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Epigenetic modifications have been implicated in a number of complex diseases as well as being a hallmark of organismal aging. Several reports have indicated an involvement of these changes in Alzheimer's disease (AD) risk and progression, most likely contributing to the dysregulation of AD-related gene expression measured by DNA methylation studies. Given that DNA methylation is tissue-specific and that AD is a brain disorder, the limitation of these studies is the ability to identify clinically useful biomarkers in a proxy tissue, reflective of the tissue of interest, that would be less invasive, more cost-effective, and easily obtainable. The age-related DNA methylation changes have also been used to develop different generations of epigenetic clocks devoted to measuring the aging in different tissues that sometimes suggests an age acceleration in AD patients. This review critically discusses epigenetic changes and aging measures as potential biomarkers for AD detection, prognosis, and progression. Given that epigenetic alterations are chemically reversible, treatments aiming at reversing these modifications will be also discussed as promising therapeutic strategies for AD.

Restless leg syndrome (RLS) is a sensorimotor disorder clinically characterized by unpleasant sensations associated to urge to move the legs, predominantly manifested at resting or in the evening. RLS is considered a complex genetic disease, and a strong familial component has been proposed also in the primary RLS. While a role of genetics in this form is well established, the aetiopathogenesis of the disease remains somewhat uncertain, and genetic studies are still an important pillar of RLS research. This chapter discusses the contribution of genetics in the pathogenesis of primary RLS, with a focus on how genetics is able to drive the clinical and imaging phenotype. Genome-wide association studies have been decisive in the identification of genes (MEIS1, BTBD9, and MAP 2K5/SKOR1) strongly related with RLS in the Caucasian and Asian populations. These disease-associated genes encode for proteins involved in the ferritin expression and iron metabolism and dopaminergic system activity. Finally, using a neuroimaging approach, we also provide to identify potential vulnerable areas for the development of RLS. Structural/functional white and gray matter changes and changes due to the iron storage alterations have been questioned, in order to decode the possible association to RLS neuropathology.

The current coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, is affecting every aspect of global society, including public healthcare systems, medical care access, and the economy. Although the respiratory tract is primarily affected by SARS-CoV-2, emerging evidence suggests that the virus may also reach the central nervous system (CNS), leading to several neurological issues. In particular, people with a diagnosis of Alzheimer’s disease (AD) are a vulnerable group at high risk of contracting COVID-19, and develop more severe forms and worse outcomes, including death. Therefore, understanding shared links between COVID-19 and AD could aid the development of therapeutic strategies against both. Herein, we reviewed common risk factors and potential pathogenetic mechanisms that might contribute to the acceleration of neurodegenerative processes in AD patients infected by SARS-CoV-2.

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is the familial form of a focal epilepsy characterized by hyperkinetic focal seizures, mainly arising during non-rapid eye movements (NREM) sleep. Mutations associated with ADSHE account for a small proportion of the genetically determined cases, suggesting the existence of other disease-causing genes. Here, we reported the results obtained by performing trio-based whole-exome sequencing (WES) in an Italian family showing ADSHE and investigated the structural impact of putative variants by in silico modeling analysis. We identified a p.(Trp276Gly) variant in MOXD1 gene encoding the monooxigenase DBH like 1 protein, cosegregating with the disease and annotated as VUS under the ACMG recommendations. Structural bioinformatic analysis predicted a high destabilizing effect of this variant, due to the loss of important hydrophilic bonds and an expansion of cavity volume in the protein hydrophobic core. Although our data support a functional effect of the p.(Trp276Gly) variant, we highlight the need to identify additional families carrying MOXD1 mutations or functional analyses in suitable models to clarify its role in ADSHE pathogenesis. Moreover, we discuss the importance of VUS reporting due to the low rate of pathogenic variant identification by NGS in epilepsy and for future reinterpretation studies.

Autism spectrum disorder (ASD) represents a group of neurodevelopmental diseases characterized by persistent deficits in social communication, interaction, and repetitive patterns of behaviors, interests, and activities. The etiopathogenesis is multifactorial with complex interactions between genetic and environmental factors. The clinical heterogeneity and complex etiology of this pediatric disorder have limited the development of pharmacological therapies. The major limit to ASD research remains a lack of relevant human disease models which can faithfully recapitulate key features of the human pathology and represent its genetic heterogeneity. Recent advances in induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of patients into all types of patient-specific neural cells, have provided a promising cellular tool for disease modeling and development of novel drug treatments. The iPSCs technology allowed not only a better investigation of the disease etiopathogenesis but also opened up the potential for personalized therapies and offered new opportunities for drug discovery, pharmacological screening, and toxicity assessment. Moreover, iPSCs can be differentiated and organized into three-dimensional (3D) organoids, providing a model which mimics the complexity of the brain's architecture and more accurately recapitulates tissue- and organ-level disease pathophysiology. The aims of this review were to describe the current state of the art of the use of human patient-derived iPSCs and brain organoids in modeling ASD and developing novel therapeutic strategies and to discuss the opportunities and major challenges in this rapidly moving field.

With more than 80 subunits, potassium (K+) channels represent a group of ion channels showing high degree of diversity and ubiquity. They play important role in the control of membrane depolarization and cell excitability in several tissues, including the brain. Controlling the intracellular and extracellular K+ flow in cells, they also modulate the hormone and neurotransmitter release, apoptosis and cell proliferation. It is therefore not surprising that an improper functioning of K+ channels in neurons has been associated with pathophysiology of a wide range of neurological disorders, especially Alzheimer's disease (AD). This review aims to give a comprehensive overview of the basic properties and pathophysiological functions of the main classes of K+ channels in the context of disease processes, also discussing the progress, challenges and opportunities to develop drugs targeting these channels as potential pharmacological approach for AD treatment.

This study aims to evaluate HPV16 variants distribution in a population of Italian women living in two different regions (Lombardy and Sardinia) by sequence analyses of HPV16-positive cervical samples, in order to reconstruct the phylogenetic relationship among variants to identify the currently circulating lineages. Analyses were conducted starting from DNA isolated from 67 HPV16-positive cervical samples collected from two different Italian centres (31 from Lombardy and 36 from Sardinia) of women with normal and abnormal cervical cytology. The entire long control region (LCR) and 300 nt of the E6 gene was sequenced to identify intra-type variants. Sequence comparison and phylogenetic analysis were made using a distance-based neighbour joining method (NJ) and Kimura two-parameter model. Data obtained reported that Italian sequences mainly belonged to the European lineage, in particular sublineage A2. Only five sequences clustered in non-European branches: two in North American lineage (sublineage D1), two in African-1 (sublineage B1) and one in African-2. A new 27 nucleotide duplication in the central segment of the LCR region was found in a sequence obtained from a sample isolated in Sardinia. A predominance of European variants was detected, with some degree of variability among the studied HPV16 strains. This study contributes to the implementation of data regarding the molecular epidemiology of HPV16 variants.

Epilepsy represents one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS). Recurrent seizures are the cardinal clinical manifestation. Although it has been reported that the underlying pathological processes include inflammation, changes in synaptic strength, apoptosis, and ion channels dysfunction, currently the pathogenesis of epilepsy is not yet completely understood. Long non-coding RNAs (lncRNAs), a class of long transcripts without protein-coding capacity, have emerged as regulatory molecules that are involved in a wide variety of biological processes. A growing number of studies reported that lncRNAs participate in the regulation of pathological processes of epilepsy and they are dysregulated during epileptogenesis. Moreover, an aberrant expression of lncRNAs linked to epilepsy has been observed both in patients and in animal models. In this review, we summarize latest advances concerning the mechanisms of action and the involvement of the most dysregulated lncRNAs in epilepsy. However, the functional roles of lncRNAs in the disease pathogenesis are still to be explored and we are only at the beginning. Additional studies are needed for the complete understanding of the underlying mechanisms and they would result in the use of lncRNAs as diagnostic biomarkers and novel therapeutic targets.

Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) defined by joint laxity, skin alterations, and joint hypermobility. The latest EDS classification recognized 13 subtypes in which the clinical and genetic phenotypes are often overlapping, making the diagnosis rather difficult and strengthening the importance of the molecular diagnostic confirmation. New genetic techniques such as next-generation sequencing (NGS) gave the opportunity to identify the genetic bases of unresolved EDS types and support clinical counseling. To date, the molecular defects have been identified in 19 genes, mainly in those encoding collagen, its modifying enzymes or other constituents of the extracellular matrix (ECM). In this review we summarize the contribution of NGS technologies to the current knowledge of the genetic background in different EDS subtypes

Migraine with and without aura, cluster headache, hypnic headache, and paroxysmal hemicranias are each reported as intrinsically related to sleep. Chronic migraine, chronic tension-type headache, and medication overuse headache may cause sleep disturbance. Otherwise, both headache and sleep disorder may be manifestations of a same systemic dysfunction. There is a vicious cycle linking sleep disorders and migraine. The poor quality or poor duration of sleep could be a trigger of migraine attack and migraineurs with poor sleep reported a higher headache frequency. Moreover, coping behaviors of migraineurs (e.g., going to sleep early to relieve migraine attacks) can be factors precipitating and perpetuating sleep disturbances themselves. During cluster headache, patients report a poor quality of sleep correlated with the amount of daylight. In particular, it was demonstrated that melatonin levels have influences on cluster headache attacks. Concerning the pathophysiology of hypnic headache, it has been hypothesized a possible role of obstructive sleep apnea in triggering nocturnal attacks: an increased number of apnea episodes has been reported in hypnic headache patients, but a lack of a temporal correlation of headache attacks with the drop of oxygen saturation has been observed. Tension-type headache is the most common headache with sleep dysregulation (lack of sleep or oversleeping) frequently reported as a triggering factor for acute attacks: management of sleep disturbances seems crucial in this form of headache

Inwardly rectifying potassium channels (Kir) have been historically associated to several cardiovascular disorders. In particular, loss-of-function mutations in the Kir2.1 channel have been reported in cases affected by Andersen-Tawil syndrome while gain-of-function mutations in the same channel cause the short QT3 syndrome. Recently, a missense mutation in Kir2.1, as well as mutations in the Kir4.1, were reported to be involved in autism spectrum disorders (ASDs) suggesting a role of potassium channels in these diseases and introducing the idea of the existence of K+ channel ASDs. Here, we report the identification in an Italian affected family of a novel missense mutation (p.Phe58Ser) in the KCNJ2 gene detected in heterozygosity in a proband affected by autism and borderline for short QT syndrome type 3. The mutation is located in the N-terminal region of the gene coding for the Kir2.1 channel and in particular in a very conserved domain. In vitro assays demonstrated that this mutation results in an increase of the channel conductance and in its open probability. This gain-of-function of the protein is consistent with the autistic phenotype, which is normally associated to an altered neuronal excitability.

Mutations in the SCN1A gene causing either loss or gain of function have been frequently found in patients affected by genetic epilepsy with febrile seizures plus (GEFS+) or Dravet syndrome (also named severe myoclonic epilepsy in infancy SMEI). By mutation screening of the SCN1A gene, we identified for the first time a case of two missense mutations in cis (p.[Arg1525Gln;Thr297Ile]) in all affected individuals of an Italian family showing GEFS+ and idiopathic generalized epilepsy (IGE). The p.Arg1525Gln mutation was not previously reported yet and was predicted to be pathological by prediction tools, whereas the p.Thr297Ile was already identified in patients showing SMEI. Functional studies revealed that the Nav1.1 channels harboring both mutations were characterized by a significant shift in the activation curve towards more positive potentials. Our data demonstrate that the p.Arg1525Gln represents a novel mutation in the SCN1A gene altering the channel properties in the co-presence of the p.Thr297Ile.

Ischemia-reperfusion injury (IRI) and oxidative stress still limit the survival of cells and organs in xenotransplantation models. Ectonucleotidases play an important role in inflammation and IRI in transplantation settings. We tested the potential protective effects derived by the co-expression of the two main vascular ectonucleotidases, ecto-5’-nucleotidase (E5NT) and ecto nucleoside triphosphate diphosphohydrolase 1 (ENTPD1), in an in vitro model of H2O2-induced oxidative stress and cytotoxicity. We produced a dicistronic plasmid (named pCX-DI-2A) for the co-expression of human E5NT and ENTPD1 by using the F2A technology. pCX-DI-2A-transfected porcine endothelial cells simultaneously overexpressed hE5NT and hENTPD1, which were correctly processed and localized on the plasma membrane. Furthermore, such co-expression system led to the synergistic enzymatic activity of hE5NT and hENTPD1 as shown by the efficient catabolism of pro-inflammatory and pro-thrombotic extracellular adenine nucleotides along with the enhanced production of the anti-inflammatory molecule adenosine. Interestingly, we found that the hE5NT/hENTPD1 co-expression system conferred protection to cells against H2O2-induced oxidative stress and cytotoxicity. pCX-DI-2A-transfected cells showed reduced activation of caspase 3/7 and cytotoxicity than mock-, hE5NT- and hENTPD1-transfected cells. Furthermore, pCX-DI-2A-transfected cells showed decreased H2O2-induced production of ROS as compared to the other control cell lines. The cytoprotective phenotype observed in pCX-DI-2A-transfected cells was associated with higher detoxifying activity of catalase as well as increased activation of the survival signaling molecules Akt, extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). Our data add new insights to the protective effects of the combination of hE5NT and hENTPD1 against oxidative stress and constitute a proof of concept for testing this new genetic com

Potassium (K+) channels are expressed in almost every cells and are ubiquitous in neuronal and glial cell membranes. These channels have been implicated in different disorders, in particular in epilepsy. K+ channel diversity depends on the presence in the human genome of a large number of genes either encoding pore-forming or accessory subunits. More than 80 genes encoding the K+ channels were cloned and they represent the largest group of ion channels regulating the electrical activity of cells in different tissues, including the brain. It is therefore not surprising that mutations in these genes lead to K+ channels dysfunctions linked to inherited epilepsy in humans and non-human model animals. This article reviews genetic and molecular progresses in exploring the pathogenesis of different human epilepsies, with special emphasis on the role of K+ channels in monogenic forms.

Objective: To study the prevalence of DEPDC5 mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Methods: Thirty unrelated families referred with ADNFLE were recruited in France, Italy, Germany, Belgium, and Norway. Whole-exome sequencing was performed in 10 probands and direct sequencing of the DEPDC5 coding sequence in 20 probands. Testing for nonsense-mediated messenger RNA decay (NMD) was performed in lymphoblastic cells. Results: Exome sequencing revealed a splice acceptor mutation (c.2355-2A>G) in DEPDC5 in the proband of aGerman family. In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family. The nonsense mutations p.Arg487* and p.Arg1087* were targeted by NMD, leading to the degradation of the mutated transcripts. At the clinical level, 78% of the patients with DEPDC5 mutations were drug resistant. Conclusions: DEPDC5 loss-of-function mutations were found in 13% of the families with a presentation of ADNFLE. The rate of drug resistance was high in patients with DEPDC5 mutations. Small ADNFLE pedigrees with DEPDC5 mutations might actually represent a part of the broader familial focal epilepsy with variable foci phenotype. © 2014 American Academy of Neurology.

Nocturnal frontal lobe epilepsy (NFLE) is a syndrome of heterogeneous etiology, characterized by the occurrence of sleep-related seizures with different complexity and duration. Genetic, lesional, and cryptogenetic NFLE forms have been described. NFLE is generally considered a benign clinical entity, although severe, drug-resistant forms do exist. A significant proportion of sleep-related complex motor seizures, hardly distinguishable from NFLE, originate outside the frontal lobe. Moreover, the distinction of NFLE from the non-rapid eye movement arousal parasomnias may be challenging. A correct diagnosis of NFLE should be based on a diagnostic approach that includes the anamnestic, video-polysomnographic, morphological, and genetic aspects. Studies on the relationships between genes, arousal regulatory mechanisms, and epileptogenesis, using both clinical and experimental models of NFLE might provide key insights in the interrelationship between sleep and epilepsy. © Springer Science+Business Media 2014.

Nocturnal frontal lobe epilepsy has been historically considered a channelopathy caused by mutations in subunits of the neuronal nicotinic acetylcholine receptor or in a recently reported potassium channel. However, these mutations account for only a minority of patients, and the existence of at least a new locus for the disease has been demonstrated. In 2005, we detected two nucleotide variations in the promoter of the CRH gene coding for the corticotropin releasing hormone in 7 patients. These variations cosegregated with the disease and were demonstrated to alter the cellular levels of this hormone. Here, we report the identification in an Italian affected family of a novel missense mutation (hpreproCRH p.Pro30Arg) located in the region of the CRH coding for the protein pro-sequence. The mutation was detected in heterozygosity in the two affected individuals. In vitro assays demonstrated that this mutation results in reduced levels of protein secretion in the short time thus suggesting that mutated people could present an altered capability to respond immediately to stress agents.

BACKGROUND:: Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy characterized by a wide spectrum of stereotyped motor manifestations, mostly occurring during non rapid eye movements sleep. NFLE is underdiagnosed since semiological similarities make it difficult to distinguish NFLE from parasomnias. In 1994, authors reported families with NFLE inherited as an autosomal dominant trait and they introduced the term of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). A family history of possible NFLE is found in about 25% of cases. The genetic bases of the disease have been detected in a minority of cases. Mutations causing a gain of function of the neuronal nicotinic acetylcholine receptors were reported in 3 different subunits. REVIEW SUMMARY:: This review discusses the clinical aspects of NFLE and the diagnostic procedures. Furthermore, the genetic aspects are outlined. The main differentiating features characterizing NFLE are: (a) several attacks per night at any time during the night; (b) brief duration of the attacks; (c) stereotyped motor pattern. Nocturnal video-polysomnography is crucial for the diagnosis. Neurological examination in NFLE/ADNFLE is normal. About 30% of NFLE cases are resistant to antiepileptic drugs. Concerning the genetics, putative susceptibility nucleotide variations affecting the promoter of the CRH gene and altering the corticotrophin-releasing hormone levels have been reported in some NFLE patients. CONCLUSIONS:: Distinguishing NFLE seizures from paroxysmal nonepileptic sleep disorders is often difficult and sometimes impossible on clinical grounds alone. Nocturnal video-polysomnography is mandatory. Further genetic studies could help the diagnosis and treatment in NFLE patients.

Autism is a strong genetic disorder, with an estimated heritability greater than 90%. Nonetheless, its specific genetic aetiology remains largely unknown. Autism is associated with epilepsy in early childhood and epilepsy occurs in 10–30% of individuals with autism. Here we report the case of a woman affected by a severe epileptic disorder with an onset at 14 years old. She is affected by a cryptogenetic focal epilepsy with complex partial (psychomotor) and secondarily and has six children: two girls are healthy, a girl and two boys are affected by autism while one boygeneralized tonic-clonic seizures, which are drug resistant. The woman is married to a healthy man shows partial seizures. The three children with autism show moderate mental retardation and an EEG with no epileptiform alterations. The child with epileptic seizures shows an asymmetric EEG that is not necessarily pathological. In this family, no chromosomal rearrangements were detected by means of classical cytogenetic analyses. The presence of FRAXA alterations and of microdeletions of the 15q11-q13 chromosome region were also excluded. A genome-wide linkage analysis using microsatellite markers revealed several chromosome regions as possible susceptibility loci.

Objective: The purpose of this research was to study factors that are involved in centromeric hypomethylation in the pathogenesis of Down syndrome (DS). Study Design: This was a case-control study to evaluate the association between methyltetrahydrofolate reductase (MTHFR) C677T and methionine synthetase-reductase (MTRR) A66G polymorphisms and the risk of DS; we compared mothers in Italy who had children with DS and matched control subjects. Results: Seventy-four cases of DS caused by an error in maternal meiosis were compared with 184 matched control subjects. The frequencies of the MTHFR C677T polymorphism were similar between the 2 groups. As regards the MTRR A66G polymorphism, the presence of the mutated G allele either in the heterozygous or homozygous form was significantly more common among mothers of children with DS than among control subjects (odds ratio, 2.21; 95% CI, 1.11-4.40). Conclusion: In a population with a high prevalence of the mutated T allele, maternal MTRR A66G, but not MTHFR, polymorphisms are associated with Down syndrome. © 2009 Mosby, Inc. All rights reserved.

Epilepsies are characterized by genetic heterogeneity and by the possible coexistence of different phenotypes in one family. Moreover, in different epilepsies, mutations in the same gene have been reported. We aimed to collect data in a large Italian cohort of 81 families with children affected by partial or generalized epilepsies and to evaluate the prevalence of several ion channel mutations. In particular, a clinical and genetic survey was performed and DNA regions known to be associated with several epilepsies were analysed by sequencing. We observed genetic complexity in all phenotype groups: any epileptic type may be transmitted as either autosomal dominant or recessive. No significant phenotype identity among generations and no differences among genders could be observed. Two missense mutations in SCN1A were identified in two GEFS+ probands confirming the importance of this channel for this epilepsy. Moreover, a previously unreported CLCN2 mutation was detected in a proband showing CAE. In conclusion, even in this highly heterogeneous cohort, the complexity of the epileptic condition was highlighted and mutations in the analysed candidate region of ion channel genes appear to explain only a minority of cases. © 2009 Elsevier Inc. All rights reserved.

Mutations of voltage-gated Na+ channels are the most common known cause of genetically determined epilepsy; Nav1.1 (SCN1A) is the most frequent target. They can cause both mild and severe forms, also in patients harboring the same mutation. We have recently characterized in a family with extreme phenotypes the first epileptogenic folding-defective Na + channel mutant (Nav1.1-M1841T), whose loss of function is attenuated by interactions with associated proteins and drugs. We hypothesized that in vivo variability of the interactions may modulate the functional effect and thus the phenotype (Rusconi et al., 2007). Here we characterize another Nav1.1 folding-defective mutant (Na v1.1-R1916G) that, however, has been identified in a GEFS+ family with relatively mild phenotypes. This novel mutant shows a number of specific characteristics, but, similarly to Nav1.1-M1841T, it can be rescued by interactions with associated proteins and drugs. Thus, loss of function caused by folding defects that can be attenuated by molecular interactions may be a common pathogenic mechanism for Nav1.1 epileptogenic mutants. Folding defects can be present also in families showing only mild phenotypes in which, however, severe phenotypes could emerge within a permissive genetic background.

Glioblastomas (GBMs) contain transformed, self-maintaining, multipotent, tumour-initiating cancer stem cells, whose identification has radically changed our perspective on the physiology of these tumours. Currently, it is unknown whether multiple types of transformed precursors, which display alternative sets of the complement of properties of true cancer stem cells, can be found in a GBM. If different subsets of such cancer stem-like cells (CSCs) do exist, they might represent distinct cell targets, with a differential therapeutic importance, also depending on their characteristics and lineage relationship. Here, we report the presence of two types of CSCs within different regions of the same human GBM. Cytogenetic and molecular analysis shows that the two types of CSCs bear quite diverse tumorigenic potential and distinct genetic anomalies, and, yet, derive from common ancestor cells. This provides critical information to unravel the development of CSCs and the key molecular/genetic components underpinning tumorigenicity in human GBMs. © 2009 Macmillan Publishers Limited. All rights reserved.

Objective: Forty-six nocturnal frontal lobe epilepsy (NFLE) patients (in which the involvement of the CHRNA4 and CHRNB2 genes coding for neuronal nicotinic acetylcholine receptor (nAChRs) subunits associated to the disease were previously excluded) were analyzed for the presence of mutations in the CHRNA2 gene coding for the alpha2 subunit of the same receptor, which has been recently associated with the disease. Methods: Mutational screening was performed by sequencing two polymerase chain reaction-amplified CHRNA2 DNA fragments, spanning the whole exon 6 and exon 7, respectively, which code for 75% of the mature protein and contain all four transmembrane domains contributing to the ion pore. Results: No mutations were identified in the analyzed region of CHRNA2. Conclusions: These data demonstrate the rarity of the identified CHRNA2 mutations in NFLE patients, supporting the recently reported hypothesis of a restricted role for this gene in the disease

Silver–Russell syndrome (SRS) is clinically variable although most cases have several common signs. Different chromosomes and chromosomal regions have been associated with SRS. Maternal uniparental disomy (UPD) of chromosome 7 is responsible for 5–10% of cases, probably because of an imbalance between maternal and paternal imprinted genes and more recently maternal duplication or epimutations in the 11p15 imprinted region have been described. To date, only two patients with maternal UPD7 and a mosaic condition for a supernumerary ring 7 marker have been reported, and we here report a further case. Standard QFQ banding of lymphocytes as well as fluorescence in-situ hybridization analyses were performed to identify and characterize the supernumerary marker. UPD testing was performed on both the patient's and parents' DNA using chromosome 7 microsatellite markers. The patient demonstrated a ring in about 4% of the analysed cells. On the basis of cytogenetic and molecular results, break points were tentatively identified as 7p11.2 and 7q21. Maternal hetero-/iso-UPD and a paternal origin for the supernumerary ring were demonstrated. Clinical data comparison between our patient who has a SRS phenotype and cases with hetero-/iso-UPD7 mat and mosaicism for a paternally derived chromosome 7 ring and previously reported ring 7 cases suggest that the SRS phenotype is probably because of the UPD rather than to the partial trisomy