Mutation In Family Research Articles

The Icelandic mutation (APP-A673T) is protective against amyloid pathology in vivo.

A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (APP) can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into App knock-in mice devoid of the Swedish mutation (AppG-F mice) to avoid potential deleterious effects of the Swedish mutation and generated AppG-F-A673T mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and APOE ε4 carriers.Significance statement The A673T mutation (Icelandic mutation) in the APP gene can protect against AD. The effect of the A673T mutation on amyloid pathology has not been evaluated in vivo. Utilizing a new AD mouse model that we have recently developed, we show that the APP-A673T attenuates amyloid pathology in vivo. We demonstrate that its protective effects are exerted by inhibiting β-cleavage and reducing the production of Aβ in the brain. Furthermore, we reveal that the Icelandic mutation also reduced neuroinflammation and neuritic alterations. Our findings indicate that specific inhibition of the APP-BACE1 interaction or introduction of protective variants via in vivo genome editing could be a promising therapeutic approach.

Heterozygous Beta-Thalassaemia in Pregnancy: Two Rare Causes of Severe Fetal Anemia Requiring Intrauterine Blood Transfusions.

In this article, we present two cases of severe fetal hemolytic anemia based on a beta-thalassaemia trait inherited from a single parent. These cases, presented at 20 and 28weeks' gestation, necessitated intra-uterine blood transfusions. This occurrence is remarkable because it challenges the common assumption that beta-thalassaemia typically has no prenatal implications regarding fetal anemia. Both fetuses inherited a rare heterozygous mutation from their mother, resulting in gamma-thalassaemia-related anemia. In the first case, the anemia was related to a deletion in the beta locus control region (βLCR) and in the second case, a deletion on chromosome 11p15.4 was the cause. These mutations not only affect the beta chain production, but also the gamma chain production, leading to a reduction in the synthesis of HbF, ineffective erythropoiesis and consequently, perinatal hemolytic anemia. Clinicians should be vigilant regarding these rare mutations in families with a history of beta-thalassaemia as the fetal clinical consequences can be severe and intra-uterine blood transfusions may prove life-saving for these fetuses.

Epileptic seizures induced by pentylenetetrazole kindling accelerate Alzheimer-like neuropathology in 5×FAD mice

Clinical studies have shown that epileptic seizures worsen Alzheimer’s disease (AD) pathology and related cognitive deficits; however, the underlying mechanism is unclear. To assess the effects of seizures on the progression of AD, chronic temporal lobe epilepsy was induced in five familial AD mutation (5×FAD) mice by kindling with the chemoconvulsant pentylenetetrazole (PTZ) at 3–3.5 months of age. The amyloidogenic pathway, tauopathy, synaptic damage, neuronal death, neurological inflammatory response and associated kinase signaling pathway dysregulation were examined at 9 months of age. We found that APP, p-APP, BACE1, Aβ and kinase-associated p-tau levels were elevated after PTZ kindling in 5×FAD mice. In addition, PTZ kindling exacerbated hippocampal synaptic damage and neuronal cell death, as determined by scanning electron microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, respectively. Finally, the levels of the neuroinflammation markers GFAP and Iba1, as well as the inflammatory cytokine IL-1β, were increased after PTZ insult. PTZ kindling profoundly exacerbated extracellular regulated kinase (ERK)-death-associated protein kinase (DAPK) signaling pathway overactivation, and acute ERK inhibitor treatment downregulated Aβ production and p-APP and p-tau levels in epileptic 5×FAD mice. In addition, long-term use of the antiseizure drug carbamazepine (CBZ) alleviated seizure-induced accelerated amyloid and tau pathology and ERK-DAPK overactivation in 5×FAD mice. Collectively, these results demonstrate that seizure-induced increases in AD-like neuropathology in 5×FAD mice are partially regulated by the ERK-DAPK pathway, suggesting that the ERK-DAPK axis could be a new therapeutic target for the treatment of AD patients with comorbid seizures.

Ependymoma Alongside Hereditary Paraganglioma-Phaeochromocytoma Syndrome Due to a SDHB Mutation: A Case Report

Mutations in the SDHB gene cause a characteristic syndrome that includes paragangliomas (PGL) and phaeochromocytomas (PCC). Herein we present a rare case of an ependymoma in a patient with a germline SDHB mutation. A 41-year-old man with a positive family history of PGL/PCC syndrome was found to have the familial SDHB mutation. Screening imaging for paragangliomas revealed an incidental presumed ependymoma originating from the fourth ventricle. He was followed with serial imaging to assess for progression of the lesion. Due to slow, substantial growth of the tumour, and increasing symptoms which included diplopia, unsteadiness, and wide-based gait, he underwent a resection 5 years after the lesion’s identification. Following resection of the tumour, the pathology confirmed the tumour as a posterior fossa type B (PFB) ependymoma of the fourth ventricle. Unfortunately, on Day 26 post-operatively, the patient had a pulmonary embolism and died. His family consented to an autopsy, which revealed the presence of a clinically-silent pituitary neuroendocrine tumour (PitNET). Though ependymomas are not commonly seen in PGL/PCC syndrome, they can occur. This case represents the first molecularly-characterised ependymal tumour described in this tumour predisposition syndrome. Clinicians ought to be aware of the risk of ependymoma in patients with PGL/PCC syndrome and consider this tumour when conducting their screening and follow-up of asymptomatic SDHx mutation carriers.

Phenotype heterogeneity of SCN5A mutations in Brugada syndrome

Abstract Introduction Although SCN5A is the main gene associated with Brs syndrome (Brs), rare variants in this gene only affect 20 to 30 % of patients. Additionally, associated phenotype may differ even among relatives sharing the same mutation emphasizing a phenotype heterogeneity that is poorly understood for now. Objective Here we aim to investigate the association between the presence of SCN5A mutations and the expression of a BrS phenotype in large families. Methods Among Brugada patients enrolled in our prospective cohort, we included patients from families with affected proband carrier of a SCN5A mutation and at least 4 relatives carriers of the same SCN5A mutation. Patient without a spontaneous type 1 ECG and no pharmacological provocative test were excluded. Results A total of 463 individuals from 45 large families were enrolled. Among them, 258 (56%) were mutation carriers of one of the 33 identified SCN5A mutations. After pharmacological test, 219 (47%) individuals were diagnosed with BrS, including 32 not carriers of the familial mutation. Seventy-five patients (30%), carriers of the familial SCN5A mutation, remain negative for Brugada syndrome after pharmacological test. The prevalence of genotype-phenotype mismatch was 24%, including 32 BrS patients non carrier of the familial mutation (phenocopy) and 75 patients with the familial mutation but without BrS (30% of uncomplete penetrance). Conclusion Our data strongly suggest that SCN5A mutation is not either necessary nor sufficient to explain the occurrence of BrS phenotype. We now aim to identify which associated factors might interfere, focusing first on the genetic background of phenotype/genotype mismatched individuals.

SLC16A8 is a causal contributor to age-related macular degeneration risk

Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD.

Metabolomic profiling of the entire UK Biobank enables interpretation of familial hypercholesterolemia mutations and prediction of severe cardiovascular outcomes

Abstract Background Familial hypercholesterolemia (FH) is an inherited disorder resulting in high levels of LDL-C from birth. Premeature coronary heart disease occurs in half of affected men by age 50 years(1). While many genetic variants that cause FH are well understood, there are also many variants in FH genes that are of uncertain clinical significance. Furthermore, the variability in residual cardiovascular risk of FH carriers after statin treatment is not fully understood. We here investigate whether metabolomic and genomic data from the 500,000 person UK Biobank cohort can aid in interpretation of candidate pathogenic variants for FH, and characterise future risk of severe cardiac events in the carriers of such variants. Methods We have quantified 249 metabolomic parameters in 490,830 blood samples from UK Biobank cohort. Among 186,483 participants with exome sequence data we identified 896 who carried known pathogenic FH variants and 405 who carried variants of unknown significance in an established FH gene. We fitted a logistic predictive model to identify pathogenic mutations using LDL levels, statin use and 17 principal components of the metabolomic parameters. We further tested whether metabolomic and genomic scores for predicting future risk of myocardial infarction (MI), that were trained in the general population (i.e. individuals without FH), could predict risk in FH carriers. Results A model including all metabolites had a higher accuracy at identifying known pathogenic FH variants (36/56 at FDR < 0.05), compared to LDL and statin use alone (30/56). Our model also identified 8 FH variants marked as uncertain significance in ClinVar with significant (FDR < 0.05) evidence of predicted pathogenicity. We found that our metabolomic risk score predicted 10-year risk of MI among FH carriers (HR=1.96 per SD, p = 0.0011). This was indeed stronger than the effect in the general population (HR = 1.64 per SD, p = 2.5e-168). A combined metabolomic and polygenic risk score had an even larger effect at predicting MI in FH carriers (HR = 3.06 per SD, p = 2.0e-6), and this score was significantly better at predicting MI in FH carriers than in non-carriers (HR = 3.06 vs 1.88 per SD, interaction p = 0.042). Conclusion Familial hypercholesterolemia is an important source of risk for early cardiovascular disease. Population-scale metabolomics can help distinguish pathogenic from benign variants that have not yet been characterised. Metabolomic and genomic scores can also identify individuals at most elevated risk, and provide even more information to FH individuals than in the general population.

Amyloid pathology and cognitive impairment in hAβ-KI and APPSAA-KI mouse models of Alzheimer's disease

The hAβ-KI and APPSAA-KI are two amyloid models that harbor mutations in the endogenous mouse App gene. Both hAβ-KI and APPSAA-KI mice contain a humanized Aβ sequence, and APPSAA-KI mice carry three additional familial AD mutations. We herein report that the Aβ levels and Aβ42/Aβ40 ratio in APPSAA-KI homozygotes are dramatically higher than those in hAβ-KI homozygotes at 14 months of age. In addition, APPSAA-KI mice display a widespread distribution of amyloid plaques in the brain, whereas the plaques are undetectable in hAβ-KI mice. Moreover, there are no sex differences in amyloid pathology in APPSAA-KI mice. Both APPSAA-KI and hAβ-KI mice exhibit cognitive impairments, wherein no significant differences are found between these two models, although APPSAA KI mice show a trend towards worse cognitive function. Notably, female hAβ-KI and APPSAA-KI mice have a more pronounced cognitive impairments compared to their respective males. Our findings suggest that Aβ humanization contributes to cognitive deficits in APPSAA-KI mice, and that amyloid deposition might not be closely associated with cognitive impairments in APPSAA-KI mice.

Pancreatic insulinomas: Our 15-year surgical experience.

Insulinomas are rare endocrine tumors of the pancreas. The majority are benign, sporadic, and solitary. Surgery is the only curative treatment. In this study, we present our experiences with the perioperative management of sporadic and benign pancreatic insulinomas. Patients who underwent surgery for pancreatic insulinoma in our clinic between 2008 and 2023 were retrospectively reviewed. Demographic data, preferred radiological methods, surgical procedures, and morbidity and mortality data were evaluated. Patients with malignant, invasive, or familial multiple endocrine neoplasia mutations were excluded from the study. Nineteen patients underwent surgery, with a median age of 49 years (range: 33-85). Symptoms related to hypoglycemia were the most commonly observed. The tumor location was identified preoperatively in 74% of cases using computed tomography. Palpation and intraoperative ultrasound identified the tumor location in 88% of patients. Enucleation (53%) were the most common surgical procedures. Pancreatic fistula occurred in three patients (17%). While serious morbidity was lower in patients who underwent enucleation, the rate of fistula formation was higher. The accurate localization of insulinomas plays a crucial role in determining the appropriate surgical procedure. With high success rates and lower morbidity, enucleation is the recommended procedure for suitable patients.

Familial adenomatous polyposis gene MUTYH mutations are identified in anaplastic thyroid carcinoma

Abstract Introduction/Objective Anaplastic thyroid carcinoma (ATC) is a rare aggressive disease unresponsive to treatment. Next-Generation Sequencing (NGS) allows identification of targets for precision therapies, such as BRAF, with implications in treating ATC. Our prior work identified ATC clusters with characteristic gene mutations and multiple previously unreported mutations. One of these is MUTYH, which is associated with colon (CRC), ovarian, breast, bladder, and duodenal carcinomas in MUTYH-associated polyposis (MAP). Its association with ATC is not defined. Methods/Case Report Exploratory analysis of pathogenic mutations in 727 ATC cases using a 324-gene panel (FoundationOneCDx) and an interactive visualization of association rules was conducted for informative maximal frequent patterns among mutated gene combinations to identify gene clusters including genes not commonly associated with ATC. TCGA database was reviewed for frequency of MUTYH mutations. My Cancer Genome and the Drug-Gene Interaction Database were used to identify potential targeted drugs for MUTYH gene-mutated cancers. Results (if a Case Study enter NA) NGS showed MUTYH short-variant mutations in 17 cases (2.34%). Germline MUTYH variants incidence is 1.43% in normal samples. 5 cases harbored only Y165C and 7 had only G382D, with 1 case having both Y165C and G382D. The other 4 cases contained sporadic truncating events in MUTYH. All instances of Y165C and G382D were predicted to be germline. 6 patients (35%) had BRAF co-mutations, correlating with expected frequency of ATC thought to transform from papillary carcinoma (PC). One case had only MUTYH mutation while a second had MUTYH with TERT and TP53. TCGA database contained 6(0.2%) cases of PC with MUTYH mutations (total 2871 MUTYH-mutated carcinomas), but no cases of ATC or other thyroid tumors were described. Conclusion MUTYH is a DNA repair enzyme linked to CRC and other cancers. MUTYH mutations occur in 6.7% of MAP patients and 1–2.2% of sporadic CRC cases that are mutually exclusive of BRAF mutations. While MAP increases the lifetime risk of CRC by over 60%, the link of MUTYH mutations to PC has only been observed in MAP and not been described outside of it. To our knowledge this is the first description of MUTYH mutations in ATC, especially without concurrent BRAF mutation (11 cases), suggesting MUTYH may independently contribute to pathogenesis of ATC. PARP inhibitors, PD-1/PD-L1 inhibitors, and ATR inhibitors demonstrate promising results in clinical trials of MUTYH-mutated cancers, warranting further research.

Alterations in the axon initial segment plasticity is involved in early pathogenesis in Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by the early presence of amyloid-β (Aβ) and hyperphosphorylated tau. Identifying the neuropathological changes preceding cognitive decline is crucial for early intervention. Axon initial segment (AIS) maintains the orderly structure of the axon and is responsible for initiating action potentials (APs). To investigate the role of AIS in early stages of AD pathogenesis, we focused on alterations in the AIS of neurons from APP/PS1 mouse models harboring familial AD mutations. AIS length and electrophysiological properties were assessed in neurons using immunostaining and patch-clamp techniques. The expression and function of ankyrin G (AnkG) isoforms were evaluated by western blot and rescue experiments. We observed a significant shortening of AIS in APP/PS1 mice, which correlated with impaired action potential propagation. Furthermore, a decrease in the 480kDa isoform of AnkG was observed. Rescue of this isoform restored AIS plasticity and improved long-term potentiation in APP/PS1 neurons. Our study implicates AIS plasticity alterations and AnkG dysregulation as early events in AD. The restoration of AIS integrity by the 480kDa AnkG isoform presents a potential therapeutic strategy for AD, underscoring the importance of targeting AIS stability in neurodegenerative diseases.

The pathogenic germline ETV4 P433L mutation identified in multiple primary lung cancer affect tumor stem-like property by Wnt/β-catenin pathway

The occurrence of multiple primary lung cancer (MPLC) has witnessed a significant surge in recent years within the Chinese population. MPLC is distinguished by its potential genetic susceptibility and notable genetic heterogeneity. Investigating the etiology of MPLC holds substantial clinical importance.The whole genome sequencing (WGS) and genome-wide linkage analysis were performed in a family affected by a dominant form of lung abnormalities. Specifically, five family members were diagnosed with MPLC, while nine members had pulmonary nodules and one normal member. To confirm the potential pathogenic germline mutations sites, Sanger sequencing was performed in an additional 162 MPLC family patients. Furthermore, molecular biology experiments were conducted to investigate the function and the mechanism of the identified pathogenic mutation site in lung cancer A549 and H322, both in vitro and in vivo. Linkage analysis revealed the presence of shared genomic regions among affected family members. Subsequent exome sequencing identified a deleterious variant within these linkage intervals, specifically a heterozygous mutation in ETS-oncogene transcription factors 4 (ETV4). This particular variant was found in affected family members at a rate of 13 out of 15 individuals. Furthermore, ETV4 P433L mutation could be detected in an additional MPLC family patients and mutation frequency was 3.7% (6 out of 162). The ETV4 P433L mutations site was introduced into lung cancer cell lines, resulting in altered migration and stem-like properties of the cancer cells. Further investigation revealed that the activation of the Wnt/β-catenin signaling pathway, which is associated with stemness, could be attributed to the presence of the ETV4 P433L mutation, suggesting its involvement in tumor promotion. A novel pathogenic germline mutation, ETV4 P433L, was identified in a dominant MPLC family, with a mutation rate of 3.7% among MPLC family patients. The ETV4 P433L mutation was found to impact the stem-like properties and migration of tumors through Wnt/β-catenin signaling pathway.

Deep brain stimulation in a patient with dystonic tremor with a novel familial VPS16 gene mutation

Dystonia is a neurological disorder characterized by intermittent muscle contractions or abnormal movements. The pathophysiology and pathogenetic variations are increasingly better understood, but their translation into appropriate treatment is still largely lacking. We present a case of a woman suffering from a dystonic tremor of the upper limbs and head. Both the patient treated with DBS and her sister carry a novel mutation in the VPS16 gene. Treatment proved to be successful through deep brain stimulation targeting the ventral intermediate nucleus of the thalamus.

NBEAL2 gene mutations do not always lead to gray platelet syndrome: A case report.

Gray platelet syndrome (GPS) is a rare disease caused by homozygosity and compound heterozygosity for autosomal mutations on the NBEAL2 gene, which is characterized by a deficiency of platelet α-granules, bleeding symptoms. However, in this study, we report 2 NBEAL2 gene mutations in an easy bruising family without gray platelet and bleeding. A 33-year-old female nurse sought admission to our laboratory due to a tendency to bruise easily and unwell in daily life. However, there are no signs of petechiae or excessive bleeding in her daily life. Coagulation tests, routine blood tests and platelet staining of blood smears were all normal. The whole exome sequencing and Sanger sequencing were used to identify the causative variant of the patient. Furthermore, the morphology of platelets was examined using electron microscopy. Whole exome sequencing revealed the presence of 2 mutations in the NBEAL2 gene: p.Thr365fs and p.Ala310Thr. This prompted the consideration of a GPS diagnosis. However, platelet electron microscopy did not identify any abnormalities, leading to the exclusion of GPS. These 2 NBEAL2 gene mutations (p.Thr365fs and p.Ala310Thr mutations) do not affect the degranulation of platelets.

Cell Senescence and the Genetics of Melanoma Development.

Cutaneous malignant melanoma is an aggressive skin cancer with an approximate lifetime risk of 1 in 38 in the UK. While exposure to ultraviolet radiation is a key environmental risk factor for melanoma, up to ~10% of patients report a family history of melanoma, and ~1% have a strong family history. The understanding of causal mutations in melanoma has been critical to the development of novel targeted therapies that have contributed to improved outcomes for late-stage patients. Here, we review current knowledge of the genes affected by familial melanoma mutations and their partial overlap with driver genes commonly mutated in sporadic melanoma development. One theme linking a set of susceptibility loci/genes is the regulation of skin pigmentation and suntanning. The largest functional set of susceptibility variants, typically with high penetrance, includes CDKN2A, RB1, and telomerase reverse transcriptase (TERT) mutations, associated with attenuation of cell senescence. We discuss the mechanisms of action of these gene sets in the biology and progression of nevi and melanoma.

Giant intra-abdominal desmoid-type fibromatosis infiltrating into the pancreas

Abstract: Intra-abdominal desmoid-type fibromatosis is a proliferative fibroblastic lesion that constitutes 8% of all desmoid tumors and 0.03% of all neoplasm. It is histologically benign with a local aggressive nature and recurs even after excision. It can occur sporadically and or associated with familial adenomatous polyposis mutation. The present case is a 25-year-old female admitted with a chief complaint of abdominal mass gradually increasing in size in the last 6 months. Ultrasound of the whole abdomen initially suggested it to be a uterine/ovarian mass, which is further detailed by the contrast-enhanced computerized tomography (CT) scan. The CT scan showed a large heterodense intraperitoneal mass lesion measuring 34 cm × 25 cm × 16 cm with foci of calcification and necrosis. The mass extended superomedially. It displaced and compressed the stomach wall. It was abutting the peritoneum and was associated with diffuse peritoneal thickening anterolaterally. Posteriorly it was abutting small bowel loops and inferiorly extending into the pelvis and compressing the urinary bladder wall. Posterosuperiorly seems to abut the left kidney and spleen. Desmoid tumor and gastrointestinal stromal tumor (GIST) remained as differentials radiologically and then the patient underwent laparotomy. Histology and immunohistochemistry confirmed it to be fibromatosis. It is, therefore, justified to describe the tumor by considering its rarity, difficulties in diagnosis, and therapeutic ambit.

Gelsolin amyloidosis associated with the p.D214N gelsolin gene mutation in a Chinese family.

Gelsolin amyloidosis associated with the p.D214N gelsolin gene mutation in a Chinese family.

Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations

Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations

Clinical, myopathological, and genetic features of two Chinese families with Andersen-Tawil syndrome.

To explore the clinical, muscle pathological, and pathogenic gene mutation characteristics of Andersen-Tawil Syndrome (ATS) and enhance the understanding of ATS among clinical practitioners. Retrospective analysis of clinical data and muscle pathology of two ATS families, along with genetic testing for probands and some family members. In Family 1, spanning four generations, four individuals were affected, while Family 2 had two affected individuals across four generations. All six patients in both families experienced onset in childhood, presenting with periodic paralysis, arrhythmias, and craniofacial skeletal abnormalities. In Family 1, the proband's periodic paralysis was more triggered by low temperature and exercise, occurring several times a year, lasting 4-7 days. All three adult patients in Family 1 had a history of hypokalemia, and the frequency and severity of attacks were reduced after regular oral potassium supplement therapy. Two adult females in Family 1 experienced limb weakness triggered by stress, exertion, and premenstrual period, with milder symptoms than the proband. In Family 2, the proband's periodic paralysis typically occurred the day after excessive exertion, with a frequency of approximately 2-3 months. Two years prior, the proband developed arrhythmias without palpitations or chest tightness. The proband's brother experienced intermittent limb weakness during adolescence, remained untreated, and had sudden death at age 40. Physical examination revealed characteristic features in Family 1 and both probands: small mandible, wide eye spacing, and fifth-digit clinodactyly. Four adult patients were shorter in stature, while the growth status of a pediatric patient was indeterminate. Supplementary tests showed a history of hypokalemia during muscle weakness episodes in Family 1, while Family 2 patients had normal potassium levels during episodes. The long exercise tests were positive in both probands. Muscle MRI showed no significant abnormalities, but muscle pathology revealed rimmed vacuoles and tubular aggregates. Genetic testing identified KCNJ2 gene mutations in two probands and some of their family members, with c.407C > T (p.S136F) heterozygous mutation in Family 1 and c.652C > T (p.R218W) heterozygous mutation in Family 2. Among the clinical symptoms of the patients with Andersen-Tawil Syndrome in this study, not everyone exhibits the full triad of signs: periodic paralysis is the most common initial symptom, craniofacial and digit skeletal abnormalities are characteristic signs, and ventricular arrhythmias pose the most serious potential risk. Given that these typical symptoms were observed in 5 out of 6 patients, clinicians should pay special attention to these typical symptoms, and patients with these symptoms should be followed up over time. Muscle biopsy May reveal pathological changes such as tubular aggregates, but genetic testing for KCNJ gene mutations remains a crucial diagnostic criterion for this syndrome.

Identification of novel CDH23 variants linked to hearing loss in a Chinese family: A case report.

Deafness is associated with both environmental and genetic factors, with hereditary deafness often caused by mutations in deafness-related genes. Identifying and analyzing deafness-related genes will aid in early diagnosis and pave the way for treating inherited deafness through gene therapy in the future. A 15-month-old girl underwent audiological examination at the outpatient clinic of the hospital due to hearing loss and her brother was diagnosed with profound bilateral sensorineural hearing loss at the age of 3. The diagnosis was determined as extremely severe sensorineural hearing loss caused by genetic factors. Clinical data of the patient were collected, and peripheral blood samples were obtained from both the patient and her family members for DNA extraction and sequencing. By utilizing targeted capture next-generation sequencing to further screen for deafness-related genes, 2 novel variants in CDH23 were identified as the causative factors for the patient's deafness. This study identified 2 novel heterozygous mutations in a Chinese family. Both the proband and her sibling have non-syndromic hearing loss (NSHL) and carry distinct heterozygous mutations of cadherin-like 23 (CDH23). One mutation, CDH23:c.2651 A>G, originated from their mother and paternal family, affecting the exon23 domain of CDH23. The other mutation, CDH23:c.2113 G>T, was inherited from their paternal grandmother, impacting the exon19 domain of CDH23. These 2 novel mutations likely cause NSHL by affecting protein function. This finding suggests that identifying 2 novel mutations in CDH23 contributes to the genetic basis of NSHL.