Assessment the carrier frequency of monogenic diseases in populations requiring assisted reproductive technology.

PURPOSE: The objective of this study is to assess the carrier frequency and pathogenic variation of monogenetic diseases in a population of 114 subjects in Han Chinese from Hebei province who are undergoing assisted reproductive technology through the utilization of Expanded Carrier Screening (ECS). METHODS: The study utilized a panel consisting of 155 severe monogenic recessive genetic diseases for ECS. Next-generation sequencing technology was employed to identify specific variants associated with ECS in a cohort of 114 subjects from 97 couples, comprising 97 females and 17 male spouses. RESULTS: A total of 114 individuals received ECS. The carrier rate of pathogenic genes in the enrolled population was 44.74% (51/114). Among the 97 females, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than in those with assisted reproduction indicators (59.09% vs. 41.33%). However, the carrier rate of pathogenic genes in males without assisted reproductive technology was slightly lower than that with assisted reproductive technology (40% vs. 41.67%). Among both female and male participants, the carrier rate of pathogenic genes between individuals without indicators of assisted reproduction and those with such indicators was 55.55% vs. 41.38%. In 51 carriers, 72.55% (37/51) carried one genetic variant, 25.49% (13/51) carried two genetic variants, and 1.96% (1/51) carried three genetic variants. A total of 38 pathogenic genes were detected in this study, and GJB2 and MMACHC were most common. The carrier rates of the two genes were both 5.26% (6/114). A total of 55 variations were detected, and c.235delC was most frequently found. The carrier rate was 3.51% (4/114). The incidence of couples carrying the same pathogenic genes was 1.03% (1/97). CONCLUSIONS: The findings elucidate the carrier rate of pathogenic genes among 155 severe monogenic recessive genetic diseases and underscore the significance of ECS as a preventive measure against congenital anomalies. When both partners carry the same genetic mutation for a monogenic disease, preventive strategies can be taken in offspring through preimplantation genetic testing (PGT), prenatal genetic testing, or the utilization of donor gametes. ECS is instrumental in assessing reproductive risk, guiding fertility-related decisions, and reducing the prevalence of monogenic recessive genetic disorders in subsequent generations.

Pseudodominant inheritance of retinitis pigmentosa in a family with mutations in the Eyes Shut Homolog (EYS) gene.

Sequence variants in Eyes Shut Homolog (EYS) gene are one of the most frequent causes of autosomal recessive retinitis pigmentosa (RP). Herein, we describe an Italian RP family characterized by EYS-related pseudodominant inheritance. The female proband, her brother, and both her sons showed typical RP, with diminished or non-recordable full-field electroretinogram, narrowing of visual field, and variable losses of central vision. To investigate this apparently autosomal dominant pedigree, next generation sequencing (NGS) of a custom panel of RP-related genes was performed, further enhanced by bioinformatic detection of copy-number variations (CNVs). Unexpectedly, all patients had a compound heterozygosity involving two known pathogenic EYS variants i.e., the exon 33 frameshift mutation c.6714delT and the exon 29 deletion c.(5927þ1_5928-1)_(6078þ1_6079-1)del, with the exception of the youngest son who was homozygous for the above-detailed frameshift mutation. No pathologic eye conditions were instead observed in the proband's husband, who was a heterozygous healthy carrier of the same c.6714delT variant in exon 33 of EYS gene. These findings provide evidence that pseudodominant pattern of inheritance can hide an autosomal recessive RP partially or totally due to CNVs, recommending CNVs study in those pedigrees which remain genetically unsolved after the completion of NGS or whole exome sequencing analysis.

LEOPARD syndrome with accelerated idioventricular rhythm and systolic anterior motion of the posterior mitral leaflet: a case report.

Background: PTPN11 is ubiquitously expressed and has a variety of phenotypes even in a single heart. We examined LEOPARD syndrome (LS) in a patient with PTPN11 variants through pathological, electrophysiological, and anatomical studies. Case summary: A 49-year-old man with no previous medical history was brought to our emergency department because of syncope. An electrocardiogram (ECG) revealed alternating bundle branch block, and echocardiography revealed hypertrophic cardiomyopathy-like morphology with systolic anterior motion of the posterior mitral valve. Atrioventricular block, left ventricular outflow tract (LVOT) obstruction, and ventricular tachycardia were considered the differential diagnoses; however, the treatment plan was difficult to determine. An electrophysiological study revealed the cause of the ECG abnormality to be accelerated idioventricular rhythm, and the programmed ventricular stimulation was negative. Genetic testing revealed LS with PTPN11 variant, which was speculated to be the cause of these various unique cardiac features. The cause of syncope was considered to be exacerbation of LVOT obstruction due to dehydration, and the patient was treated with oral beta-blockers. Implantable loop recorder observation for 1 year revealed no arrhythmia causing syncope, and an implantable cardioverter-defibrillator and pacemaker were deemed unnecessary for primary prevention of syncope. During 2.5 years of follow-up, the LVOT peak velocity fluctuated between 2.5 and 3.5 m/s, but the patient remained stable with no recurrent syncope. Conclusion: We confirmed that LS is distinct from other cardiomyopathies using characterization, physiological, electrophysiological, and pathological examinations. Evidence supporting a specific treatment strategy for LS is limited, and understanding the pathogenesis may help establish effective treatment strategies.

Identification of a novel METTL23 gene variant in a patient with an intellectual development disorder: a literature review and case report.

METTL23 belongs to a family of protein lysine methyltransferases that methylate non-histone proteins. Recently, the METTL23 gene has been reported to be related to an intellectual developmental disorder, autosomal recessive 44. Patients present with developmental delay, intellectual disability (ID), and variable dysmorphic features. Here, we report on a Chinese girl who presented with global developmental delay, abnormal brain structure, and multiple facial deformities, including a short/upturned nose with a sunken bridge, thin lips, and flat occiput. Whole-exome sequencing identified a novel variant (NM_001080510.5: c.322+1del) on the METTL23 gene. This variant was not collected on public human variants databases such as gnomAD, predicted to influence the splicing as a classical splicing variant, and classified as Pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Since patients with METTL23-related ID are rare, we summarize and compare the clinical phenotype of reported patients with METTL23 variants. Our report further expands the METTL23 variants and provides new evidence for clinical diagnosis of METTL23-related ID.

Emerging perspectives on precision therapy for Parkinson's disease: multidimensional evidence leading to a new breakthrough in personalized medicine.

PD is a prevalent and progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Genes play a significant role in the onset and progression of the disease. While the complexity and pleiotropy of gene expression networks have posed challenges for gene-targeted therapies, numerous pathways of gene variant expression show promise as therapeutic targets in preclinical studies, with some already in clinical trials. With the recognition of the numerous genes and complex pathways that can influence PD, it may be possible to take a novel approach to choose a treatment for the condition. This approach would be based on the symptoms, genomics, and underlying mechanisms of the disease. We discuss the utilization of emerging genetic and pathological knowledge of PD patients to categorize the disease into subgroups. Our long-term objective is to generate new insights for the therapeutic approach to the disease, aiming to delay and treat it more effectively, and ultimately reduce the burden on individuals and society.

Adult presentation of a rare mitochondrial tRNA Val gene mutation-an expanding clinical phenotype.

BACKGROUND AND PURPOSE: Late-onset mitochondrial disorders are diagnostically challenging with significant heterogeneity in disease presentation. A case is reported of a 67-year-old gentleman who presented with a 3-month history of seizures, recurrent encephalopathy, ataxia and weight loss, preceded by recent initiation of haemodialysis for end-stage chronic kidney disease. METHODS: Extensive work-up including serological, cerebrospinal fluid, magnetic resonance imaging and electroencephalography was performed. Whole exome sequencing and muscle biopsy confirmed the diagnosis. RESULTS: Magnetic resonance imaging brain demonstrated a single non-enhancing T2 fluid attenuated inversion recovery hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. Given the subacute presentation of uncertain aetiology, he was empirically treated for autoimmune/paraneoplastic encephalitis. Despite radiological resolution of the cortical abnormality 2 weeks later, there was no clinical improvement. Further collateral history unveiled a mildly ataxic gait and longstanding hearing loss suggestive of a genetic cause. Whole exome sequencing revealed a likely pathogenic, heteroplasmic mitochondrial DNA variant in the MT-TV gene, m.1659T>C, present at higher levels of heteroplasmy in muscle (91%) compared to other mitotic tissues. A high fat/protein diet and multivitamins including co-enzyme Q10 were commenced. Treatment of the nutritional deficiency and avoidance of intermittent fasting due to unreliable oral intake secondary to encephalopathy probably contributed to the clinical improvement seen over the ensuing few months, with resolution of his encephalopathy and return to his baseline gait and weight. CONCLUSION: An adult case is reported with an acute neurological presentation mimicking encephalitis, caused by a heteroplasmic m.1659T>C MT-TV variant, previously reported once in a child who displayed a different clinical phenotype.

Clinical and molecular study of patients with thyroid dyshormogenesis and variants in the thyroglobulin gene.

Introduction: Defects in any thyroid hormone synthesis steps cause thyroid dyshormonogenesis (THD). THD due to thyroglobulin (TG) gene variants is a cause of congenital hypothyroidism (CH) with a wide clinical spectrum, ranging from mild to severe permanent hypothyroidism. We present high-throughput sequencing results of patients with TG variants. Methods: A CH high-throughput sequencing-panel of the main genes involved in the regulation of thyroid hormonogenesis was performed to identify those TG variants that may be related to patient THD phenotype. Results: We identified 21 TG gene variants in 19 patients (11.8%) which could explain their phenotype. Ten of those (47.6%) were not previously described. CH was biochemically severe in these 19 patients. Eight of them were reevaluated after one month of discontinuing LT4 treatment and all had severe permanent hypothyroidism. We also identified another 16 patients who presented heterozygous TG variants, of whom, at reevaluation, five had mild permanent and only one had severe permanent hypothyroidisms. Discussions: In this study, 10 novel and 11 previously reported variants in the TG gene have been identified that could explain the phenotype of 19 patients from non-consanguineous families from a large THD cohort. Although not all these TG gene variants can explain all the patients' THD phenotypes, some of them had severe or mild permanent hypothyroidism at reevaluation.

Whole-Exome Sequencing in Turkish Patients with Inherited Retinal Dystrophies Reveals Novel Variants in Ten Genes.

Introduction: Inherited retinal dystrophies (IRDs) associated with more than 300 genes are a clinically and genetically heterogeneous group of retinal diseases. This study aimed to identify causative gene variants and molecular basis of Turkish patients with IRD. Methods: Whole-exome sequencing was performed in 28 unrelated patients. The potential pathogenicity of variants was evaluated using the American College of Medical Genetics variant interpretation guidelines, in silico prediction tools, published literature or Human Gene Mutation Database, and compatibility with inheritance patterns or known phenotypes. Results: Causative variants in 21 genes, including MERTK, SNRP200, MYO7A, AIPL1, RDH12, OTX2, ADGRV1, RPGRIP1, SPATA7, USH2A, MFSD8, CDHR1, EYS, CACNA1F, CNGA3, RDH5, TULP1, BBS2, BEST1, RS1, GUCY2D were detected in 26 (92.9%) of 28 patients. The most prevalent causative variants were observed MERTK (10.7% of cases), followed by CDHR1, AIPL1, RDH12, SPATA7, CNGA3, TULP1 (7.1% of cases, each). The most common variant type in this study was missense variants (53%), followed by frameshift (21%), nonsense (20%), and splice (6%). Twelve novel variants, 6 of frameshift and 6 of missense, were detected in ten genes. Retinitis pigmentosa was the most common phenotype followed by Leber congenital amaurosis. Conclusion: This study provides an overview of causative gene variants in Turkish patients with IRD. Variants identified in this study expand the variant spectrum of IRD genes. We believe it is essential to combine molecular and clinical data to diagnose IRD patients, especially with the emergence of therapeutic options.

Novel Germline KIT Variants in Families With Severe Piebaldism: Case Series and Literature Review.

INTRODUCTION: Piebaldism is a rare autosomal dominant disorder characterized by congenital white forelock and depigmented patches, which is most commonly caused by deleterious variants in the KIT gene. METHODS: Four KIT variants were identified in a piebaldism case series by whole-exome sequencing. Functional experiments, including in vitro minigene reporter assay and enzyme-linked immunosorbent assay, were carried out to elucidate the pathogenicity of the variants. The genotype-phenotype correlation was summarized through extensive literature reviewing. RESULTS: All the four cases had severe piebaldism presented with typical white forelock and diffuse depigmentation on the ventral trunk and limbs. Four germline variants at the tyrosine kinase (TK) domains of the KIT gene were identified: two novel variants c.1990+1G>A (p.Pro627_Gly664delinsArg) and c.2716T>C (p.Cys906Arg), and two known variants c.1879+1G>A (p.Gly592_Pro627delinsAla) and c.1747G>A (p.Glu583Lys). Both splicing variants caused exon skipping and inframe deletions in the TK1 domain. The missense variants resided at the TK1 and TK2 domains respectively impairing PI3K/AKT and MAPK/ERK signaling pathways, the downstream of KIT. All severe cases were associated with variants in the TK domains, eliciting a major dominant-negative mechanism of the disease. CONCLUSION: Our data expand the mutation spectrum of KIT, emphasized by a dominant-negative effect of variants in the critical TK domains in severe cases. We also share the experience of prenatal diagnosis and informed reproductive choices for the affected families.

Genetic Variants in KNDy Pathway Lack Association with Premature Ovarian Insufficiency in Mexican Women: A Sequencing-Based Cohort Study.

Previous studies have demonstrated the essential role of the Kisspeptin/Neurokinin B/Dynorphin A (KNDy) pathway in female reproductive biology by regulating the activity of the hypothalamic-pituitary-gonadal axis. Identified loss-of-function mutations in these genes are linked to various reproductive disorders. This study investigated genetic disorders linked to mutations in the KNDy genes related to premature ovarian insufficiency (POI). A cohort of 14 Mexican POI patients underwent genetic screening using PCR-SSCP and Sanger sequencing, assessing the genetic variations' impact on protein function thereafter using multiple in silico tools. The PCR excluded extensive deletions, insertions, and duplications, while SSCP detected five genetic variants. Variations occurred in the KISS1 (c.58G>A and c.242C>G), KISS1R (c.1091A>T), PDYN (c.600C>T), and OPRK1 (c.36G>T) genes, whereas no genetic anomalies were found in NK3/NK3R genes. Each single-nucleotide variant underwent genotyping using PCR-SSCP in 100 POI-free subjects. Their allelic frequencies paralleled the patient group. These observations indicate that allelic variations in the KNDy genes may not contribute to POI etiology. Hence, screening for mutations in KNDy genes should not be a part of the diagnostic protocol for POI.

Whole exome sequencing and proteomics-based investigation of the pathogenesis of coronary artery disease with diffuse long lesion.

OBJECTIVES: The long-term prognosis of patients with coronary artery disease (CAD) with diffuse long lesion underwent coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) remains worse. Here, we aimed to identify distinctive genes involved and offer novel insights into the pathogenesis of diffuse long lesion. MATERIALS AND METHODS: Whole exome sequencing was performed on peripheral blood samples from 20 CAD patients with diffuse long lesion (CAD-DLL) and from 10 controls with focal lesion (CAD-FL) through a uniform pipeline. Proteomics analysis was conducted on the serum samples from 10 CAD-DLL patients and from 10 controls with CAD-FL by mass spectrometry. Bioinformatics analysis was performed to elucidate the involved genes, including functional annotation and protein-protein interaction analysis. RESULTS: A total of 742 shared variant genes were found in CAD-DLL patients but not in controls. Of these, 46 genes were identified as high-frequency variant genes (≥ 4/20) distinctive genes. According to the consensus variant site, 148 shared variant sites were found in the CAD-DLL group. The lysosome and cellular senescence-related pathway may be the most significant pathway in diffuse long lesion. Following the DNA-protein combined analysis, eight genes were screened whose expression levels were altered at both DNA and protein levels. Among these genes, the MAN2A2 gene, the only one that was highly expressed at the protein level, was associated with metabolic and immune-inflammatory dysregulation. CONCLUSIONS: Compared to individuals with CAD-FL, patients with CAD-DLL show additional variants. These findings contribute to the understanding of the mechanism of CAD-DLL and provide potential targets for the diagnosis and treatment of CAD-DLL.

Single nucleotide variants in the CCL2, OAS1 and DPP9 genes and their association with the severity of COVID-19 in an Ecuadorian population.

COVID-19 has a broad clinical spectrum, ranging from asymptomatic-mild form to severe phenotype. The severity of COVID-19 is a complex trait influenced by various genetic and environmental factors. Ethnic differences have been observed in relation to COVID-19 severity during the pandemic. It is currently unknown whether genetic variations may contribute to the increased risk of severity observed in Latin-American individuals The aim of this study is to investigate the potential correlation between gene variants at CCL2, OAS1, and DPP9 genes and the severity of COVID-19 in a population from Quito, Ecuador. This observational case-control study was conducted at the Carrera de Biologia from the Universidad Central del Ecuador and the Hospital Quito Sur of the Instituto Ecuatoriano de Seguridad Social (Quito-SUR-IESS), Quito, Ecuador. Genotyping for gene variants at rs1024611 (A>G), rs10774671 (A>G), and rs10406145 (G>C) of CCL2, OAS1, and DPP9 genes was performed on 100 COVID-19 patients (43 with severe form and 57 asymptomatic-mild) using RFLP-PCR. The genotype distribution of all SNVs throughout the entire sample of 100 individuals showed Hardy Weinberg equilibrium (P=0.53, 0.35, and 0.4 for CCL2, OAS1, and DPP9, respectively). The HWE test did not find any statistically significant difference in genotype distribution between the study and control groups for any of the three SNVs. The multivariable logistic regression analysis showed that individuals with the GG of the CCL2 rs1024611 gene variant had an increased association with the severe COVID-19 phenotype in a recessive model (P = 0.0003, OR = 6.43, 95% CI 2.19-18.89) and for the OAS1 rs10774671 gene variant, the log-additive model showed a significant association with the severe phenotype of COVID-19 (P=0.0084, OR=3.85, 95% CI 1.33-11.12). Analysis of haplotype frequencies revealed that the coexistence of GAG at CCL2, OAS1, and DPP9 variants, respectively, in the same individual increased the presence of the severe COVID-19 phenotype (OR=2.273, 95% CI: 1.271-4.068, P=0.005305). The findings of the current study suggests that the ethnic background affects the allele and genotype frequencies of genes associated with the severity of COVID-19. The experience with COVID-19 has provided an opportunity to identify an ethnicity-based approach to recognize genetically high-risk individuals in different populations for emerging diseases.

Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease.

Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the ATP2A2 gene that causes an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far, although a high incidence of neuropsychiatric syndromes suggests an involvement of the central nervous system. We report that the pathogenic ATP2A2 gene variant c.118G>A may cause cardiac involvement in patients with DD, consisting of keratinocyte and cardiomyocyte disconnection. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsies because cardiac dilatation and dysfunction appeared several decades after skin manifestations. Keratinocyte disconnection was paralleled by cardiomyocyte separation at the lateral junction. Cardiomyocyte separation was associated with cell disarray, sarcoplasmic reticulum dilatation, and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules are associated with chest pain, severe muscle exhaustion, and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation. Cardiac pathologic changes are similar to those documented in the skin, including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors that enhance SERCA2 protein phosphorylation may substantially attenuate the symptoms.

Abnormal biochemical indicators of neonatal inherited metabolic disease in carriers.

BACKGROUND: Traditional biochemical screening for neonatal inherited metabolic diseases has high false-positive rates and low positive predictive values, which are not conducive to early diagnosis and increase parents' anxiety. This study analysed the relationship between gene variant carriers and their biochemical indicators in traditional biochemical screening, aiming to find explanations for false positives in newborns. RESULTS: This retrospective study included 962 newborns. Newborns underwent traditional biochemical screening at birth using blood staining and genomic sequencing of their stored blood staining using the NeoSeq Pro panel, which was able to detect 154 pathogenic genes and 86 diseases. A total of 632 newborns were carriers of gene variants. 56% of congenital hypothyroidism carriers had higher thyroid-stimulating hormone levels than normal newborns. Abnormal biochemical indices were detected in 71% of carriers of organic acid metabolic diseases, 69% of carriers of amino acid metabolic diseases, and 85% of carriers of fatty acid ß oxidation disorders. In carriers associated with organic acid metabolic diseases, the propionylcarnitine (C3), C3/acetylcarnitine (C2), and methylmalonylcarnitine (C4DC) + 3-hydroxyisovalerylcarnitine (C5OH) levels were higher than those in non-carriers (C3: 4.12 vs. 1.66 µmol/L; C3/C2: 0.15 vs. 0.09; C4DC + C5OH: 0.22 vs. 0.19 µmol/L). In carriers associated with amino acid metabolic diseases, phenylalanine levels were higher than those in non-carriers (68.00 vs. 52.05 µmol/L). For carriers of fatty acid ß oxidation disorders, butyrylcarnitine levels were higher than those in non-carriers (0.31 vs. 0.21 µmol/L), while the free carnitine levels were lower than those in non-carriers (14.65 vs. 21.87 µmol/L). There was a higher occurrence of carriers among newborns who received false-positive results for amino acid metabolic diseases compared to those who received negative results (15.52% vs. 6.71%). Similarly, there was a higher occurrence of carriers among newborns who received false-positive results for fatty acid ß oxidation disorders compared to those who received negative results (28.30% vs. 7.29%). CONCLUSIONS: This study showed that the carriers comprised a large number of newborns. Carriers had abnormal biochemical indicators compared with non-carriers, which could explain the false-positive rate for newborns using traditional newborn biochemical screening, especially in amino acid metabolic and fatty acid ß oxidation disorders.

Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants.

Background: This study aimed to characterize the clinical phenotype and genetic variations in patients with Kallmann syndrome (KS). Methods: This study involved the collection and analysis of clinical data from an individual with sporadic KS. Following this, peripheral blood samples were obtained from the patient and his parents. Genomic deoxyribonucleic acid was extracted and subjected to whole-exome sequencing and genomic copy number variation (CNV) detection. Finally, Sanger sequencing was performed to validate the suspected pathogenic variants. Results: Whole-exome sequencing confirmed that the child carried both the IL17RD variant (c.2101G>A, p.Gly701Ser) inherited from the mother and the new CPEB4 variant (c.1414C>T, p.Arg472*). No pathogenic CNVs were identified in CNV testing. Conclusion: Bioinformatics analysis shows that the IL17RD protein undergoing Gly701Ser mutation and is speculated to be phosphorylated and modified, thereby disrupting fibroblast growth factor signaling. This study also suggested that the CPEB4 might play a crucial role in the key signaling process affecting olfactory bulb morphogenesis. Overall, the findings of this study broaden the gene expression profile of KS-related pathogenic genes. This offers a new avenue for exploring the pathogenic mechanism of KS and provides valuable insights for precise clinical diagnosis and treatment strategies for this condition.

Neurofilament Light Chains in Systemic Amyloidosis: A Systematic Review.

Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (TTRv) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 TTRv carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis.

Case report: Association between PTEN-gene variant and an aggressive case of multiple dAVFs.

Introduction: Mutations of the phosphatase and tensin homolog (PTEN) gene have been associated with a spectrum of disorders called PTEN hamartoma tumor syndrome, which predisposes the individual to develop various types of tumors and vascular anomalies. Its phenotypic spectrum includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome, autism spectrum disorders (ASD), some sporadic cancers, Lhermitte-Duclos disease (LDD), and various types of associated vascular anomalies. Clinical presentation: A previously healthy 27-year-old woman was experiencing visual scintillating scotomas and mild chronic headaches for the past 2 years. The initial computed tomographic (CT) and magnetic resonance imaging (MRI) scans did not reveal any abnormalities, but the possibility of pseudotumor cerebri was considered. Furthermore, a cerebral angiogram showed a posterior fossa dural arteriovenous fistula (dAVF), which was initially treated through embolization. However, in spite of proper treatment, this patient experienced multiple recurrent dAVFs in different locations, requiring multiple embolizations and surgeries. Despite exhibiting altered cerebral perfusion and hemodynamics, the patient did not display any significant symptoms until she experienced a sudden stroke resulting from deep venous thrombosis, which was not associated with any medical procedures or medication use. A comprehensive analysis was performed due to the aggressive nature of the dAVFs. Surprisingly, exome sequencing of a blood sample revealed a PTEN gene variant in chromosome 10, indicative of Cowden syndrome. However, no tumors or other vascular lesions were detected in other systems that would constitute Cowden syndrome. Conclusion: The rapid formation of multiple and complex dAVFs, coupled with not meeting the criteria for any other PTEN-related syndrome, unequivocally leads to the presentation of a novel phenotype of the PTEN germline variant.

Cystic fibrosis in Iceland and the high prevalence of the N1303K variant.

BACKGROUND: Cystic fibrosis (CF) is most common in populations of Northern European ancestry where the F508del variant predominates. In 2020, Iceland became a member of the European Cystic Fibrosis Society Patient Registry, and we launched an epidemiological study of CF in Iceland. The study aimed to determine the prevalence and the genetic variants present in the country. Furthermore, we aimed to describe the previous and the current situation regarding lung function, infections, complications, treatment, and follow-up to understand the strengths and weaknesses of CF care in Iceland. METHODS: This retrospective study included all individuals in Iceland with a confirmed CF diagnosis between 1955 and 2021. We conducted a medical records search for CF diagnosis codes and found 30 people with CF who were included in the study. Two hundred sixteen clinical variables were registered. A descriptive analysis of these was performed. RESULTS: The prevalence of CF in Iceland is 0.372:10,000 inhabitants. The F508del is the most common CF transmembrane conductance regulator (CFTR) variant (46.4%), closely followed by N1303K (44.6%). Staphylococcus aureus was the most common airway pathogen, followed by Pseudomonas aeruginosa. Nasal polyps and CF-related diabetes were the most common complications. Modern CF medications, including the recent CFTR modulators, are available. CONCLUSION: Even though Iceland has a relatively low prevalence of CF, it holds the highest known prevalence of the N1303K variant in Europe. Access to necessary treatment is satisfactory, but improvements are advisable for some aspects of the routine assessments by best practice guidelines.

Impacts of gene variants on drug effects-the foundation of genotype-guided pharmacologic therapy for long QT syndrome and short QT syndrome.

The clinical significance of optimal pharmacotherapy for inherited arrhythmias such as short QT syndrome (SQTS) and long QT syndrome (LQTS) has been increasingly recognised. The advancement of gene technology has opened up new possibilities for identifying genetic variations and investigating the pathophysiological roles and mechanisms of genetic arrhythmias. Numerous variants in various genes have been proven to be causative in genetic arrhythmias. Studies have demonstrated that the effectiveness of certain drugs is specific to the patient or genotype, indicating the important role of gene-variants in drug response. This review aims to summarize the reported data on the impact of different gene-variants on drug response in SQTS and LQTS, as well as discuss the potential mechanisms by which gene-variants alter drug response. These findings may provide valuable information for future studies on the influence of gene variants on drug efficacy and the development of genotype-guided or precision treatment for these diseases.