Dominant Inheritance Research Articles

MATURITY-ONSET DIABETES OF THE YOUNG (MODY): FIRST CASE REPORTED OF GCK-MODY TYPE IN HATTA HOSPITAL, DAHC, UAE

Maturity-onset diabetes of the young (MODY) is a genetically diverse endocrine disorder of autosomal dominant inheritance characterized by pancreatic β-cell dysfunction.Since the clinical symptoms are so similar, it can be difficult to diagnose MODY accurately, so it is important to consider a patients family history and any other genetic risk factors when making a diagnosis.Glucokinase (GCK) was the first MODY gene identified it has been associated with defects in several genes.(1)

Autosomal dominant tubulointerstitial kidney disease: Diagnostic challenges in the absence of genetic testing. A case report

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of rare uncommon genetic disorders characterized by tubular damage and interstitial fibrosis in the absence of glomerular lesions. It has autosomal dominant inheritance and inevitable progression to end-stage kidney disease (ESKD). In nephrological practice, we usually face glomerular diseases that have well-recognized symptoms. Therefore, when we see a patient with impaired kidney function but without any signs of glomerular disease, it is always more challenging to discover the reason for it. The present case illustrates tubulointerstitial lesions due to possible genetic reasons. A 38-year-old non-hypertensive female presented with impaired renal function, a family history of CKD, proteinuria 0,5 g/day, and urinary sediment unremarkable. Relying on her family history, the middle age of onset, the progression to the end-stage kidney disease, and laboratory and histological results, an autosomal dominant tubulointerstitial kidney disease was suspected. Initially, diagnosed tubulointerstitial kidney disease is likely to be secondary to a mutation in genes encoding mucin-1. Pathology findings in this case played a pivotal role in establishing the diagnosis. However, it still needs to be proven by genetic tests. The purpose of this manuscript was to summarize the case of ADTKD, discuss the challenges in diagnosing ADTKD without genetic testing, and emphasize the importance of genetic testing in confirming the diagnosis.

Association of Interleukin-2 Gene Polymorphism with Henoch-schönlein Purpura Nephritis.

Henoch-Schönlein purpura nephritis (HSPN) is a common vasculitis that mostly affects children, and previous studies have indicated that genetic factors may influence disease susceptibility. The aim of this study was to evaluate a possible association of three interleukin-2(IL-2) gene polymorphisms (rs3136534, rs2069776, and rs2069762) with HSPN in the Chinese population. A total of 81 patients with HSPN and 200 healthy children were enrolled. The distribution of genotypes, allelic frequencies, and haplotype frequencies among the three IL-2 polymorphisms were analyzed using the Sequenom MassARRAY system by means of matrix-assisted laser desorption ionization-time of flight mass spectrometry method. Compared to the healthy controls, genotyping analysis demonstrated rs3136534 was associated with a decreased HSPN risk in the dominant inheritance model (G/T+T/T vs. G/G; OR, 0.54; 95% CI, 0.31-0.93). However, the frequency of the T allele and haplotypes of rs3136534 showed no statistical significance. For the frequency of genotype, allele, and haplotype of the rs2069776 and rs20697622 polymorphisms, no significant differences were observed between HSPN patients and controls. Our results suggest that the rs3136534 polymorphism of the IL-2 gene is associated with susceptibility to HSPN in Chinese children.

Hyper IgE syndrome with congenital hypothyroidism: a rare association

Hyper IgE syndrome (HIES) is a rare immunodeficiency syndrome, with autosomal dominant inheritance, caused mainly due to STAT 3 mutation. The affected children usually present with atopic dermatitis, recurrent staphylococcal infections, phenotypic characteristics and increased IgE levels. Though, there is a case report of autoimmune thyroiditis in HIES, congenital hypothyroidism is not reported. Here we report a case of HIES with typical phenotypic features with congenital hypothyroidism that presented to us with recurrent infections, atopic dermatitis and pneumatocele of right lung. Child was subsequently managed with antibiotics, levothyroxine and lobectomy.

A case report of Apert syndrome

Link of Video Abstract: https://youtu.be/ahjJloTwZQE Introduction: Apert syndrome (AS) is a rare type 1 acrocephalosyndactyly syndrome, characterized by craniosynostosis, severe syndactyly of the hands and feet, and dysmorphic facial features. It exhibits autosomal dominant inheritance assigned to mutations in the fibroblast growth factor receptor gene. Case Illustration: We presently describe the case of a 14 years old male patient with acrocephaly, prominent forehead, ocular hypertelorism, proptosis, short and broad nose, pseudoprognathism, crowding of teeth and ectopia, maxillary hypoplasia, low hairline, webbed neck, pectus excavatum, and severe bilateral syndactyly of hands and feet. The examination revealed apical cranium, occipital flattening, enlargement and hypoplasia of the premaxillary opening, crowding, ectopic teeth, tapering of the mandibular apex, and pseudognathia. Conclusion: We reported a 14 years old male patient with AS with craniosynostosis and acrocephalosyndactyly. The characteristics of clinical manifestation of AS should be aware by physicians to be able to diagnose the disease.

Whole-Exome Sequencing Identified Two Novel Pathogenic Mutations in the PTCH1 Gene in BCNS.

Basal cell nevus syndrome (BCNS, OMIM 109400) is a familial cancer syndrome characterized by the development of numerous basal cell cancers and various other developmental abnormalities, including epidermal cysts of the skin, calcified dural folds, keratocysts of the jaw, palmar and plantar pits, ovarian fibromas, medulloblastomas, lymphomesenteric cysts, and fetal rhabdomyomas. BCNS shows autosomal dominant inheritance and is caused by mutations in the patched 1 (PTCH1) gene and the suppressor of the fused homolog (SUFU) gene. In a few cases, variants of patched 2 (PTCH2) have been found in patients who met the criteria for BCNS. In an investigation of 11 Hungarian families who fulfilled the diagnostic criteria for BCNS, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) identified two novel pathogenic variants (c.2994C>A; p.Cys998Ter and c.814_818del; p.Asn272SerfsTer11), one recently identified variant (c.1737_1745del p.Val580_Val582del), and three recurrent disease-causing variants of the PTCH1 gene with a diagnosis rate of 63.6%. Disease-causing variants were not found for the SUFU and PTCH2 genes. These applied methods could not fully elucidate the genetic background of all the BCNS cases that we investigated. To uncover the missing heritability of BCNS, whole-genome sequencing or an epigenetic approach might be considered in the future.

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM's morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin-proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM.

The spontaneous mouse mutant low set ears (Lse) is caused by tandem duplication of Fgf3 and Fgf4.

The external ear develops from an organized convergence of ventrally migrating neural crest cells into the first and second branchial arches. Defects in external ear position are often symptomatic of complex syndromes such as Apert, Treacher-Collins, and Crouzon Syndrome. The low set ears (Lse) spontaneous mouse mutant is characterized by the dominant inheritance of a ventrally shifted external ear position and an abnormal external auditory meatus (EAM). We identified the causative mutation as a 148Kb tandem duplication on Chromosome 7, which includes the entire coding sequences of Fgf3 and Fgf4. Duplications of FGF3 and FGF4 occur in 11q duplication syndrome in humans and are associated with craniofacial anomalies, among other features. Intercrosses of Lse-affected mice revealed perinatal lethality in homozygotes, and Lse/Lse embryos display additional phenotypes including polydactyly, abnormal eye morphology, and cleft secondary palate. The duplication results in increased Fgf3 and Fgf4 expression in the branchial arches and additional discrete domains in the developing embryo. This ectopic overexpression resulted in functional FGF signaling, demonstrated by increased Spry2 and Etv5 expression in overlapping domains of the developing arches. Finally, a genetic interaction between Fgf3/4 overexpression and Twist1, a regulator of skull suture development, resulted in perinatal lethality, cleft palate, and polydactyly in compound heterozygotes. These data indicate a role for Fgf3 and Fgf4 in external ear and palate development and provide a novel mouse model for further interrogation of the biological consequences of human FGF3/4 duplication.

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Disruption of Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary Spastic Paraplegia in Patient-Derived Stem Cell Models

Hereditary spastic paraplegia (HSP) is a category of neurodegenerative illnesses with significant clinical and genetic heterogeneity. Homozygous truncated variants of the ERLIN2 gene lead to HSP18 (MIM #611225). However, it is still unclear whether there is an autosomal dominant pathogenic pattern. The specific molecular mechanism needs to be investigated. We generated patient-derived iPSC models to study the mechanism of ERLIN2 heterogeneous variants leading to HSP. We identified a heterozygous missense variant p.Val71Ala of ERLIN2 in an HSP family. Based on IP-mass spectrometry, we found that the ERLIN2 heterozygous missense variant protein recruited the ubiquitin E3 ligase RNF213 to degrade IP3R1. The degradation of IP3R1 leads to the reduction of intracellular free calcium, which triggered endoplasmic reticulum (ER) stress-mediated apoptosis. Calcium homeostasis imbalance inhibited the MAPK signaling pathway that contributed to decreased cell proliferation. In summary, these results suggest that the autosomal dominant inheritance of heterozygous missense variants in ERLIN2 is a novel pathogenic mode of HSP. Furthermore, the disruption of intracellular calcium homeostasis is the pathological mechanism.

#5158 AUTOSOMAL DOMINANT TUBULAR KIDNEY DISEASE: FROM PHENOTYPE TO GENOTYPE

Abstract Background and Aims Autosomal dominant tubulointerstitial kidney disease (ADTKD) represent a recently described group of kidney diseases, characterized by chronic interstitial nephritis (CIN), in most cases hereditary, with an autosomal dominant inheritance pattern, subclassified according to its genetic cause, when identified. Mutations in UMOD, MUC1, REN and HNF1B genes have been implicated in their pathogenesis. Recent molecular diagnostic technologies, such as Next-Generation Sequencing (NGS), and particularly the use of restriction and Snapshot method for the detection of a cytosine insertion on the coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1, have allowed the nephrologists to diagnose renal diseases of previously unknown cause, with a real prevalence probably underestimated. We present the cohort of patients identified with ADTKD in the Nephrogenetics’ clinic from the Nephrology department of our hospital from 2015 to 2022. Method Patients with chronic kidney disease (CKD) of unknown etiology and renal phenotype suggesting CIN (bland urine analysis, hyperuricemia and/or anemia unrelated to the degree of CKD, hypo/hypercalcemia, acidemia, urinary concentration defects, absent hypertension, renal cysts), especially with a family history of similar CKD, were referred for the Nephrogenetics’ clinic and ADTKD was investigated. In these cases, we performed a genetic study of ADTKD by the following steps: 1) UMOD, REN, HNF1B mutations studied through NGS; 2) if negative, search for the insertion of a single cytosine of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1 (see Kirby et al Nat Genet. 2013). It is used a restriction and Snapshot method. 3) if negative, search for HNF1B Large deletion, detected by MLPA (kit P241-D2, MRC-Holland). Pre-genetic counselling was performed by the nephrologist, and post-genetic counselling was performed by the nephrologist and geneticist, namely to proceed with family screening of potentially affected family members when a pathogenic mutation was identified or when segregation studies were necessary. Results 31 families were studied and a confirmed genetic diagnosis was obtained in 11 (35%), allowing the identification of 30 patients with ADTKD; the mutations identified were in MUC1 in 4 families (13 patients), UMOD in 4 families (11 patients), HNF1B (2 families, 5 patients) and REN: 1 patient with a phenotype compatible with ADTKD but with a genotype compatible with renal tubular dysgenesis (two mutations in REN gene from each of the parents). One patient with HNF1B deletion also presented with a heterozygous variant of unknown significance in PKD1 gene, and a pathogenic variant of SLC12A3, heterozygous. Three families are still under study: 2 families are being studied with segregation studies to evaluate the pathogenicity of mutations in UMOD (1 family) and HNF1B (1 family), and 1 family with a phenotype of ADTKD (3 young patients with positive family history) with negative results for mutations in ADTKD genes is in study, with a negative result in WES. The study will be pursued in a specialized laboratory to better study MUC1, but at this moment we classify this family as ADTKD-NOS. If positive results are obtained for these 3 families, the percentage of families identified using this protocol will increase to 43,3% of the families studied through this model. Conclusion In our cohort, a genetic diagnosis was established in 35% of the families studied. MUC1 and UMOD are the most prevalent genes implicated in ADTKD at our center, similarly to what has been reported in other cohorts of ADTKD. Given the rarity of these diseases and the fact that they require specific molecular techniques for accurate diagnosis, we believe that Nephrogenetics’ clinics with dedicated nephrologists and geneticists in close cooperation are critical for an accurate diagnosis.

#3593 COEXISTENCE OF 2 (DE NOVO) MUTATIONS IN 2 DIVERSE GENES (PKD1, LRP5) IN A PATIENT WITH RENAL AND LIVER POLYCYSTIC DISEASE

Abstract Introduction In Autosomal Dominant Polycystic Kidney Disease (ADPKD) the phenotype is variable. The most common extrarenal manifestation of the disease is the presence of hepatic cysts. Parallel cysts appearance in two different organs is possibly related to the genetic injury. We present in this report the case of a patient without family history of ADPKD and 2 different mutations related to cyst formation. Case report A 53 year old woman came to our outpatient ADPKD clinic with known multiple hepatic and renal cysts, diagnosed 11 years ago. She had no family history of ADPKD, both her parents aged 89 years old, had no renal or liver cysts on recent ultrasound scans. The patient had a background of recurrent UTIs, nephrolithiasis and hypertension diagnosed at 40 years old. Currently she was found to have e-GFR 49ml/min and liver function tests within normal range. Genetic testing and Magnetic Resonance Imaging (MRI) for estimating Total Kidney Volume (TKV) and hepatic imaging were conducted. In the genetic testing with a second generation sequencing, two heterozygous mutations in two different genes were depicted. The first was found in PKD1 gene: c.1396G>A (p.Val466Met) and causes the amino acid valine to be replaced by methionine at position 466 of the produced protein (Polycystin 1). It is reported as a variant of uncertain clinical significance because while it has been described in the literature in individuals with ADPKD, no functional studies have been performed to confirm its pathogenetic role. The second mutation concerned the LRP5 gene: c.3586G>A (p.Ala1196Thr) and causes the replacement of the amino acid alanine by threonine at position 1196 of the produced protein (Low density lipoprotein Receptor-related Protein-5). It is also referred as a variant of uncertain clinical significance, and exhibits autosomal dominant inheritance also. The MRI shows a particularly high cystic load in the liver (innumerable cysts) and multiple renal cysts in the two large kidneys, in a quite atypical form (not innumerable but many large cysts). The TKV was 1842 ml (1071 ml/m) and classified her in the class 1C (or possibly 2C because of the atypical form) according to the Mayo Clinic imaging classification system for ADPKD. The estimated prediction of the End-Stage Chronic Kidney Disease (ESCKD) (as long as the disease is not atypical) was according to the Mayo Clinic formula, 11 years. Discussion In a recent publication, pathological nucleotide variants of the LRP5 gene were associated with hepatic cystogenesis. Coexistence of PKD1 and LRP5 mutations was also identified in 2 families with polycystic kidney and liver disease. The underlying pathogenetic mechanism appears to be related to the connection between Polycystin-1 (the product of PKD1 involved in the pathogenesis of ADPKD) and the Wnt signaling pathway (affected by LRP5 gene mutations and linked to hepatic cystogenesis). The coexistence of the two mutations possibly means synergistic action. Unique facts and important phenotypic characteristics in this particular patient, is the de novo simultaneous appearance of the two mutations (the parents were not genetically tested but do not have cysts in very old age), the particularly large cystic liver load (which is also observed in typical ADPKD, especially in women), the atypical renal cyst imaging and the moderate to severe renal disease (expected ESCKD at 64 years, which it is more than expected in a PKD1 mutation only, but less than in a solitary PKD2 mutation). In conclusion, genetic complexity appears to go hand in hand with phenotype diversity in ADPKD and polycystic liver disease.

#4215 MONOALLELIC IFT140-RELATED POLYCYSTIC KIDNEY DISEASE IN AN ITALIAN ADPKD COHORT

Abstract Background and Aims Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder characterized by progressive bilateral renal cysts development and extrarenal phenotype, i.e. liver and/or pancreatic cysts, intracranial aneurism, hernias, mitral valve prolapse and diverticulosis. More than 90% of patients harbour heterozygous pathogenic variant in PKD1 or PKD2 genes, rarely in other cystogenes (e.g. GANAB, DNAJB11, ALG8, ALG9). Recently Senum et al. demonstrated that monoallelic loss of function (LoF) IFT140 variants are an important cause of ADPKD-like disease distinguished by large renal cysts, few liver cysts and mostly mild renal failure. The aim of our study was to define prevalence and phenotype of IFT140-ADPKD in an Italian ADPKD cohort. Methods The study included ADPKD patients, evaluated in 2021 and 2022, at Outpatient Clinic of Genetic Kidney Diseases of Brescia, Italy, that underwent in-depth clinical, laboratory, and instrumental assessments. ADPKD was clinically diagnosed according to Pei modified criteria, in patients with age-specific ultrasound criteria and family history consistent with autosomal dominant inheritance. From January 2022, NGS genetic testing protocol for ADPKD has been updated with IFT140 gene, thus the ADPKD gene panel included: ALG8, ALG9, ANKS6, DNAJB11, GANAB, IFT140, LRP5, PARN, PKD1, PKD2, PRKCSH, SEC61A1, SEC63. The new protocol has been offered to patients evaluated since January 2022 and to all genetically unresolved patients evaluated in 2021. All patients performed also multiple ligation probe amplification (MPLA) analysis of PKD1 or PKD2. Results In 2021 and 2022 ADPKD genes testing has been performed in 129 patients. Pathogenic variants in PKD1 or PKD2 genes were detected in 110/129 patients (85%); among the negative cases (19/129, 15%), 3 patients (P1,P2,P3) resulted heterozygous carrier of LoF variants in IFT140 gene: p.Arg307*, p.Lys1275Argfs*23 and p.Arg834* respectively. Overall 2,3% of ADPKD patients harboured IFT140 pathogenic variant; considering unresolved cases only, the prevalence was 15.7% (3/19). Segregation analysis identified the LoF variant in 3 daughters of P1 and in a son of P2. The 3 probands were diagnosed with renal disease in adulthood from fourth to sixth decade. In P1 eGFR (CKD-EPI formula) slowly declined from 104 ml/min/1.73 at onset (43 year-old) to 74.6 ml/min/1.73 at age 55. In P2 eGFR at first evaluation was 38 ml/min/1.73 (68 year-old); at last follow-up 32.9 ml/min/1.73 (73 year-old). In P3 eGFR declined from 51.7 ml/min/1.73 (55 year-old) to 42 ml/min/1.73 at age 67. Renal imaging in P1 at and P2 disclosed increased total kidney volume (TKV 1042 and 5520 cc respectively), large cysts and absence of cystic liver disease. P3 had slightly increased kidneys (TKV 447cc) with large renal cysts and few liver cysts. Hypertension was present in 4 patients, all with adult-onset (46-60 years). Two patients had an early diagnosis of kidney stones (age 24 and 18). No macroscopic hematuria or cyst infections were reported. In accordance with an ADPKD-like disease form, P1 presented inguinal hernia. Imaging data are summarized in Figure 1. Conclusion In this Italian cohort, heterozygous LoF variants in IFT140 gene is confirmed to be the third most common genetic cause of ADPKD-spectrum disease, the prevalence being 2,3%. The major features are late onset hypertension, increased kidney volume due to large cysts and slow progressive renal failure. IFT140 gene must be included in diagnostic protocol of ADPKD patients to better define renal prognosis, therapy and familial screening.

Characterization of an MLC patient carrying two MLC1 variants showing radiological improvement

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy. Approximately 75% of MLC patients have variants in MLC1, while the rest in GLIALCAM, GPRC5B and AQP4. From the GLIALCAM patients, a classical and a benign phenotype can be distinguished, in which a recessive and dominant inheritance is observed, respectively. Here, we report a new MLC patient harboring two variants in MLC1 with radiological improvement. The patient is heterozygous for the variants c.597+37C>G and c.895–1G>T affecting both mRNA splicing, and the latest causes the deletion p.Pro299_Glu353del. By analyzing mRNA and protein obtained from patient's peripheral blood leukocytes, we could demonstrate the expression of a small amount of wild-type MLC1 mRNA and protein in the patient. Thus, we suggest that the improvement of clinical and radiological abnormalities observed in all remitting MLC patients might be due to the presence of residual amounts of MLC1 protein.

De novo retinoic acid receptor beta (RARB) variant associated with microphthalmia and dystonia

BackgroundDefinition of the individual genotypes that cause a Mendelian phenotype is of great importance both to clinical diagnostics and disease characterization. Heterozygous de novo gain-of-function missense variants in RARB are associated with syndromic microphthalmia 12 (MCOPS12), a developmental disorder characterized by eye malformations and variable involvement of other organs. A subset of patients were described with poorly delineated movement disorders. Additionally, RARB bi-allelic loss-of-function variants, inherited from asymptomatic heterozygous carrier parents, have been found in a recessive family with four MCOPS12-affected members. Patient/methodsWe used trio whole-exome sequencing to explore the molecular basis of disease in an individual with congenital eye abnormality and movement disorder. All patients with reported RARB variants were reviewed. ResultsWe report on identification of a heterozygous de novo RARB nonsense variant in a girl with microphthalmia and progressive generalized dystonia. Public database entries indicate that the de novo variant is recurrently present in clinically affected subjects but a literature report has not yet been available. ConclusionsWe provide the first detailed evidence for a role of dominant RARB truncating alterations in congenital eye-brain disease, expanding the spectrum of MCOPS12-associated mutations. Considered together with the published family with bi-allelic variants, the data suggest manifestation and non-manifestation of disease in relation to almost identical RARB loss-of-function variations, an apparent paradox that is seen in a growing number of human genetic conditions associated with both recessive and dominant inheritance patterns.

Congenital mirror movements are associated with defective polymerisation of RAD51

BackgroundMirror movements are involuntary movements of one hand that mirror intentional movements of the other hand. Congenital mirror movements (CMM) is a rare genetic disorder with autosomal dominant inheritance, in...

Biochemical association of regulatory variant of KLF14 genotype in the pathogenesis of cardiodiabetic patients.

The study focuses on examining the relationship between a single nucleotide polymorphism (SNP) in KLF14 rs4731702 and risk of type 2 diabetes mellitus (T2DM) and dyslipidemia in different ethnic populations. The purpose of this study was to evaluate the association between KLF14 rs4731702 and serum lipid profile and to determine the frequency distribution of KLF14 rs4731702 among T2DM and cardiometabolic patients. A total of 300 volunteers were recruited, consisting of three groups: 100 healthy individuals, 100 individuals diagnosed with T2DM, and 100 individuals diagnosed with cardiometabolic disorders. Biochemical analysis of blood samples was conducted to assess various biomarkers related to glycemic control and lipid profile. This involved measuring levels of glucose, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and ApoA1. Genotyping analysis was performed to investigate KLF14 rs4731702 polymorphism. The Tetra ARMS-PCR method was employed for genotyping analysis. The results of biochemical profiling revealed a significant association between altered glycemic biomarkers and lipid profile in diseased patients compared to healthy participants. The frequencies of KLF14 rs4731702 alleles and genotypes were compared between the control group and T2DM group. A statistically significant difference was observed, indicating a potential association between KLF14 rs4731702 and T2DM. In the dominant inheritance model of KLF14 rs4731702 SNP, a statistically significant difference [odds ratio (95% confidence interval)] of 0.56 (0.34 -0.96) was found between the control and T2DM subjects. This suggests that the presence of certain genotypes influences the risk of T2DM. In T2DM patients, individuals carrying the C allele exhibited compromised insulin sensitivity, decreased HDL-C and ApoA1 levels, and increased serum glucose, TG, and LDL-C concentrations. Conversely, TT genotype carriers demonstrated increased levels of HDL-C and ApoA1, lower insulin resistance, serum glucose, LDL-C, and TG levels. The study's findings indicate that dyslipidemia in T2DM patients is associated with reduced KLF14 functionality due to CC and CT genotypes, leading to insulin resistance and an increased risk of cardiovascular diseases. Additionally, risk of KLF14 rs4731702 polymorphism was found to increase with age and was more prevalent in female than in male individuals. These insights contribute to understanding genetic factors influencing the development and progression of T2DM and dyslipidemia in different ethnic populations.

Novel c.2654+1G>A mutation in the CSF1R gene in a family with CSF1R‐microglial encephalopathy

AbstractBackgroundThe colony‐stimulating factor‐1 receptor (CSF1R) is a transmembrane tyrosine kinase receptor that is mainly expressed in the brain‐resident microglia. Thus, microglial dysfunction due to CSF1R mutation may play a primary and pivotal role in the pathogenesis of CSF1R‐microglial encephalopathy. Neither the functional consequences of all known CSF1R mutations nor the full genetic spectrum of mutations causing CSF1R‐microglial encephalopathy have been fully elucidated. We aimed to describe a novel heterozygous splicing variant of the CSF1R gene that caused CSF1R‐microglial encephalopathy in a Han Chinese family.MethodThe demographic data, detailed medical history, and clinical manifestations were collected from a family with CSF1R‐microglial encephalopathy. Some family members also underwent neuropsychological evaluation, structural and functional magnetic resonance imaging (MRI), and whole‐exome sequence analyses.ResultFour generations of this family, including 27 members, presented with a medical history of a dominant hereditary pattern (Figure 1). Seven of these 27 individuals had died, while five presented with similar cognitive impairments clinically, including the proband, and his sister, father, uncle, and grandmother during their life. Brain MRI of the proband (Figure 2) and his sister (Figure 3) depicted symmetric confluent and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The brother of the proband remained asymptomatic, and the structural brain MRI only revealed minimal white matter changes; however, pseudo‐continuous arterial spin labeling (pCASL) demonstrated marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum (Figure 4). Whole‐exome sequencing was performed for seven family members, which identified a novel splice‐site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members (Figure 5).ConclusionWe identified a novel splicing mutation (c.2319+1C>A) in intron 20 of CSF1R as the cause of CSF1R‐microglial encephalopathy in a Han Chinese family, which broadens the genetic spectrum of CSF1R‐microglial encephalopathy. We opine that clinically feasible pCASL techniques may be more sensitive to the alterations in CBF of associated with microglial density and cellular changes. This study highlights the potential value of pCASL techniques to improve the clinical diagnostic accuracy of CSF1R‐microglial encephalopathy.

A rare case of isolated IBM — HNRNPA2B1associated myopathy with inclusion bodies

Hereditary inclusion body myopathy (IBM) is a variant of multisystem proteinopathy. It is a generalized progressive disease with autosomal recessive or autosomal dominant inheritance, characterized by the development of a degenerative process in muscle fi bers due to the accumulation of rimmed vacuoles and nuclear intermediate fi laments. This article presents a clinical observation of a rare variant of IBM — HNRNPA2B1-associated myopathy with a phenotypically diverse picture in representatives of one family from diff erent generations.

Elevated levels of mosaic aneuploidy in brain cells and fibroblast cell lines from human Huntington’s disease donors and in brain cells from Huntington’s disease mouse models

AbstractBackgroundHuntington’s disease (HD) is a progressive neurodegenerative disorder that presents with motor and cognitive deficits and psychiatric disturbances. HD is associated with autosomal dominant inheritance of a CAG trinucleotide repeat expansion mutation in the huntingtin (HTT) gene. The huntingtin protein localizes to spindle poles and is required for proper mitotic spindle orientation, chromosome segregation, and cell cycle regulation. The mature mutant huntingtin protein has an expanded polyglutamine region (>35 repeats) near its N terminus, which leads to neuronal dysfunction and death. Mouse models of HD exhibit defects in microtubule function and cell cycle regulation. Studies from our laboratory and others have shown elevated levels of aneuploidy in many neurodegenerative disorders characterized by cognitive deficits, including Alzheimer’s disease and frontotemporal lobar degeneration. Here, we investigated whether chromosome segregation defects that lead to mosaic aneuploidy and consequent apoptosis may also contribute to neuronal loss in HD.MethodsSingle‐cell suspensions from cortex and cerebellum from human HD donors were analyzed using FISH for chromosome 21, NeuN immunostaining, and/or TUNEL staining. Fibroblast cell lines from human HD donors were also analyzed using FISH. Single‐cell suspensions from cortex and cerebellum from HD mouse models were analyzed using FISH for chromosomes 5 and 16. Cell cycle arrest, mitotic spindle defects, ploidy, and apoptosis profiles in the HD fibroblast cell lines are being analyzed by flow cytometry and immunofluorescence microscopy.ResultsIncreased levels of mosaic aneuploidy and apoptosis were observed in brain cells and in fibroblast cell lines from HD donors compared to age‐matched healthy control donors. Increased levels of mosaic aneuploidy were also observed in brain cells from HD mice compared to age‐matched wild‐type control mice. Results of ongoing studies of cell cycle and mitotic defects will also be presented.ConclusionsTaken together with the results of our previous studies, these data provide evidence that chromosome segregation defects that lead to genomic instability may serve as a shared mechanism underlying many neurodegenerative disorders. Our findings highlight the need to further investigate the biological mechanism(s) that contribute to HD pathology and set the stage for novel therapeutic approaches to HD that may also be applied to other neurodegenerative disorders.