Search Results (77)

Introduction: Fraser syndrome (FS) is a rare autosomal recessive disorder. However, the clinical presentation remains variable. Diagnosis is based on a series of major and minor clinical criteria that can be supported by genetic tests. Prenatal diagnosis remains challenging. Methods: Herein, we reported a case of Fraser syndrome that was missed by ultrasound and diagnosed late at birth. The newborn presented with cryptophthalmos–syndactyly syndrome and absence of the right kidney. Based on a literature review of articles from the past 20 years, the authors found 40 cases, including indexed cases on PUBMED, Scopus, Web of Science, and Scholar using keywords related to “Fraser syndrome”. Through this report, we discuss the polymalformative syndrome, the clinical and paraclinical aspects of this syndrome, its clinical management, and highlight the importance of prenatal diagnosis in the light of research. Results: Our study found that consanguine parents (41.0%) were increasing risk factors for FS and poor socio-economic status delayed the early detection of FS. Among the 40 cases, 27 cases were detected postnatally. More than half of the cases resulted in poor perinatal outcomes. The common findings were cryptophthalmos (87.5%), syndactyly (87.5%), renal abnormalities (55.5%), and genital abnormalities (42.5%). Conclusions: A prenatal diagnosis of Fraser syndrome is still difficult. Thus, a counseled ultrasound scan at a specialized center should be recommended in suspected cases with indirect signs and risk factors of consanguinity. Full article

Rare autosomal recessive diseases are a major cause of mortality and morbidity. They occur more frequently in individuals with consanguineous parents, in which case the pathogenic variants are often located within regions of genetic identity by descent. A well-established and effective way of identifying these “autozygous” genomic regions has been to search for runs of homozygous genotypes in microarray SNP data. However, with the widespread use of whole-genome and exome sequencing in both diagnostic and research settings, it has become desirable to be able to both map autozygous regions and identify the deleterious variants using a single dataset. We have developed AgileMultiIdeogram, an application that can identify and visualize autozygous regions in inbred individuals using exome data as well as microarray SNP genotype data. This application has been successfully used in both research and diagnostic settings to map pathogenic mutations. Full article

Background: Uniparental disomy (UPD) refers to the condition in which both chromosomes (or part of chromosome) of a pair are inherited from the same parent. There are two types of UPD: uniparental isodisomy (both chromosomes inherited from one parent are identical copies) and uniparental heterodisomy (two different chromosomes are inherited from one parent). UPD presents two primary developmental risks: recessive trait inheritance or an imprinting disorder. These risks may coexist, leading to an ultra-rare comorbidity. Managing the comorbidities associated with rare diseases presents unique clinical challenges. Results: The existence of such phenomena is evidenced by our case report of a boy who was ultimately diagnosed with two rare diseases: Prader–Willi syndrome (PWS), due to the maternal uniparental disomy of chromosome 15 (UPD), and autosomal recessive Lodder–Merla type 1 syndrome, linked to a novel pathogenic variant in the G protein subunit β 5 (GNB5) gene, as detailed in this paper. Conclusions: An unusual or severe phenotype in a patient diagnosed with PWS should invariably prompt the consideration of a comorbid genetic disease attributable to genes located in the PWS critical region of chromosome 15q, or elsewhere on chromosome 15. In cases of epileptic encephalopathy with cardiac arrhythmia, prompt consultation with a cardiologist and comprehensive genetic testing are essential to reduce the risks associated with untreated arrhythmia and ensure the provision of appropriate and safe anti-epileptic therapy. The presented case provides further support for the hypothesis that uniparental disomy may serve as an underlying cause of Lodder–Merla syndrome. This underscores the significance of comprehensive genetic testing, encompassing parental testing and familial cascade testing (in selected cases where there is consanguinity, or the likelihood of close common ancestral background between partners) to establish the recurrence risk. Full article

Background: Dyggve–Melchior–Clausen syndrome (DMC) is a rare autosomal recessive skeletal dysplasia characterized by dwarfism, coarse facial features, and intellectual disability. Caused by loss-of-function variants in the DYM gene, which encodes dymeclin, DMC is predominantly reported in consanguineous populations but remains poorly studied in South America. Methods: We report a 21-year-old Ecuadorian male with clinical features suggestive of DMC. Comprehensive clinical, radiological, and genetic evaluations were conducted, including clinical exome sequencing and Sanger sequencing, followed by an in silico analysis to assess the structural and functional consequences of the identified variant. Results: Exome sequencing identified a homozygous c.1878delA (p.Lys626fs) frameshift variant in the DYM gene, which was confirmed by Sanger sequencing as inherited from heterozygous parents. Variants of uncertain significance were detected in other skeletal dysplasia-related genes but did not correlate with the phenotype. A comprehensive review of reported DYM variants was also conducted. Conclusions: This report documents the first case of DMC in Ecuador and the second in South America, expanding the global understanding of DMC’s genetic diversity. It underscores the value of next-generation sequencing in rare disease diagnostics and highlights the critical need for inclusive genomic research in underrepresented populations to improve the understanding of genetic heterogeneity and rare disease epidemiology. Full article

Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune condition that impacts the central nervous system and has a rising incidence globally, especially in Saudi Arabia. Materials and Methods: This study examines environmental, lifestyle, and familial risk factors associated with MS in the Aljouf Region by a cross-sectional analysis of 155 clinically diagnosed MS patients. Data were gathered using structured questionnaires and medical record examinations to evaluate sociodemographic characteristics, sun exposure, smoking, obesity, eating habits, and childhood infections. Results: Logistic regression research found insufficient daily sun exposure (<15 min/day), smoking, obesity, and childhood measles infection as significant risk factors, but substantial weekend sun exposure (>4 h/day), exclusive breastfeeding, and regular fish consumption were deemed protective. While familial history of MS was statistically significant (5.5%, p = 0.04), parental consanguinity (38.7%) did not show a significant association with MS risk (p = 0.07). Conclusions: The findings underscore the complex nature of MS and the pressing necessity for preventive efforts, such as advocating for vitamin D supplementation, smoking cessation, obesity prevention, and dietary adjustments. Mitigating these controllable risk factors may alleviate the prevalence of MS in Saudi Arabia. Full article

Background/Objectives: Cerebral folate transporter deficiency is characterized by pauses and regression in general development stages, with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment. The aim of this study was to comprehensively evaluate cases followed up in two centres in Türkiye for a diagnosis of folate receptor-α deficiency. Methods: The study included nine cases from six different families. Results: The patients comprised 22.2% males and there was parental consanguinity in 88.9% of cases. The mean age at which complaints were first noticed was 3.7 years, and the age of definitive diagnosis was 10.4 years. The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties. The diagnosis most commonly made before the definitive diagnosis was epilepsy, and the first seizure occurred at a mean of 5.2 years. On cranial imaging, white matter involvement, cerebellar atrophy and cerebral atrophy were determined most often. Definitive diagnosis was established solely through clinical findings and genetic analysis. Three different variants in the FOLR1 gene were determined. Treatment with folinic acid at a dose of 5.2 mg/kg/day of PO was started at the age of 9.8 years on average, and intravenous folinate was started at different doses. Conclusions: This study stands out as one of the largest case series in the literature and identifies a previously unreported novel variant. Our study suggests that FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy. Due to an asymptomatic early period, CFD diagnosis may be delayed, and treatment after symptom onset may be less effective. Incorporating FOLR1 gene analysis into newborn screening programmes could facilitate early diagnosis and treatment. It is thought that the application of vagus nerve stimulation, in addition to folinic acid and anticonvulsant drug treatment, could be effective in seizure control. Full article

India’s population complexity presents varied challenges in genetic research, and while facilities have gained traction in tier-1 and -2 cities, reliance on international collaborations often delays such investigations. COVID-19 further exacerbated the issues with such sample sharing. Congenital Hyperinsulinism (CHI) is a rare genetic disorder of pancreatic β-cells causing hypoglycaemia in children due to abnormal insulin secretion. Given India’s high birth rate and consanguineous populations, annual CHI cases are estimated to be around up to 10,000, with up to 50% having unexplained genetic causes. Diffuse or atypical lesions in such patients often necessitate near-total-pancreatectomy, risking pancreatic exocrine insufficiency and diabetes, requiring lifelong therapy. Also, novel genetic variations complicate accurate diagnosis, risk assessment, and counselling, emphasising the need for rapid genetic assessment to prevent neurological injuries and inform treatment decisions. Despite significant efforts at many institutes, there are no dedicated organisations for CHI in India. With the implementation of the National Policy for Rare Diseases 2021, we plan to form a non-profit organisation, “Congenital Hyperinsulinism India Association (CHIA)”, comprising paediatric endocrinologists, paediatricians, geneticists, and independent researchers. The aims of this association are to generate a national database registry of patients, formulate a parent support group and CHIA consortium, design patient information leaflets, as well as foster genomic collaborations and promote clinical trials. Such steps will help sensitise the health authorities and policy makers, urging them to improve the allocation of health budgets for rare diseases, as well as empower patients and their families, contributing towards a better quality of life. Full article

The children born of consanguineous union were found to have a higher incidence of recessive genetic diseases than the offspring of unrelated parents. The reason for this was predicted to be the presence of more deleterious rare homozygous genetic variants in the former compared to the latter. However, the magnitude of this difference is unknown. Using more than 2500 whole genomes, we show here that the individuals born of the union between double (paternal and maternal) first cousins had 20 times more deleterious rare homozygous single nucleotide variants (SNVs) than those who had unrelated parents. Furthermore, the children of first cousins had 10 times, and the children of second cousins had two times more of these SNVs compared to those present in the offspring of unrelated parents. Similar magnitudes of differences were found for the nonsynonymous deleterious rare homozygous SNVs (19, 10, and 2 times, respectively). In contrast, the differences in the number of deleterious low-frequency and common homozygous variants between the children of cousins and those of unrelated parents were 1–3 times and 1–7%, respectively. These results suggest that the offspring of consanguineous union could have a 20 times higher risk of recessive autosomal diseases caused by rare variants. Conversely, consanguinity appears to have little effect on the risk of common diseases. These findings have implications for future clinical research in identifying genetic variants associated with inherited diseases. Furthermore, the magnitude of the elevated risk revealed in this study could be useful in genetic counseling and for public health in creating awareness. Full article

Degenerative and developmental eye disorders, including inherited retinal dystrophies (IRDs), anophthalmia, and congenital cataracts arise from genetic mutations, causing progressive vision loss or congenital structural abnormalities. IRDs include a group of rare, genetically, and clinically heterogeneous retinal diseases. It is caused by variations in at least 324 genes, affecting numerous retinal regions. In addition to IRDs, other developmental eye disorders such as anophthalmia and congenital cataracts also have a strong genetic basis. Autosomal recessive IRDs, anophthalmia, and congenital cataracts are common in consanguineous populations. In many endogamous populations, including those in Pakistan, a significant proportion of IRD and anophthalmia cases remain genetically undiagnosed. The present study investigated the variations in IRDs, anophthalmia, and congenital cataracts genes in 50 affected families. These unrelated consanguineous families were recruited from the different provinces of Pakistan including Punjab, Khyber Pakhtoon Khwa, Sindh, Gilgit Baltistan, and Azad Kashmir. Whole exome sequencing (WES) was conducted for the proband of each family. An in-house customized pipeline examined the data, and bioinformatics analysis predicted the pathogenic effects of identified variants. The relevant identified DNA variants of selected families were assessed in parents and healthy siblings via Sanger sequencing. WES identified 12 novel variants across 10 known IRD-associated genes. The four most frequently implicated genes were CRB1 (14.3%), GUCY2D (9.5%), AIPL1 (9.5%), and CERKL (7.1%) that together accounted for 40.4% of all molecularly diagnosed cases. Additionally, 25 reported variants in 19 known IRDs, anophthalmia, and congenital cataracts-associated genes were found. Among the identified variants, p. Trp278X, a stop–gain mutation in the AIPL1 (NM_014336) gene, was the most common causative variant detected. The most frequently observed phenotype was retinitis pigmentosa (46.5%) followed by Leber congenital amaurosis (18.6%). Furthermore, 98% of pedigrees (49 out of 50) were affected by autosomal recessive IRDs, anophthalmia and congenital cataracts. The discovery of 12 novel likely pathogenic variants in 10 IRD genes, 25 reported variants in 19 known IRDs, anophthalmia and congenital cataracts genes, atypical phenotypes, and inter and intra-familial variability underscores the genetic and phenotypic heterogeneity of developmental and degenerative eye disorders in the Pakistani population and further expands the mutational spectrum of genes associated with these ocular disorders. Full article

Background: Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the GBA1 gene, leading to deficient β-glucocerebrosidase activity. This results in the accumulation of glucocerebroside in macrophages, primarily affecting the liver, spleen, bone marrow, and bones. Understanding the clinical outcomes and genetic mutation profiles in specific populations, such as Turkish patients, is essential for optimized disease management and personalized therapy and preventing morbidity and mortality. Method: This retrospective study analyzed data from 29 Turkish patients with previously diagnosed type 1 GD at a single center between September and December 2023. Genetic analyses were performed to identify GBA1 mutations using next-generation sequencing. Genetic mutations were the primary criterion for diagnosing GD. Clinical features, treatment responses, and outcomes were evaluated. Clinical parameters included hematological findings, organomegaly, and bone involvement. Data were analyzed to identify potential correlations between genetic mutations and clinical manifestations. Results: This study included 14 male and 15 female patients, with a mean diagnosis age of 22.1 years. A significant family history was observed in 93% of cases, and 52% had consanguineous parents. Epistaxis (72%) was the most common pre-diagnosis symptom. Most patients received enzyme replacement therapy with 60 units/kg. Treatment led to significant improvements, including increased hemoglobin (21.1%), higher platelet count (86.1%), and reduced organomegaly (liver (10.02%), spleen (25.22%)). Genetic analysis identified seven mutations, with c.1226A>G (p.N409S) being the most frequent. Conclusions: This study highlights the spectrum of clinical outcomes and genetic mutations in Turkish patients with GD, emphasizing the variability in disease severity based on genotype. GD should be considered for patients with unexplained nosebleeds, hepatosplenomegaly, bone pain, weakness, or siblings or other family members with similar symptoms. The genetic analysis revealed considerable heterogeneity among patients, which indicates the necessity of observing this in the development of personalized treatment strategies. Future studies with larger cohorts and long-term follow-up are needed to further elucidate genotype–phenotype correlations in this population. Full article

Background: Premarital screening (PMS) is a nationwide program that helps high-risk individuals make decisions to avoid genetic and sexually transmitted diseases from spreading to their spouse or future offspring. This study examined the knowledge and attitudes towards inherited hemoglobinopathies in PMS among the people of Northern Border Region in Saudi Arabia and their relationship to various sociodemographic factors. Methods: A cross-sectional study was undertaken in the Northern region of Saudi Arabia from January to March 2024. Data were gathered via questionnaire from 478 Saudi participants aged 18 years and older. The chi-square test was employed to determine the association between categorical variables. Results: All participants in the study were familiar with the PMS program. A significant portion of participants, 79.3%, acknowledged that consanguinity can increase the risk of hereditary blood disorders, while 69.9% believed that if both parents are carriers of the same genetic blood disease, their child may inherit it. Higher education, female gender, and age group (30–40) were found to be the main predictors of knowledge regarding PMS. Most of the participants (98.5%) had a positive attitude regarding the necessity of PMS as a prerequisite for marriage completion. About 82.8% indicated they would not continue with the marriage if the PMS results were incompatible. Conclusions: The study indicates a growing awareness and positive attitude towards premarital screening among the general population, with an increasing number of individuals opting for it. The findings suggest that PMS programs contribute to informed decision making, as evidenced by the rise in participants choosing to forgo marriage due to partner incompatibility. The study recommends the enhancement of health education campaigns by considering demographic factors such as age, education, and marital status. Additionally, it advocates for expanding the scope of PMS to include a wider range of health and genetic disorders to improve its overall efficacy. Full article

Background and Clinical Significance: Congenital myasthenic syndrome-4C (CMS4C) associated with acetylcholine receptor (AChR) deficiency is an autosomal recessive defect of the motor endplate caused by homozygous or compound heterozygous mutations in the CHRNE gene on chromosome 17p13. Case Presentation: The authors present a familial case of CMS4C with three affected children in a consanguineous Romani family. Muscle weakness, fatigue, and ocular muscle impairment were present in all cases; two of the three siblings had delayed motor milestones, highly arched palates, and facial weakness. None of the children expressed bulbar symptoms. One child expressed a severe form, with recurrent respiratory infections, and multiple hospitalizations, while the other siblings expressed a mild phenotype, without hospital admissions. Repetitive nerve stimulation showed a myasthenic-type decrement greater than 10% of several muscles. A pathogenic frameshift variant (NM_000080.4: c.1327del) in the CHRNE gene was found in a homozygous status in all the affected children and in both parents. After 6 months of Pyridostigmine and Salbutamol treatment, the evolution of the case was good, with the improvement of most of the signs and no need for hospitalization. Conclusions: Early genetic diagnosis and appropriate therapy in the context of a multidisciplinary approach is mandatory for an optimal long-term prognosis. Community-wide carrier screening through comprehensive genetic testing is imperative to ensure accurate genetic counseling in genetic isolates. The authors report this case due to the increased number of affected children in a consanguine family from a small Romani community. Full article

This study describes two siblings from consanguineous parents who exhibit intellectual disability, microcephaly, photosensitivity, bilateral sensorineural hearing loss, numerous freckles, and other clinical features that suggest a potential disruption of the nucleotide excision repair (NER) pathway. Whole exome sequencing (WES) identified a novel homozygous missense variant in the ERCC4 gene, which was predicted to be pathogenic. However, a subsequent peculiar audiometric finding prompted further investigation, revealing a homozygous deletion in the OTOA gene linked to neurosensorial hearing loss. Both variants were located within a run of homozygosity (ROH) on chromosome 16p13.12-p12.2, implicating a complex genetic basis for the observed phenotype. While this study reports a potentially novel ERCC4 variant, it underscores the importance of comprehensive analysis and deep phenotyping in WES data to improve diagnostic accuracy. Our findings advocate for an expanded approach in WES analysis, ensuring more precise diagnoses and improved genetic counseling, particularly when specialized tests for structural variant analysis are unavailable. Full article

Background: Runs of homozygosity (ROHs), continuous homozygous regions across the genome, are often linked to consanguinity, with their size and frequency reflecting shared parental ancestry. Homozygosity mapping (HM) leverages ROHs to identify genes associated with autosomal recessive diseases. Whole-exome sequencing (WES) improves HM by detecting ROHs and disease-causing variants. Methods: To streamline personalized multigene panel creation, using WES and ROHs, we developed a methodology integrating ROHMMCLI and HomozygosityMapper algorithms, and, optionally, Human Phenotype Ontology (HPO) terms, implemented in a Django Web application. Resorting to a dataset of 12,167 WES, we performed the first ROH profiling of the Portuguese population. Clustering models were applied to predict consanguinity from ROH features. Results: These resources were applied for the genetic characterization of two siblings with epilepsy, myoclonus and dystonia, pinpointing the CSTB gene as disease-causing. Using the 2021 Census population distribution, we created a representative sample (3941 WES) and measured genome-wide autozygosity (F_ROH). Portalegre, Viseu, Bragança, Madeira, and Vila Real districts presented the highest F_ROH scores. Multidimensional scaling showed that ROH count and sum were key predictors of consanguinity, achieving a test F1-score of 0.96 with additional features. Conclusions: This study contributes with new bioinformatics tools for ROH analysis in a clinical setting, providing unprecedented population-level ROH data for Portugal. Full article

Adenylate cyclase 3 (ADCY3) is a transmembrane protein predominantly expressed in the primary cilia of neurons. It plays a vital role in converting ATP to cAMP, a secondary messenger that regulates various downstream signaling pathways such as carbohydrates and lipids metabolism. Homozygous loss-of-function variants in the ADCY3 gene lead to severe early-onset obesity and insulin resistance whereas gain-of-function variants protect against obesity. To describe a novel pathogenic ADCY3 variant implicated in early-onset obesity and functionally characterize this variant via in vitro and in silico validation, we identified a novel homozygous nonsense variant c.2520C>G, p.Thr840X in the ADCY3 gene using gene panel sequencing in a four-year-old girl. She was born to first-cousin consanguineous parents. The patient presented with severe obesity, and exhibited hepatomegaly and insulin resistance, with other biochemical and hormonal tests being normal. In vitro and in silico functional analyses showed downregulation and impaired activation of the ADCY3 protein. Our findings contribute to existing research that supports the role of ADCY3 in the genetic pathogenesis of early-onset obesity. In vitro and in silico functional characterization of the novel p.Thr840X variant showed impaired enzymatic activity leading to receptor loss of function, consistent with the patient’s phenotype. Genetic testing is essential in severe early-onset obesity and early diagnosis could benefit patients with personalized treatment strategies. Full article