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Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a dominant neurodegenerative disease caused by the expansion of a CAG repeat tract in ATXN3. Anticipation and worsening of clinical picture in subsequent generations were repeatedly reported, but there is no indication that SCA3/MJD frequency is changing. Thus, we performed a systematic review and meta‐analysis on phenomena with potential effect on SCA3/MJD recurrency in populations: instability of CAG repeat transmissions, anticipation, fitness, and segregation of alleles. Transmission of the mutant allele was associated with an increase of 1.23 CAG repeats in the next generation, and the average change in age at onset showed an anticipation of 7.75 years per generation; but biased recruitments cannot be ruled out. Affected SCA3/MJD individuals had 45% more children than related controls. Transmissions from SCA3/MJD carriers showed that the expanded allele was segregated in 64% of their children. In contrast, transmissions from normal subjects showed that the minor allele was segregated in 54%. The present meta‐analysis concluded that there is a segregation distortion favoring the expanded allele, among children of carriers. Therefore, further studies on transmissions and anticipation phenomena as well as more observations about fertility are required to clarify these selective forces over SCA3/MJD. [ABSTRACT FROM AUTHOR]

In-person genetic counselling (GC) is the model typically used to provide patients with information regarding their genetic testing options. Current and emerging demand for genetic testing may overburden the health care system and exceed the available numbers of genetic counsellors. Furthermore, GC is not always available at times and places convenient for patients. There is little evidence that the in-person model alone is always optimal and alternatives to in-person GC have been studied in genetics and other areas of health care. This review summarizes the published evidence between 1994 and March 2014 for interactive e-learning and decisional support e-tools that could be used in pre-test GC. A total of 21 papers from 15 heterogeneous studies of interactive e-learning tools, with or without decision aids, were reviewed. Study populations, designs, and outcomes varied widely but most used an e-tool as an adjunct to conventional GC. Knowledge acquisition and decisional comfort were achieved and the e-tools were generally well-accepted by users. In a time when health care budgets are constrained and availability of GC is limited, research is needed to determine the specific circumstances in which e-tools might replace or supplement some of the functions of genetic counsellors. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer. Prognosis evaluation is of great significance in guiding individualized treatment and monitoring of GBM. By integrating different prognostic variables, nomograms simplify the statistical risk prediction model into numerical estimates for death or recurrence, and are hence widely applied in prognosis prediction. In the past two decades, the application of high-throughput profiling technology and the establishment of TCGA database and other public data deposits have provided opportunities to identify cancer-related molecules and prognostic biomarkers. As a result, both molecular features and clinical characteristics of cancer have been reported to be the key factors in nomogram model construction. This article comprehensively reviewed 35 studies of GBM nomograms, analyzed the present situation of GBM nomograms, and discussed the role and significance of nomograms in personalized risk assessment and clinical treatment decision-making. To facilitate the application of nomograms in the prognostic prediction of GBM patients, a website has been established for the online access of nomograms based on the studies of this review, which is called Consensus Nomogram Spectrum for Glioblastoma (CNSgbm) and is accessible through https://bioinfo.henu.edu.cn/nom/NomList.jsp., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In 2021, the Indian Undiagnosed Diseases Program was initiated for patients without a definite diagnosis despite extensive evaluation in four participating sites. Between February 2021 and March 2023, a total of 88 patients were recruited and underwent deep phenotyping. A uniform methodology for data re-analysis was implemented as the first step prior to conducting additional genomic testing. The largest cohort was of 38 patients with neurodevelopmental disorders (NDD). A genetic diagnosis was achieved in 24 of the 88 patients (27.2%), including 7 cases within the NDD cohort. Factors contributing to the increased diagnostic yield included: (a) identification of a novel disease association in DAAM2 gene, and (b) limitations of the standard analysis pipeline, particularly for synonymous variants in SELENOI and KIAA0753 genes, non-frameshift variant in GLRX5 gene, low-coverage variant in GJC2 gene, large deletions in PCNT and PHKG2 genes, and intronic variants in VPS33B and FBN1. Improved phenotyping led to a diagnosis in three cases, while genomic variants missed in the previous bioinformatics analysis were identified in 12 cases. The study also contributed to the development of enhanced bioinformatics scripts for variant prioritization and more refined literature search for novel disease associations. It highlights the importance of incorporating data reanalysis into clinical workflows before pursuing advanced diagnostic tests, particularly in resource-limited settings where healthcare expenses are often borne out of pocket., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

ATP6V1B2 encodes the subunit of the vacuolar H + -ATPase, which is an enzyme responsible for the acidification of intracellular organelles and essential for cell signaling and neurotransmitter release. The aim of the study is to identify the correlation between ATP6V1B2 and epilepsy. Trio-exome sequencing was performed. Reverse Transcription-PCR and Quantitative real-time PCR analyses were carried out to determine whether this variant leads to nonsense-mediated mRNA decay (NMD). Drosophila models with knocked-down homologous genes of ATP6V1B2 were generated to study the causal relationship between the ATP6V1B2 and the phenotype of epilepsy. We described a 5-year-old male with a novel variant c.1163delT(p.Tyr389IlefsTer13) in ATP6V1B2, who presented with epilepsy. The expression level of the premature termination codon (PTC) transcript was normal in the patient, which indicated that NMD evasion existed in the PTC transcript. We generated an animal model using Drosophila to study the knock down effects of Vha55, which is the ATP6V1B2 ortholog in fly. The Vha55 knockdown flies show seizure-like behaviors and climbing defects. This study expands the variation spectrum of the ATP6V1B2 gene. Cross-species animal model demonstrates the causal relationship between ATP6V1B2 defect and epilepsy, and shed new insights into the disease mechanism caused by ATP6V1B2 LOF variants., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Patient 2 (II:2) was born with bilateral lower extremity pitting edema and a severe scalp defect with exposure of the underlying dura mater. A short report of two male siblings born with cutis aplasia, lymphedema and intestinal lymphangiectasia, one found to carry bi-allelic variants in the TIE1 gene known to be associated with congenital lymphedema. Up to 30% of scalp ACC cases are associated with an underlying bony and dura mater defect exposing the brain tissue and sagittal sinus. [Extracted from the article]

This article provides an overview of the current knowledge on medical complications, health characteristics, and psychosocial issues in adults with achondroplasia. We have used a scoping review methodology particularly recommended for mapping and summarizing existing research evidence, and to identify knowledge gaps. The review process was conducted in accordance with the PRISMA‐ScR guidelines (Preferred Reporting Items for Systematic reviews and Meta‐Analyses Extension for Scoping Reviews). The selection of studies was based on criteria predefined in a review protocol. Twenty‐nine publications were included; 2 reviews, and 27 primary studies. Key information such as reference details, study characteristics, topics of interest, main findings and the study author's conclusion are presented in text and tables. Over the past decades, there has only been a slight increase in publications on adults with achondroplasia. The reported morbidity rates and prevalence of medical complications are often based on a few studies where the methodology and representativeness can be questioned. Studies on sleep‐related disorders and pregnancy‐related complications were lacking. Multicenter natural history studies have recently been initiated. Future studies should report in accordance to methodological reference standards, to strengthen the reliability and generalizability of the findings, and to increase the relevance for implementing in clinical practice. [ABSTRACT FROM AUTHOR]

Twin studies provide a method for estimating the heritability of phenotypes and for examining genetic and environmental relationships between phenotypes. We conducted a systematic review of twin studies of pain, including both clinical and experimental pain phenotypes. Fifty-six papers were included, whereof 52 addressed clinical phenotypes. Of the most comprehensively studied phenotypes, available data indicates heritability around 50% for migraine, tension-type headache and chronic widespread pain, around 35% for back and neck pain, and around 25% for irritable bowel syndrome. However, differences in phenotype definitions make these results somewhat uncertain. All clinical studies relied on dichotomous outcomes and none used pain intensity as continuous phenotype. This is a major weakness of the reviewed studies and gives reason to question their validity with respect to pain mechanisms. Experimental pain studies indicate large differences in heritability across pain modalities. Whereas there is evidence for substantial common genetic risk across many clinical pain conditions, different experimental pain phenotypes appear to be associated with different genetic factors. Recommendations for future research include inclusion of pain intensity scaling and number of pain sites in phenotyping. Furthermore, studies examining the genetic relationships between pain phenotypes, in particular between clinical and experimental phenotypes, should be prioritized. [ABSTRACT FROM AUTHOR]

Al-Owain M, Imtiaz F, Shuaib T, Edrees A, Al-Amoudi M, Sakati N, Al-Hassnan Z, Bamashmous H, Rahbeeni Z, Al-Ameer S, Faqeih E, Meyer B, Al-Hashem A, Garout W, Al-Odaib A, Rashed M, Al-Aama JY. Smith-Lemli-Opitz syndrome among Arabs. Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of variable presentation caused by the deficiency of the 3 β- hydroxycholesterol Δ7- reductase. Over the past 10 years, our biochemical laboratory has screened 191 plasma samples for possible SLOS, measuring the plasma cholesterol and 7-dehydrocholesterol using gas chromatography-mass spectrometry (GC-MS). The SLOS was confirmed in only five Arab patients with growth retardation, global developmental delay, dysmorphic features, and 2-3 toe syndactyly, among other findings. All cases represented moderate to severe form of SLOS. One patient had a unique cardiovascular malformation (cor triatriatum with significant obstruction of the right pulmonary veins). Two previously reported N287K (861 C>A) and R352Q (1055 G>A) and a novel R352L (1055 G>T) mutations were identified in the DHCR7 gene in these patients. The paper sheds light on this rare disease among Arabs and reviews all reported SLOS cases in the Arab population. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore the literature on quality of life (QoL) in patients with hereditary thoracic aortic aneurysm and dissection (HTAAD); including Marfan syndrome (MFS), Loeys‐Dietz syndrome (LDS), vascular Ehlers‐Danlos syndrome (vEDS) and other HTAAD diagnoses, critically appraising and synthesizing the relevant literature. A systematic review was performed by searching the published literature using available medical, physical, psychological, social databases and other sources. Studies addressing QoL in persons with an HTAAD diagnosis, published in peer‐reviewed journals were assessed. Of 227 search results, 20 articles satisfied the eligibility criteria. No studies of QoL in LDS, vEDS, or other HTAAD were found, only on MFS. Most studies had been published in the last 3 years. All were cross‐sectional quantitative studies besides one pilot intervention study. Most studies were of small sample size, had low response rate or participants without verified diagnosis. Despite these limitations, most studies indicate that having an HTAAD diagnosis as MFS may negatively impact QoL, but few studies found any associations between the biomedical symptoms and decreased QoL. More research is needed on QoL in samples with verified HTAAD diagnosis to develop evidence‐based knowledge and appropriate guidelines for these diagnoses. [ABSTRACT FROM AUTHOR]

Hofer D, Paul K, Fantur K, Beck M, Roubergue A, Vellodi A, Poorthuis BJ, Michelakakis H, Plecko B, Paschke E. Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations. GM1 gangliosidosis manifests with progressive psychomotor deterioration and dysostosis of infantile, juvenile, or adult onset, caused by alterations in the structural gene coding for lysosomal acid ß-galactosidase ( GLB1). In addition, allelic variants of this gene can result in Morquio B disease (MBD), a phenotype with dysostosis multiplex and entire lack of neurologic involvement. More than 100 sequence alterations in the GLB1 gene have been identified so far, but only few could be proven to be predictive for one of the GM1 gangliosidosis subtypes or MBD. We performed genotype analyses in 16 GM1 gangliosidosis patients of all phenotypes and detected 28 different genetic lesions. Among these, p.I55FfsX16, p.W65X, p.F107L, p.H112P, p.C127Y, p.W161X, p.I181K, p.C230R, p.W273X, p.R299VfsX5, p.A301V, p.F357L, p.K359KfsX23, p.L389P, p.D448V, p.D448GfsX8, and the intronic mutation IVS6-8A>G have not been published so far. Due to their occurrence in homozygous patients, four mutations could be correlated to a distinct GM1 gangliosidosis phenotype. Furthermore, the missense mutations from heteroallelic patients and three artificial nonsense mutations were characterized by overexpression in COS-1 cells, and the subcellular localization of the mutant proteins in fibroblasts was assessed. The phenotype specificity of 10 alleles can be proposed on the basis of our results and previous data. [ABSTRACT FROM AUTHOR]

Gastroschisis is a significant birth defect that in many countries has shown an increased prevalence in recent decades, and the change has affected primarily younger mothers. Despite numerous epidemiological studies no other consistent associated risk factor has been identified. In this paper we review the five main theories related to the pathogenesis of this malformation and outline the reasons why we think none fully explains the embryogenesis of gastroschisis. We briefly present some clinical observations we have made that we consider germane to the pathogenesis and outline a hypothesis that we think can account for the origins of this malformation. Our proposal is that the determining defect in gastroschisis is failure of the yolk sac and related vitelline structures to be incorporated into the umbilical stalk. Otherwise, ventral closure of the lateral abdominal walls occurs normally, thus orphaning the vitelline duct and yolk sac outside both the main body stalk and the abdominal wall. Thus, in addition to the umbilicus, the abdominal wall has a separate perforation through which the midpoint of the gut is attached to the exteriorized vitelline structures. This connection through the ventral wall prevents normal egress of the gut into the umbilical cord during the second month of development and acts as the egress point for the gut resulting in gastroschisis. [ABSTRACT FROM AUTHOR]

Mutations in the α-1a Tubulin ( TUBA1A) gene have recently been found to cause cortical malformations resemblant of classical lissencephaly but with a specific combination of features. To date, TUBA1A mutations have been described in five patients and three foetuses. Our aims were to establish how common TUBA1A mutations are in patients with lissencephaly and to contribute to defining the phenotype associated with TUBA1A mutation. We performed mutation analysis in the TUBA1A gene in 46 patients with classical lissencephaly. In 44 of the patients, mutations in the LIS1 and/or DCX genes had previously been excluded; in 2 patients, mutation analysis was only performed in TUBA1A based on magnetic resonance imaging (MRI) findings. We identified three new mutations and one recurrent mutation in five patients with variable patterns of lissencephaly on brain MRI. Four of the five patients had congenital microcephaly, and all had dysgenesis of the corpus callosum and cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. We estimate the frequency of mutation in TUBA1A gene in patients with classical lissencephaly to be approximately 4%, and although not as common as mutations in the LIS1 or DCX genes, mutation analysis in TUBA1A should be included in the molecular genetic diagnosis of classical lissencephaly, particularly in patients with the combination of features highlighted in this paper. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is one of the most common inborn errors of metabolism with an annual incidence of approximately 1:16,000 live births in North America. Contemporary therapy relies upon lifelong dietary protein restriction and supplementation with phenylalanine-free medical foods. This therapy is expensive and unpalatable; dietary compliance is difficult to maintain throughout life. Non-adherence to the diet is associated with learning disabilities, adult-onset neurodegenerative disease, and maternal PKU syndrome. The fervent dream of many individuals with PKU is a more permanent cure for this disease. This paper will review ongoing efforts to develop viable cell-directed therapies, in particular cell transplantation and gene therapy, for the treatment of PKU. [ABSTRACT FROM AUTHOR]

The matrix metalloproteinases (MMPs) can degrade various components of the extracellular matrix and are implicated in the development and progression of cancer. There is evidence suggesting an association of MMP gene polymorphisms with cancer susceptibility and/or metastasis. This paper reviews the findings on several single nucleotide polymorphisms in the collagenase, stromelysin and gelatinase genes in lung cancer, breast cancer and colorectal cancer. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to summarize some of the newly recognized in utero factors that interact with gene expression to establish the structural and physiologic processes that will serve the individual long term. These may be common to all mammals and probably reflect evolutionary plasticity, which improves species survival. The concepts of programming, fetal-maternal microchimerism, growth factors, and transgenerational nutritional affects are explored. [ABSTRACT FROM AUTHOR]

This paper reports on the presentations from the second session of a 2-day workshop on genetic diversity and science communication, organized by the Institute of Genetics. The four talks in this session (by Sarah Cunningham-Burley, Gail Geller, Michael Hayden, and Theresa Marteau) focused on the topic of risk assessment in the context of genetic testing, screening and preventive medicine for complex disease. Each talk underscored the urgency and importance of evaluating when and for whom risk assessment may be useful. A recurrent theme was the need to attend closely to the diverse ways that risk is constructed, perceived and communicated in a variety of contexts and the significant implications of this for laypersons as well as experts. Although there was no consensus on when genetic risk assessment ceases (or might begin) to be useful, ensuing dialogue between presenters and participants reflected what is perhaps a new and critical engagement with how risk assessment itself is assessed. In response to this impetus, I use the word RISK as a heuristic to identify, extract and amplify four tendencies that appear to advance understandings of risk assessment towards a more explicitly reflexive, interpretive, and situated form of knowing. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal disorder caused by the deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A). In males, the laboratory diagnosis is based on the demonstration of decreased levels of α-Gal A activity, while in females, the disease is diagnosed by the identification of a mutation in α-Gal A gene. Fabry disease in Argentina is underdiagnosed. To date, no comprehensive screening study of Fabry disease in our country has been reported. The present study aimed at developing a targeted screening for the detection of Fabry patients from Argentina based on the set of typical signs and symptoms. We received 121 blood samples from probable Fabry patients for enzymatic and genetic assay. We diagnosed six Fabry patients from six unrelated families, representing a yield of detection of 4.96%. The mutations detected in five of the families analysed were missense mutations: p.Leu243Trp, p.Asp155His, p.Leu415Pro, p.Cys94Tyr and p.Leu191Pro. After the detection of a Fabry patient, his/her relatives were also screened. In the course of these family studies, other 64 Fabry patients, 29 males and 35 females, were detected. To our knowledge, this is the first comprehensive screening of Fabry disease in Argentina. We detected 70 patients in a period of 2.5 years. The development of targeted protocols and the constitution of interdisciplinary groups for the identification of patients with Fabry disease are recommended to obtain a higher yield in the process. [ABSTRACT FROM AUTHOR]

Despite a rapidly expanding literature on the issue of duty to warn at-risk relatives in the context of clinical genetic testing, little has been written on parallel issues with regard to the management of genetic research results. Some might view this lack as an indication that there is little to discuss in this regard. That is, standard practice is that data obtained through medical research should not be treated as though they are clinically relevant, and this standard should hold for genetic research as well. This paper challenges this conclusion and its underlying assumptions. We argue that the line between genetic research and clinical practice is often ambiguous. In some cases, research data gathered from a very small number of subjects could have immediate clinical implications. Hence, it is unethical for genetic researchers to absolve themselves of clinical responsibilities for research subjects and/or their families, on the grounds that the data were obtained for research purposes. Indeed, we argue that it could well be unethical to embark on some forms of genetic research unless advance arrangements have been made for genetic counseling and clinical follow-up. Furthermore, in some cases, it might be unethical to enroll subjects in studies if the subjects are unwilling to receive their individual results. [ABSTRACT FROM AUTHOR]

The article comments on the paper "Predictive genetic testing in young people for adult onset conditions: where is the empiric evidence?" by Duncan and Delatycki. In the paper, the authors presents arguments against and in support of the predictive genetic testing of children. More information on the subject matter is given in the article.

Azevedo ACMM, Schwartz IV, Kalakun L, Brustolin S, Burin MG, Beheregaray APC, Leistner S, Giugliani C, Rosa M, Barrios P, Marinho D, Esteves P, Valadares E, Boy R, Horovitz D, Mabe P, da Silva LCS, de Souza ICN, Ribeiro M, Martins AM, Palhares D, Kim CA, Giugliani R. Clinical and biochemical study of 28 patients with mucopolysaccharidosis type VI. This paper presents data collected by a Brazilian center in a multinational multicenter observational study of patients with mucopolysaccharidosis type VI (MPS VI), aiming at determining the epidemiological, clinical, and biochemical profile of these patients. Twenty-eight south-American patients with MPS VI were evaluated through medical interview, physical exam, echocardiogram, electrocardiogram, ophthalmologic evaluation, quantification of glycosaminoglycans (GAGs) in urine, and measurement of the activity of N-acetylgalactosamine-4-sulfatase (ARSB) in leukocytes. 92.9% of patients were Brazilian. Mean age at diagnosis and at evaluation was 48.4 months and 97.1 months, respectively. 88% of patients had onset of symptomatology before the age of 36 months. Consanguinity was reported by 27% of the families. Mean weight and height at birth were 3.481 kg and 51.3 cm, respectively. The most frequently reported clinical manifestations were short stature, corneal clouding, coarse facial features, joint contractures, and claw hands. All patients presented with echocardiogram changes as well as corneal clouding. Mean ARSB activity in leukocytes was 5.4 nmoles/h/mg protein (reference values: 72–174), and urinary excretion of GAGs was on average 7.9 times higher than normal. The number of clinical manifestations did not show a significant correlation with the levels of urinary GAGs nor with the ARSB activity. Also, no significant correlation was found between the levels of urinary GAGs and the ARSB activity. It was concluded that MPS VI has high morbidity and that, when compared with data published in the literature, patients in our study were diagnosed later and presented with a higher frequency of cardiological findings. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatases (PTPases) have recently been recognized as important modulators of various signal transduction pathways in immune cells. Genetic polymorphisms have been described in genes codifying for members of this family of enzymes, and the genetics of PTPases is predicted to play an important role in the etiology of immune diseases and of their clinical variability. The low molecular weight protein tyrosine phosphatase (ACP1 or LMPTP) is one of the few PTPases with a known genetic polymorphism, and has been proposed to be associated with atopic dermatitis in a small sample from an Italian population. In this paper we describe the association of the ACP1 polymorphism with total IgE levels in two independent samples from English and Italian populations. In both the samples the mean value of serum IgE is lower among subjects carrying the BC genotype than in other ACP1 genotypes. The BC genotype is associated with the highest total ACP1 enzymatic activity. Our data suggest that one or both of the ACP1 isoforms exert an inhibitory role on some signal transduction pathway relevant for IgE hyperproduction. [ABSTRACT FROM AUTHOR]

Diploid/triploid mosaicism is a dysmorphology syndrome consisting of mental retardation, truncal obesity, body and/or facial asymmetry, growth retardation, hypotonia, a small phallus, malformed low-set ears and micrognathia. In 75% of the cases, the blood karyotype is normal and the diagnosis can only be established after analysis of cultured fibroblasts. This chromosome abnormality may therefore be underdiagnosed. This paper focuses on the identification of mentally retarded and dysmorphic patients with diploid/triploid mosaicism. Detailed clinical description of well-defined patients may help in deciding if a skin biopsy for karyotyping of fibroblasts should be taken. Three new cases are presented, in which DNA marker analysis showed that the extra set of chromosomes in each case was derived from the mother. We present a review of 25 cases described in the literature and we discuss the inclusion of a second polar body into an early diploid embryo as the most likely mechanism. [ABSTRACT FROM AUTHOR]

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder exhibiting a wide clinical spectrum ranging from minimal anomalies to classic CCD. Mutations scattered throughout the entire CBFA1 gene have been related to this disorder. However, it seems that most of them affect the highly conserved Runt domain, abolishing the DNA-binding ability of this transcription factor. Moreover, no systematic effect has been found to relate the type of mutation to the severity of the clinical features. In this paper, we studied two unrelated patients with classic CCD. DNA analysis revealed two novel mutations and three undescribed polymorphisms. One of the substitutions was a missense mutation in the Q/A domain leading to the replacement of a polar residue by a nonpolar one (158 A → T [Q53L]). The second was an uncommon heterozygous stop codon mutation (1565 G → C [X522S]) which theoretically results in a longer protein with 23 additional amino acids. This is the first report of this type of mutation in CBFA1 . We discuss the possible consequences of these mutant sequences, although no phenotype–genotype correlation could be established. Our findings expand the existing number of allelic variants in this pathology. [ABSTRACT FROM AUTHOR]

This is a time of unprecedented increase in knowledge about the genetic basis of disease against a background of rapidly changing technology. Advances happen quickly, with the new knowledge rapidly becoming relevant to services for patients, and hence there is an increasing demand for, and expectation of, genetic services. This brings a challenge for health services worldwide to keep pace with the expectations of their populations. There is also a need for public and professional education and dialogue to dispel some of the hype and myths about what can be achieved. It should not be forgotten that any services must be provided and developed within a broad ethical framework. A statement from a WHO expert consultation (1) concluded that ‘Genetic advances will only be acceptable if their application is carried out ethically, with due regard to autonomy, justice, education and the beliefs and resources of each nation and community’. That so many public bodies have commented on genetic services and their associated ethical, legal and social issues emphasizes not only the importance of this area in health care, but also that the wider issues are of great importance in democratic societies. The aim of this paper is to review the current situation in the provision of genetic services, to examine the drivers for change, to speculate on the likely need for future services and to suggest models for the development of such services. Pharmacogenetics and the determination of genetic factors indicating susceptibility to infection will not be discussed since these have been the subject of several recent excellent reviews (2, 3). Genetic services have been defined as health measures implemented to help people with a genetic disadvantage and their families to live and reproduce as normally as possible (4). Broadly they can be divided into those services which target whole populations with a view to identifying those at increased risk; and those which focus on the... [ABSTRACT FROM AUTHOR]

In this paper we present the case of a girl at the age of 32 months with dysmorphic features, including general muscular hypotonia, developmental delay and mental retardation. The cytogenetic analysis revealed de novo partial duplication of Xp: 46,X,dup(X)(p11.23→p22.33: :p11.23→p22.33). To characterize the duplication, X painting, Kallman (KAL), yeast artificial chromosomes (YACs) and bacterial artificial chromosomes (BACs) covering Xp11.23→Xp22.33 region were used. Selective inactivation of the abnormal X chromosome using Hpa II digestion of the AR gene was evident. After BrdU incorporation the abnormal X was late-replicating in all lymphocytes examined. There was one peculiar exception observed: the break-point region was consistently early replicating. The replicating pattern of this region corresponded to the active X chromosome. Methylation pattern of late replicating X chromosome was studied also using antibodies against 5-methylcytosine. The pattern corresponded to the normally inactive X chromosome, with the exception of the previously observed break-point region which revealed an early replicating pattern with strong fluorescent signal, similar to the pattern of the active X chromosome. The observed phenomenon could lead to the abnormal phenotype of the patient, with some normally inactive genes of the break-point region escaping the inactivation process. The abnormal clinical findings could also be due to tissue-dependent differences in the inactivation pattern. [ABSTRACT FROM AUTHOR]

The logistic regression model is a popular model for data analysis in epidemiological research. In this paper, we use this model to analyze genetic data collected from gene–longevity association studies. This new approach models the probability of observing one genotype as a function of the age of investigated individuals. Applying the model to genotype data on the TH and 3′ApoB-VNTR loci collected from an Italian centenarian study, we show how it can be used to model the different ways that genes affect survival, including sex- and age-specific influences. We highlight the advantages of this application over other available models. The application of the model to empirical data indicates that it is an efficient and easily applicable approach for determining the influences of genes on human longevity. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is notably difficult to diagnose in the early stages. One reason is that the early clinical manifestations of HD vary widely and sometimes have an atypical onset. In this paper we primarily sought information on affected patients who initially presented with movement disorders other than chorea. We also investigated atypical motor presentations in relation to triplet CAG expansions. After reviewing the clinical records of two neurological centres, we identified patients with a final, documented diagnosis of HD and selected for study 205 patients according to their onset of motor manifestations. CAG repeats were analysed. Of the 205 patients studied, 15 had atypical motor symptoms at onset. In this group we identified three types of initial clinical manifestations other than chorea: parkinsonism, ataxia and dystonia. We conclude that HD patients may have different motor manifestations at the initiation of the illness. Patients with atypical movement disorders in the early stages have larger CAG expansions and an earlier age at onset than HD patients with typical onset chorea. [ABSTRACT FROM AUTHOR]

We have performed cytogenetic and molecular analyses of 45,X mosaics involving structurally abnormal Y chromosomes. Karyotypes were performed by standard cytogenetic methods and, in some cases, by fluorescence in situ hybridization, to distinguish monocentric and dicentric chromosomes. In addition, the deletions of Yq have been mapped using Southern blotting and polymerase chain reaction analysis. This paper provides additional information on the analysis of Y chromosome aberrations, and suggests that the stability of the Y chromosome in these instances is related to the site of the break point on Yq. [ABSTRACT FROM AUTHOR]

The investigation of environmental effects on clinical measurements using individual samples is challenging because their genetic and environmental factors are different. However, using monozygotic twins (MZ) makes it possible to investigate the influence of environmental factors as they have the same genetic factors within pairs because the difference in the clinical traits within the MZ mostly reflect the influence of environmental factors. We hypothesized that the within‐pair differences in the traits that are strongly affected by genetic factors become larger after genetic risk score (GRS) correction. Using 278 Japanese MZ pairs, we compared the change in within‐pair differences in each of the 45 normalized clinical measurements before and after GRS correction, and we also attempted to correct for the effects of genetic factors to identify Cytosine‐phosphodiester‐Guanine (CpG) sites in DNA sequences with epigenetic effects that are regulated by genetic factors. Five traits were classified into the high heritability group, which was strongly affected by genetic factors. CpG sites could be classified into three groups: regulated only by environmental factors, regulated by environmental factors masked by genetic factors, and regulated only by genetic factors. Our method has the potential to identify trait‐related methylation sites that have not yet been discovered. [ABSTRACT FROM AUTHOR]

Marbach‐Rustad progeroid syndrome is an extremely rare disease caused by a heterozygous variant in the LEMD2 gene. To date, only two patients and one LEMD2 pathogenic variant have been reported in Marbach‐Rustad progeroid syndrome. Here we describe the third case of Marbach‐Rustad progeroid syndrome worldwide, which is also the first case in China. The proband was affected with premature birth, failed to thrive, facial abnormalities, feeding difficulties, skull defects and delayed motor milestones, but had a normal intelligence and speech. Whole exome sequencing (WES) initially did not find a phenotype‐causing variant when the proband was 1 year of age. The reanalysis of WES data 4 years later revealed the proband harbored a de novo heterozygous c.1436C>T(p.Ser479Phe) variant in the LEMD2 gene, which is known responsible for Marbach‐Rustad progeroid syndrome. Sanger sequencing confirmed the presence of this variant in the proband and absence in his parents and two elder sisters. Our study provides accurate clinical diagnosis for the proband and adds a new patient with Marbach‐Rustad progeroid syndrome. Our study suggests the LEMD2 c.1436C>T(p.Ser479Phe) variant as a hotspot. Our work also indicates reanalysis of WES data of negative cases might identify pathogenic variant and improve diagnostic efficiency. [ABSTRACT FROM AUTHOR]

Genetic and genomic technologies can effectively diagnose numerous genetic disorders. Patients benefit when genetic counselling accompanies genetic testing and international guidelines recommend pre‐ and post‐test genetic counselling with genome‐wide sequencing. However, there is a gap in knowledge regarding the unique genetic counselling considerations with different types of genetic testing in the Neonatal Intensive Care Unit (NICU) and the Pediatric Intensive Care Unit (PICU). This scoping review was conducted to identify the gaps in care with respect to genetic counselling for infants/pediatric patients undergoing genetic and genomic testing in NICUs and PICUs and understand areas in need of improvement in order to optimize clinical care for patients, caregivers, and healthcare providers. Five databases (MEDLINE [Ovid], Embase [Ovid], PsycINFO [Ebsco], CENTRAL [Ovid], and CINHAL [Ebsco]) and grey literature were searched. A total of 170 studies were included and used for data extraction and analysis. This scoping review includes descriptive analysis, followed by a narrative account of the extracted data. Results were divided into three groups: pre‐test, post‐test, and comprehensive (both pre‐ and post‐test) genetic counselling considerations based on indication for testing. More studies were conducted in the NICU than the PICU. Comprehensive genetic counselling was discussed in only 31% of all the included studies demonstrating the need for both pre‐test and post‐test genetic counselling for different clinical indications in addition to the need to account for different cultural aspects based on ethnicity and geographic factors. [ABSTRACT FROM AUTHOR]

Genomic medicine has been transformed by next‐generation sequencing (NGS), inclusive of exome sequencing (ES) and genome sequencing (GS). Currently, ES is offered widely in clinical settings, with a less prevalent alternative model consisting of hybrid programs that incorporate research ES along with clinical patient workflows. We were among the earliest to implement a hybrid ES clinic, have provided diagnoses to 45% of probands, and have identified several novel candidate genes. Our program is enabled by a cost‐effective investment by the health system and is unique in encompassing all the processes that have been variably included in other hybrid/clinical programs. These include careful patient selection, utilization of a phenotype‐agnostic bioinformatics pipeline followed by manual curation of variants and phenotype integration by clinicians, close collaborations between the clinicians and the bioinformatician, pursuit of interesting variants, communication of results to patients in categories that are predicated upon the certainty of a diagnosis, and tracking changes in results over time and the underlying mechanisms for such changes. Due to its effectiveness, scalability to GS and its resource efficiency, specific elements of our paradigm can be incorporated into existing clinical settings, or the entire hybrid model can be implemented within health systems that have genomic medicine programs, to provide NGS in a scientifically rigorous, yet pragmatic setting. [ABSTRACT FROM AUTHOR]

Lipid disorders play a critical role in the intricate development of atherosclerosis and its clinical consequences, such as coronary heart disease and stroke. These disorders are responsible for a significant number of deaths in many adult populations worldwide. Familial hypercholesterolemia (FH) is a genetic disorder that causes extremely high levels of LDL cholesterol. The most common mutations occur in genes responsible for low‐density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). While genetic testing is a dependable method for diagnosing the disease, it may not detect primary mutations in 20%–40% of FH cases. [ABSTRACT FROM AUTHOR]

With advances in gene‐based therapies for heritable retinal diseases, primary eye care clinicians should be informed on ocular genetics topics. This cross‐sectional survey evaluated knowledge, attitudes, and concerns regarding genetic testing and gene therapy for retinal diseases among optometrists in Australia and New Zealand. Survey data included practitioner background, attitudes and practices towards genetic testing for monogenic inherited retinal disease (IRDs) and age‐related macular degeneration, and knowledge of ocular genetics and gene therapy. Responses were received from 516 optometrists between 1 April and 31 December 2022. Key perceived barriers to accessing genetic testing were lack of clarity on referral pathways (81%), cost (65%), and lack of treatment options if a genetic cause is identified (50%). Almost all respondents (98%) believed that ophthalmologists should initiate genetic testing for IRDs and fewer understood the role of genetic counsellors and clinical geneticists. This study found that optometrists in Australia and New Zealand have a high level of interest in ocular genetics topics. However, knowledge gaps include referral pathways and awareness of genetic testing and gene therapy outcomes. Addressing perceived barriers to access and promoting sharing of knowledge between interdisciplinary networks can set the foundation for genetic education agendas in primary eye care. [ABSTRACT FROM AUTHOR]

Lamb–Shaffer Syndrome (LSS; OMIM #616803; ORPHA #313892; ORPHA #313884) is an infrequent genetic disorder that affects multiple aspects of human development especially those related to the development of the nervous system. LSS is caused by variants in the SOX5 gene. At the molecular level, SOX5 gene encodes for a transcription factor containing a High Mobility Group (HMG) DNA‐Binding domain with relevant functions in brain development in different vertebrate species. Clinical features of Lamb–Shaffer syndrome may include intellectual disability, delayed speech and language development, attention deficits, hyperactivity, autism spectrum disorder, visual problems and seizures. Additionally, patients with the syndrome may present distinct facial dimorphism such as a wide mouth with full lips, small chin, broad nasal bridge, and deep‐set eyes. Other physical features that have been reported in some patients include short stature, scoliosis, and joint hypermobility. Here, we report the clinical and molecular characterization of a Spanish LSS cohort of new 20 patients and review all the patients published so far which amount for 111 patients. The most frequent features included developmental delay, intellectual disability, visual problems, poor speech development and facial dysmorphic features. Strikingly, pain insensitivity and hypermetropia seems to be more frequent than previously reported, based on the frequency seen in the Spanish cohort. Eighty‐three variants have been reported so far, single nucleotide variants (SNV) and copy number variants represent 47% and 53%, respectively, from the total of variants reported. Similarly to previous reports, the majority of the SNVs variants of the novel patients reported herein fall in the HMG domain of the protein. However, new variants, affecting other functional domains, were also detected. In conclusion, LLS is a rare genetic disorder mostly characterized by a wide range of developmental and neurological symptoms. Early diagnosis would allow to start of care programs, clinical follow up, prospective studies and appropriate genetic counseling, to promote clinical and social improvement to have profound lifelong benefits for patients and their families. Further research is needed to better understand the underlying mechanisms of the syndrome related to SOX5 haploinsufficiency. [ABSTRACT FROM AUTHOR]

Herein we discuss Mexican geneticists’ views of ethical issues in genetic testing and screening, analyzing whether eugenic principles are involved in this activity. The information was obtained from a comprehensive survey on genetics, ethics, and society organized by Wertz and Fletcher in 1993, in which 37 nations participated. The responses to 21 questions from 64 out of 89 (72%) geneticists invited to participate are analyzed in this paper. The questions were practically the same as those answered recently by a group of Chinese geneticists (Mao X. Chinese geneticists’ views of ethical issues in genetic testing and screening: evidence for eugenics in China. Am J Hum Genet 1998: 63: 688–695), who work in a country where the furtherance of eugenic principles is considered to be the goal of human genetics. We concluded that although there are many similarities in the answers from both countries, this is not indicative of Mexican geneticists pursuing eugenic goals because: a) there is no coercion involved; and b) there is no intention of improving the gene pool. [ABSTRACT FROM AUTHOR]

Comments on an article entitled `Familial Porphyria Cutanea Tarda: Characterization of Seven Novel Uroporphyrinogen Decarboxylase Mutations and Frequency of Common Hemochromatosis Alleles,' by Mendez et, al. which appeared in the 1998 issue of the periodical`American Journal of Human Genetics.' Information on Familial Porphyria Cutanea Tarda; Objective and results of the paper; Recommendations.

Comments on two papers about the ionizing radiation and enhanced phosphorylation of the p53 gene in ataxia telangiectasia (AT) which appeared on the 1998 issue of the periodical `Science.' Information on AT; Role of p53 in the cellular response to DNA damage; Conclusion.

Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary condition transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. The syndrome is characterised by numerous basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, palmar and/or plantar pits, skeletal abnormalities and intracranial calcifications.In this paper, the clinical features of 37 Italian patients are reviewed. Jaw cysts and calcification of falx cerebri were the most frequently observed anomalies, followed by BCCs and palmar/plantar pits. Similar to the case of African–Americans, the relatively low frequency of BCCs in the Italian population is probably due to protective skin pigmentation. A future search based on mutation screening might establish a possible genotype–phenotype correlation in Italian patients. [ABSTRACT FROM AUTHOR]

Limb girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of muscular dystrophies. The study presents an overview of molecular characteristics of a large cohort of LGMD patients who are representative of the Czech LGMD population. We present 226 LGMD probands in which 433 mutant alleles carrying 157 different variants with a supposed pathogenic effect were identified. Fifty‐four variants have been described only in the Czech LGMD population so far. LGMD R1 caplain3‐related is the most frequent subtype of LGMD involving 53.1% of patients with genetically confirmed LGMD, followed by LGMD R9 FKRP‐related (11.1%), and LGMD R12 anoctamin5‐related (7.1%). If we consider identified variants, then all but five were small‐scale variants. One large gene deletion was identified in the LAMA2 gene and two deletions in each of CAPN3 and SGCG. We performed comparison our result with other published studies. The results obtained in the Czech LGMD population clearly differ from the outcome of other LGMD populations in two aspects—we have a more significant proportion of patients with LGMD R1 calpain3‐related and a smaller proportion of LGMD R2 dysferlin‐related. [ABSTRACT FROM AUTHOR]

CTNNB1 [OMIM *116806] encodes β‐catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal diagnosis relies on the presence in maternal blood of circulating cell‐free fetal DNA released by apoptotic trophoblast cells. Widely used for aneuploidy screening, it can also be applied to monogenic diseases (NIPD‐M) in case of known parental mutations. Due to the confounding effect of maternal DNA, detection of maternal or biparental mutations requires relative haplotype dosage (RHDO), a method relying on the presence of SNPs that are heterozygous in one parent and homozygous in the other. Unavoidably, there is a risk of test failure by lack of such informative SNPs, an event particularly likely for consanguineous couples who often share common haplotypes in regions of identity‐by‐descent. Here we present a novel approach, relative genotype dosage (RGDO) that bypasses this predicament by directly assessing fetal genotype with SNPs that are heterozygous in both parents (frequent in regions of identity‐by‐descent). We show that RGDO is as sensitive as RHDO and that it performs well over a large range of fetal fractions and DNA amounts, thereby opening NIPD‐M to most consanguineous couples. We also report examples of couples, consanguineous or not, where combining RGDO and RHDO allowed a diagnosis that would not have been possible with only one approach. [ABSTRACT FROM AUTHOR]

Male infertility affects more than 20 million men worldwide and is a major public health concern. Male infertility has a strong genetic basis, particularly for those unexplained cases. Here, through genetic analysis of three Pakistani families having eight infertile men with normal parameters in routine semen analysis, we identified a novel ACTL7A variant (c.149_150del, p.E50Afs*6), recessively co‐segregating with infertility in these three families. This variant leads to the loss of ACTL7A proteins in spermatozoa from patients. Transmission EM analyses revealed acrosome detachment from nuclei in 98.9% spermatozoa of patients. Interestingly, this ACTL7A variant was frequently detected in our sequenced Pakistani Pashtuns with a minor allele frequency of ~0.021 and all the carriers shared a common haplotype of about 240 kb flanking ACTL7A, indicating that it is likely originated from a single founder. Our findings reveal that a founder ACTL7A pathogenic variant confers a high genetic susceptibility for male infertility with normal routine semen parameters but acrosomal ultrastructural defects in Pakistani Pashtun descendants, and highlight that variants not rare should also be considered when trying to identify disease‐causing variants in ethnic groups with the tradition of intra‐ethnic marriages. [ABSTRACT FROM AUTHOR]

Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss‐of‐function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. Remarkably, we identified a homozygous, presumably loss‐of‐function mutation in ZMPSTE24 [c.28_29insA, p.(Leu10Tyrfs*37)] in two consanguineous Pakistani families segregating MADB. To clarify how lethal consequences are prevented in affected individuals, functional analysis was performed. Expression experiments supported utilization of two alternative translation initiation sites, preventing complete loss of protein function consistent with the relatively mild phenotypic outcome in affected patients. One of these alternative start codons is newly formed at the insertion site. Our findings indicate that the creation of new potential start codons through N‐terminal mutations in other disease‐associated genes should generally be taken into consideration in the variant interpretation process. [ABSTRACT FROM AUTHOR]

The current study investigated the association between polymorphisms of the ICAM‐1 gene and prognosis of Ischemic cardiomyopathy (ICM), and developed a prognostic nomogram for ICM on the basis of ICAM‐1 gene variants. The current study included totally 252 patients with ICM. In addition, PCR‐RFLP (polymerase chain reaction‐restriction fragment length polymorphism) was used to genotype SNPs in the ICAM‐1 gene in the patients. Later, the nomogram model was built by combining clinical data and ICAM‐1 gene variants. This study used the least absolute shrinkage and selection operator (LASSO) regression model to optimize feature selection into an ICM prognostic model. Furthermore, multivariate Cox‐regression was applied to build the prognostic model, which included clinical and gene features chosen by the LASSO regression model. Following that, the receiver operating characteristic (ROC) curve, C‐index, calibration plot analyses and decision curve analysis (DCA) were carried out to evaluate the discrimination ability, consistency, and clinical utility of the prognostic model, and the bootstrap method was adopted for internal validation. predicting factors rs112872667, treating by PCI or CABG, ventricular arrhythmia, left ventricular end‐diastolic diameter (LVDD), use of β‐blockers, systolic blood pressure (SBP), heart rate (HR), and serum sodium were incorporated into the prognostic nomogram. The constructed nomogram performed well in discrimination ability, as observed by the time‐dependent C‐index. Furthermore, as shown by calibration curves, our nomogram's predicted probabilities were highly consistent with measured values. With threshold probabilities, DCA suggested that our nomogram could be useful in the clinic. mutation of rs112872667 have critical predictive value on the prognosis of ICM, ICM patients with the mutant genotype (CT or TT) have higher survival probability than those with the wild genotype (CC). Mutation of rs112872667 in ICAM‐1 gene have critical predictive value on the prognosis of ICM, ICM patients with the mutant genotype (CT or TT) have higher survival probability than those with the wild genotype (CC). [ABSTRACT FROM AUTHOR]

The genetic spectrum of genetic kidney diseases (GKD) and the application of genetic diagnoses to patient care were assessed by whole exome sequencing (WES) of the DNA of 172 pediatric or adult patients with various kidney diseases. WES diagnosed genetic diseases in 63 (36.6%) patients. The diagnostic yields in patients with glomerulopathy were 33.8% (25/74 pts) due to variants in 10 genes, 58.8% (20/34) in patients with tubulointerstitial disease due to variants in 18 genes, 33.3% (15/45) in patients with cystic disease/ciliopathy due to variants in 10 genes, 18.2% (2/11) in patients with congenital anomalies of the kidneys and urinary tract (CAKUT) due to variants in two genes, and 12.5% (1/8) in patients with end stage kidney disease (ESKD). The diagnosis rate was high in patients aged <1–6 years (46–50.0%), and low in patients aged ≥40 years (9.1%). Renal phenotype was reclassified in 10 (15.9%) of 63 patients and clinical management altered in 10 (15.9%) of 63 patients after genetic diagnosis. In conclusion, these findings demonstrated the diagnostic utility of WES and its effective clinical application in patients, with various kinds of kidney diseases, across the different age groups. [ABSTRACT FROM AUTHOR]