributions among the different Lebanese religious groups confirmed that Muslim sub-populations (Shiites and Sunnites) as well as Christian ones, including Armenians who were formerly settled in the South-Eastern part of Asia Minor (Cilicia), are all derived from an ancient common ancestral population in which most of the MEFV mutations were already present with their respective associated haplotypes. [ABSTRACT FROM AUTHOR]

It is very important to efficiently study and use genetic diversity resources in crop breeding and sustainable agriculture. In this study, different sampling methods and sample sizes were compared in order to optimize the strategies for building a rationally sized core collection of Chinese soybean ( Glycine max). The diversity in the core collection captured more than 70% of that in the pre-core collection, no matter what sampling methods were used, at a sampling proportion of 1%. Core collections established with both simple sequence repeat (SSR) marker data and agronomic traits were more representative than those chosen on an independent basis. An optimal sampling method for a soybean core collection was determined, in which strategy ‘S’ (allocating accessions to clusters according to the proportion of square root of the original sample size within each ecotype) was used based on SSR and agronomic data. Curve estimation was used to estimate the allelic richness of the entire Chinese soybean germplasm and a minimum sample size for a core collection, on which a sampling proportion of about 2% was determined to be optimal for a core collection. Further analysis on the core collection with fourteen agronomic traits and allelic constitution at 60 SSR loci suggested that it highly represented the entire collections both on genetic structure and diversity distribution. This core collection would provide an effective platform in proper exploitation of soybean germplasm resources for the study of complex traits and discovering important novel traits for crop genetic development. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Three forms of idiopathic partial epilepsy with autosomal dominant inheritance have been described: (a) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); (b) autosomal dominant lateral temporal epilepsy (ADLTE) or partial epilepsy with auditory features (ADPEAF); and (c) familial partial epilepsy with variable foci (FPEVF). Here we describe linkage analysis in a Dutch four-generation family with epilepsy fulfilling criteria of both ADNFLE and FPEVF. Methods: Clinical characteristics and results of EEG, computed tomography (CT), and magnetic resonance imaging (MRI) were evaluated in a family with autosomal dominantly inherited partial epilepsy with apparent incomplete penetrance. Linkage analysis was performed with markers of the ADNFLE (1p21, 15q24, 20q13.3) and FPEVF (2q, 22q11-q12) loci. Results: Epilepsy was diagnosed in 10 relatives. Age at onset ranged from 3 months to 24 years. Seizures were mostly tonic, tonic–clonic, or hyperkinetic, with a wide variety in symptoms and severity. Most interictal EEGs showed no abnormalities, but some showed frontal, central, and/or temporal spikes and spike–wave complexes. From two patients, an ictal EEG was available, showing frontotemporal abnormalities in one and frontal and central abnormalities in the other. Linkage analysis with the known loci for ADNFLE and FPEVF revealed linkage to chromosome 22q in this family. Conclusions: The clinical characteristics of this family fulfilled criteria of both ADNFLE and FPEVF. The frequent occurrence of seizures during daytime and the observation of interictal EEG abnormalities originating from different cortical areas were more in agreement with FPEVF. The observed linkage to chromosome 22q supported the diagnosis of FPEVF and confirmed that this locus is responsible for this syndrome. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Mutations in genes coding for the α4 and β2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. Methods: All affected family members underwent a detailed clinical evaluation and review of available EEG, neuroimaging, and videotapes of seizures. The molecular study of family D is reported here; family S has a previously reported mutation in the β2 subunit of CHRN. Results: A total of 16 individuals with ADNFLE were identified in the two families. In both families, seizure semiology, age at seizure onset, and the natural history of the seizure disorder was similar. Intrafamilial variation in terms of severity of epilepsy syndrome was present in both families. A significant number of individuals from each family had a history of psychological problems. The molecular study of family D revealed a Ser248Phe mutation in the α4 subunit of CHRN. Conclusions: The epilepsy phenotype is not distinguishable in the two families who have ADNFLE as a result of mutations in genes coding for different CHRN subunits. This is likely to be due to the similar functional consequences of each mutation on the CHRN receptor. [ABSTRACT FROM AUTHOR]

Summary: Recent molecular insights into the human idiopathic epilepsies have suggested the central role of ligand-gated and voltage-gated ion channels in their etiology. So far, genes coding for sodium and potassium channel subunits as well as a nicotinic cholinergic receptor subunit have been identified for mendelian idiopathic epilepsies. In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights into mechanisms underlying hyperexcitability. Similarly, spontaneous murine epilepsy models have been associated with calcium channel molecular defects. The major challenge before us in understanding the genetics of the epilepsies is to identify genes for common forms of epilepsy following complex inheritance. Once such genes are discovered, the gene–gene–environmental interactions producing specific epilepsy syndromes can be explored. [ABSTRACT FROM AUTHOR]