Recessive Inheritance Research Articles

Seizure solver- pyridoxine dependent seizures

Pyridoxine dependency is a rare cause of seizures. Pyridoxine dependent seizures (PDS) occur despite normal vitamin B6 levels and is due to defective binding of pyridoxine to its apoenzyme, glutamate decarboxylase, which converts glutamic acid to gamma aminobutyric acid (GABA). Pyridoxine-dependent seizure is a rare autosomal recessive disorder that usually presents with neonatal intractable seizures. Parenteral pyridoxine injection test is a highly effective and reproducible test in confirming the diagnosis. Hunt, et al.(l) described the first case of PDS with autosomal recessive inheritance. Since then, several cases have been reported with onset of seizures after neonatal period (2-6). Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is characterized by seizures not well controlled with anti-seizure medication that are responsive clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). This is true across a phenotypic spectrum that ranges from classic to atypical PDE-ALDH7A1. Intellectual disability is common, particularly in classic PDE-ALDH7A1.(7)

Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1

Canine multiple system degeneration (CMSD) is an early onset, progressive movement disorder affecting Kerry Blue Terriers and Chinese Crested dogs. The associated pathologic lesions include degeneration of the cerebellum, caudate nucleus, and substantia nigra. CMSD is inherited as an autosomal recessive trait in both dog breeds. Previous linkage mapping localized the CMSD locus to a 15 MB region on canine chromosome 1 (CFA1). Next-generation sequencing was used to generate whole-genome sequences from the DNA of an affected dog from each breed. The resulting sequence reads were aligned to the NCBI canine reference genome (build 3.1). Among the homozygous sequence variants within the CFA1 target region, a nonsense variant in exon 15 of SERAC1 was identified in the affected Kerry Blue Terrier, while in the Chinese Crested dog, a 4 bp deletion in the SERAC1 exon 4 acceptor splice site was found. RT-PCR showed that this deletion resulted in exon 4 skipping. Genotyping of large cohorts of Kerry Blue Terriers and Chinese Crested dogs for the respective breed-specific SERAC1 variants showed complete concordance between genotype and disease phenotype. Genotype–phenotype concordance was also observed in offspring generated by cross breeding between SERAC1-heterozygous Kerry Blue Terrier and Chinese Crested dogs, with only the compound heterozygotes exhibiting the disease phenotype, further confirming the recessive inheritance of CMSD. Variants in human SERAC1 are associated with disorders with a range of ages of disease onset and patterns of clinical signs, but that are all characterized by movement abnormalities similar to those of the dogs with CMSD. Canine CMSD could serve as a valuable model to elucidate the mechanisms underlying SERAC1-deficiency disorders and to evaluate potential therapeutic interventions.

Intragenic duplication disrupting the reading frame of MFSD8 in Small Swiss Hounds with neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis (NCL) represents a heterogenous group of lysosomal storage diseases resulting in progressive neurodegeneration. We investigated two Small Swiss Hound littermates that showed progressive ataxia and loss of cognitive functions and vision starting around the age of 12 months. Both dogs had to be euthanized a few months after the onset of disease owing to the severity of their clinical signs. Pathological investigation of one affected dog revealed cerebral and cerebellar atrophy with cytoplasmic accumulation of autofluorescent material in degenerating neurons. The clinical signs in combination with the characteristic histopathology led to a tentative diagnosis of NCL. In the subsequent genetic investigation, the genome of one affected dog was sequenced. This revealed a duplication of 18 819 bp within the MFSD8 gene. The duplication breakpoints were located in intron 3 and exon 12 of the gene and were predicted to disrupt the reading frame. Both affected dogs carried the duplication in a homozygous state and there was perfect cosegregation of the genotypes with the phenotype in a large pedigree, consistent with autosomal recessive inheritance. MFSD8 loss-of-function variants are a known cause of NCL7 in human patients, dogs and other mammalian species. The existing knowledge on MFSD8 together with the experimental data strongly suggests that the identified intragenic MFSD8 duplication caused the disease in the Small Swiss Hounds. These results allow their diagnosis to be refined to NCL7 and enable genetic testing in the breed to avoid further unintentional carrier × carrier matings.

FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature.

Background/Objectives: The genetic underpinnings of Parkinson's disease (PD) and parkinsonism have drawn increasing attention in recent years. Mutations in the Factor-Induced Gene 4 (FIG4) have been implicated in various neurological disorders, including Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis (ALS), and Yunis-Varón syndrome. This review aims to explore the association between FIG4 mutations and parkinsonism, with a specific focus on the rare missense mutation p.Ile41Thr (I41T). Methods: We identified 12 cases from 10 different families in which parkinsonism was reported in conjunction with CMT4J polyneuropathy. All cases involved the I41T mutation in a compound heterozygous state, combined with a FIG4 loss-of-function mutation. Data from clinical observations, neuroimaging studies, and genetic analyses were evaluated to understand the characteristics of parkinsonism in these patients. Results: In all 12 cases, parkinsonism developed either concurrently or following the onset of CMT4J neuropathy, but was never observed in isolation. Cases of both early- and late-onset parkinsonism were identified, reflecting similarities to genetic forms of parkinsonism with autosomal recessive inheritance. Imaging studies, including Dopamine transporter Single Photon Emission Computed Tomography (DaTscan) and brain magnetic resonance imaging (MRI), revealed abnormalities indicative of neurodegeneration, consistent with findings in other neurodegenerative disorders. Conclusions: The co-occurrence of parkinsonism with CMT4J in patients carrying the I41T mutation suggests an expanded spectrum of FIG4-related disorders, potentially implicating the same molecular mechanisms seen in other neurodegenerative disorders. Further research into FIG4-mediated pathways may offer valuable insights into potential therapeutic targets for disorders of both the central and peripheral nervous systems.

Genetic heterogeneity in autosomal recessive hearing loss: a survey of Brazilian families

IntroductionHearing loss is a frequent sensory impairment type in humans, with about 50% of prelingual cases being attributed to genetic factors. Autosomal recessive hearing loss (ARHL) exhibits great locus heterogeneity and is responsible for 70%–80% of hereditary nonsyndromic cases.MethodsA total of 90 unrelated Brazilian individuals were selected for having hearing loss of presumably autosomal recessive inheritance, either born from consanguineous marriages or belonging to families with two or more affected individuals in the sibship and most cases were of normal hearing parents. In all cases, common pathogenic variants in GJB2 (c.35delG), GJB6 [del(GJB6-D13S1830) and del(GJB6-D13S1854)] and MT-RNR1 (m.1555A>G) were discarded and most were previously assessed by complete Sanger sequencing of GJB2. Their genetic material was analyzed through next-generation sequencing, targeting 99 hearing loss-related genes and/or whole exome sequencing.ResultsIn 32 of the 90 probands (36,7%) causative variants were identified, with autosomal recessive inheritance confirmed in all, except for two cases due to dominant variants (SIX1 and P2RX2). Thirty-nine different causative variants were found in 24 different known hearing loss-associated genes, among which 10 variants are novel, indicating wide genetic heterogeneity in the sample, after exclusion of common pathogenic variants. Despite the genetic heterogeneity, some genes showed greater contribution: GJB2, CDH23, MYO15A, OTOF, and USH2A.ConclusionThe present results confirmed that next-generation sequencing is an effective tool for identifying causative variants in autosomal recessive hearing loss. To our knowledge, this is the first report of next-generation sequencing being applied to a large cohort of pedigrees with presumable autosomal recessive hearing loss in Brazil and South America.

Expanding the genetic spectrum of hereditary motor sensory neuropathies in Pakistan

BackgroundHereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis.MethodsFamilies from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen’s h.ResultsWES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies.ConclusionsThis study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families.

Скачена с x-хромозомата рецесивна наследственост интердисциплинарен урок по биология, история и английски език

The lesson “X-linked recessive inheritance” is interdisciplinary, part of the curriculum of the innovative subject of Science and technology. It is based on Content Language Integrated Learning and not only combines subject content and foreign language skills, but unites more than one scientific field. In our case, we examined a biological process through the lens of the English language and in a historical context. This provided a deeper understanding of the processes in our surroundings, proving that nothing operates in isolation, but in constant and predictable connections with the world around us. The topic deals with basic concepts of genetics in English, tracing the ability of recessive genes on the X-chromosome to be inherited only by the female descendants. We worked with VIII grade students, for whom this lesson was their first encounter with genetics. The content of all lesson material is adapted to the age and grade of the students.

A Novel Homozygous Variant in CPLANE1 Gene in a Patient with Developmental Deficits

Background: Oral-facial-digital syndrome (OFDS) type 6 is a rare subtype of Joubert syndrome characterized by orofacial anomalies and polydactyly with neurological features of Joubert syndrome. This rare syndrome is divided into thirteen subtypes, all of which demonstrate autosomal recessive inheritance, except for OFDS type 1 which demonstrates X-linked dominant inheritance. Case Presentation: A 19-year-old man with mild developmental delay was brought to a rural community clinic, as he had become irritable and angry, in the recent past. There was no history of prior medical conditions. In view of orofacial anomalies, and developmental deficits, a genetic analysis was requested. Karyotype analysis revealed a normal male karyotype (46,XY) in all 30 metaphase spreads analyzed. No numerical or structural chromosomal abnormalities were observed. Clinical exome sequencing and chromosomal microarray detected a variant of uncertain significance in exon 5 of CPLANE1 gene c.365T>G (p.Val122Gly) leading to substitution of Glycine for Valine. This was confirmed by Sanger sequencing. Parents were heterozygous, and the unaffected sibling was homozygous for the wild-type allele. This variant has not been reported earlier in the mutation databases or gnomAD. Runs of homozygosity (ROH) analysis showed a 3.2 Mb ROH around the CPLANE1 gene in the proband, which was absent in both parents and the unaffected sibling. Conclusion: We find a novel homozygous mutation in the CPLANE1 gene in a patient of non-consanguineous parentage with atypical orofacial features. This suggests that potentially deleterious, rare variants may occur in the heterozygous state in the population. Hence, sequencing of population samples might help understand the genetic epidemiology of rare syndromes.

Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia.

Variation in the non-coding genome represents an understudied mechanism of disease and it remains challenging to predict if single nucleotide variants, small insertions and deletions, or structural variants in non-coding genomic regions will be detrimental. Our approach using complementary RNA-seq and targeted long-read DNA sequencing can prioritize identification of non-coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the SPAG1 gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern. RNA sequencing revealed reduced SPAG1 transcript levels and exclusive allele specific expression of the known pathogenic allele, suggesting the presence of a non-coding variant on the second allele that impacts transcription. Targeted long-read DNA sequencing identified a heterozygous 3 kilobase deletion of the 5' untranslated region of SPAG1, overlapping the promoter and first non-coding exon. This non-coding deletion was missed by whole exome sequencing and gene-specific deletion/duplication analysis, highlighting the importance of investigating the non-coding genome in patients with "missing" disease-causing variation. This paradigm demonstrates the utility of both RNA and long-read DNA sequencing in identifying pathogenic non-coding variants in patients with unexplained genetic disease.

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.

Genomic instability disorders are characterized by DNA or chromosomal instability resulting in various clinical manifestations including developmental anomalies, immunodeficiency, and increased risk to develop cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association of Cancer Research held the second Childhood Cancer Predisposition Workshop where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article will discuss childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, Xeroderma Pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anti-cancer therapy.

XMEN-associated Systemic EBV-positive T-cell Lymphoma of Childhood: Report of Two Cases and Literature Review.

X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) is an extremely rare inborn error of immunity (IEI) caused by X-linked recessive inheritance and loss-of-function mutations in the MAGT1 gene, resulting in magnesium ion channel defects. This article reports 2 cases of systemic EBV-positive T-cell Lymphoma of childhood (SETLC) associated with XMEN, which have not been reported before. Whole exome sequencing (WES) in their family revealed previously unreported MAGT1 gene mutations (c.77T>C, p.I26T; c.956-957del: p.Ser319Tyrfs) inherited from their mothers. These mutations expand the spectrum of gene mutations in XMEN disease. The importance of genetic testing for MAGT1 mutations in the initial diagnosis of SETLC was emphasized. We also review the literature on this uncommon IEI.

DNAH17 deficiency causes disruption in the assembly and docking of sperm flagellar ODAs but not total fertilization failure after ICSI

Research questionAre there other variants in DNAH17 related to male infertility? What is the correlation between total fertilization failure and DNAH17 deficiency? DesignWhole-exome sequencing and Sanger sequencing were performed in a cohort of 75 Chinese patients with MMAF to identify potential novel gene variants. Papanicolaou staining and electron microscopy were employed to observe sperm morphology and ultrastructure. Proteomic analysis and comprehensive functional analysis were performed to elucidate the relationship between DNAH17 deficiency and total fertilization failure at the molecular level. ResultsTen novel variants in DNAH17 were identified in five unrelated families with six infertile males. These identified variants exhibited an autosomal recessive inheritance pattern and caused the deficiency of DNAH17 in sperm. Papanicolaou staining and electron microscopy demonstrated typical MMAF characteristics and deformations in flagellar ultrastructure of DNAH17-deficient sperm. Furthermore, our comprehensive functional analysis revealed that DNAH17 deficiency impaired the assembly and docking of ODAs, affected the acrosome reaction, and disrupted mitochondrial function. Interestingly, the fertilization-related proteins such as ACTL7A and PICK1 were normal, while reduced yet ≥30% PLCζ levels were detected, implying an indirect correlation between DNAH17 deficiency and total fertilization failure. Moreover, four of the affected couples got transferable embryos successfully through intracytoplasmic sperm injection (ICSI) without artificial oocyte activation (AOA). ConclusionsOur findings significantly broaden the variant spectrum of DNAH17 and illuminate the complex molecular basis of male infertility associated with DNAH17 deficiency, particularly its heterogeneous impact on fertilization. The favourable fertility outcomes of ICSI will provide vital insights for genetic diagnosis and counselling in males affected by MMAF.

Spectrum of Leukodystrophy and Genetic Leukoencephalopathy in Indian Population Diagnosed by Clinical Exome Sequencing and Clinical Utility.

Next-generation sequencing (NGS) has expedited the diagnostic process and unearthed many rare disorders in leukodystrophy (LD) and genetic leukoencephalopathy (gLE). Despite the progress in genomics, there is a paucity of data on the distribution of genetic white matter disorders (WMDs) and the diagnostic utility of NGS-based assays in a clinical setting. This study was initiated to explore the clinical, radiologic, and genetic spectrum of LD and gLE in the Indian population and also to estimate the diagnostic yield of clinical exome sequencing (CES). This is a retrospective descriptive analysis of patients with a diagnosis of genetic WMDs from a single tertiary referral center who had CES performed as part of the diagnostic evaluation between January 2016 and December 2021. The demographic, clinical, radiologic, and genetic data were collected. The variants were classified using the American College of Medical Genetics and Genomics criteria. Pathogenic and likely pathogenic variants were included in the calculation of the diagnostic yield. In the study period, 138 patients were clinically diagnosed with either LD or gLE, of which 86 patients underwent CES. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance with phenotype match were seen in 40 (41.8%), 13 (29.1%), and 15 (15.2%) patients, respectively. The mean age at onset in these 68 patients was 6.35 years (range 1 month-39 years), and 38 (55.9%) were male. LDs and gLE were diagnosed in 31 and 37 patients, respectively. 56 patients (71.8%) had autosomal recessive inheritance. The common clinical presentations were developmental delay (23.5%), psychomotor regression (20.6%), progressive myoclonic epilepsy syndrome (19.1%), and spastic ataxia (14.7%). Myelin disorders (48.5%) and leuko-axonopathies (41.2%) were the commonest type of disorders. The most frequently identified genes were ARSA, CLN5, ABCD1, CLN6, TPP1, HEXA, and L2HGDH. The diagnostic yield of the study was 61.6% (53/86), which increased to 79.1% when VUS with phenotype match were included. This study demonstrated a high diagnostic yield from proband-only CES in the evaluation of genetic WMDs and should be considered as a first-line investigation for genetic diagnosis. This study provides Class IV evidence that proband-only clinical exome sequencing is a useful "first-line investigation" for patients with genetic white matter disorders.

N-glycoproteomic and proteomic alterations in SRD5A3-deficient fibroblasts.

SRD5A3-CDG is a congenital disorder of glycosylation (CDG) resulting from pathogenic variants in SRD5A3 and follows an autosomal recessive inheritance pattern. The enzyme encoded by SRD5A3, polyprenal reductase, plays a crucial role in synthesizing lipid precursors essential for N-linked glycosylation. Despite insights from functional studies into its enzymatic function, there remains a gap in understanding global changes in patient cells. We sought to identify N-glycoproteomic and proteomic signatures specific to SRD5A3-CDG, potentially aiding in biomarker discovery and advancing our understanding of disease mechanisms. Using tandem mass tag (TMT)-based relative quantitation, we analyzed fibroblasts derived from five patients along with control fibroblasts. N-glycoproteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 3,047 glycopeptides with 544 unique N-glycosylation sites from 276 glycoproteins. Of these, 418 glycopeptides showed statistically significant changes with 379 glycopeptides decreased (P<0.05) in SRD5A3-CDG patient-derived samples. These included high mannose, complex and hybrid glycan-bearing glycopeptides. High mannose glycopeptides from protocadherin Fat 4 and integrin alpha-11 and complex glycopeptides from CD55 were among the most significantly decreased glycopeptides. Proteomics analysis led to the identification of 5,933 proteins, of which 873 proteins showed statistically significant changes. Decreased proteins included cell surface glycoproteins, various mitochondrial protein populations and proteins involved in the N-glycosylation pathway. Lysosomal proteins such as N-acetylglucosamine-6-sulfatase and procathepsin-L also showed reduced levels of phosphorylated mannose-containing glycopeptides. Our findings point to disruptions in glycosylation pathways as well as energy metabolism and lysosomal functions in SRD5A3-CDG, providing clues to improved understanding and management of patients with this disorder.

Association of β1- and β2-Adrenergic Receptor Gene Polymorphisms with the Effectiveness of Bisoprolol and Carvedilol in Patients with Heart Failure of Ischemic Etiology

The aim. To study the relationship between β1-, β2-adrenergic receptor (β-AR) gene polymorphisms and the effectiveness of bisoprolol and carvedilol in patients with heart failure (HF) and coronary heart disease. Materials and methods. We examined 201 patients with HF on the background of post-infarction cardiosclerosis. Control group included 43 healthy individuals of comparable age and sex. Genotyping was carried out for 3 polymorphisms (rs1801253 and rs1801252 of the β1-AR gene; rs1042714 of the β2-AR gene). The patients were divided into 2 groups: the first group included 104 (51.7%) patients who took bisoprolol during the year of observation; 97 (48.3%) patients of the second group were treated with carvedilol. Statistical analysis was performed using Statistica 10.0 and SNPStats programs. Results. In patients with HF, the mutant C-allele (rs1801253 polymorphism) of the β1-AR gene was associated with a decrease in the probability of heart rate reduction &gt;15 min-1 against the background of the use of β-blocker during the year (odds ratio [OR] = 0.42 [0.16-0.98], p = 0.041, recessive inheritance model; OR = 0.62 [0.40-0.97], p = 0.038; log-additive inheritance model). The probability of positive dynamics of the left ventricular ejection fraction (LVEF) increased in carriers of the wild A-allele of the rs1801252 (Ser49Gly) polymorphism of the β1-AR gene (OR = 4.86 [2.35-10.08], p &lt; 0.0001, codominant model; OR = 5.18 [2.51-10.68], p &lt; 0.0001, dominant model; OR = 4.68 [2.26-9.68], p &lt; 0.0001, over-dominant model; OR = 5.05 [2.48-10.28], p &lt; 0.0001, log-additive inheritance model). The probability of an increase in LVEF within a year increased with treatment with carvedilol in homozygous mutant G/G rs1042714 polymorphism (Gln27Glu) of the β2-AR gene in patients with HF (OR = 6.09 [1.16-31.88], p = 0.038, dominant inheritance model). Conclusions. Patients with HF of ischemic etiology, carriers of the mutant C-allele of rs1801253 polymorphism of the β1-adrenoceptor gene, are worse responders to the use of β-blockers compared to patients with the wild G-allele (a lower proportion of patients with a decrease in heart rate &gt;15 min-1: 6.8% vs. 14.5%, respectively; OR = 0.42 [0.16-0.98], p = 0.041). The frequency of an increase in the value of the LVEF &gt;10% was higher compared to patients with the mutant G-allele (39.3% vs. 11.1%, respectively; OR = 4.86 [2.35-10.08], p &lt; 0.0001) against the background of application of β-blockers. The use of carvedilol was more appropriate in homozygous carriers of the mutant G-allele of the rs1042714 polymorphism (Gln27Glu) of the β2-AR gene compared to bisoprolol (a greater proportion of patients with an increase in the LVEF: 17.6% vs. 9.1%, respectively; OR = 6.09 [1.16-31.88], p = 0.038). No probable associations of rs1801253 and rs1801252 polymorphisms of the β1-AR gene with the pharmacodynamics of bisoprolol and carvedilol in patients with HF of ischemic etiology were found.

A comprehensive review of Alport syndrome: definition, pathophysiology, clinical manifestations, and diagnostic considerations.

Alport syndrome, a rare genetic disorder affecting around 1 in 50,000 individuals, primarily presents as microscopic hematuria and chronic kidney disease (CKD) with associated extrarenal complications. The Alport syndrome results from mutations in COL4A3, COL4A4, and COL4A5 genes, disrupting the formation of the α3-α4-α5 chain in the collagen IV network. The etiology involves X chromosome-related, autosomal dominant, autosomal recessive, and digenic inheritance patterns. The disease primarily manifests as kidney involvement, featuring persistent hematuria, proteinuria, and a progressive decline in renal function. Hearing loss, ocular abnormalities, and extrarenal manifestations further contribute to its complexity. Genotype-phenotype correlations are relatively evident, with distinct presentations in X-linked, autosomal recessive, and autosomal dominant cases. Diagnosis relies on urinalysis, histologic examination, and genetic testing with advancements in next-generation sequencing aiding identification. Although no specific treatment exists, early diagnosis improves outcomes, emphasizing the importance of genetic testing for prognosis and familial screening. The purpose of this review is to advance knowledge and enhance understanding of Alport syndrome.

Investigation of Transcription Factor and Cytokine Gene Expression Levels in Helper T Cell Subsets Among Turkish Patients Diagnosed with ICF2 (Novel ZBTB24 gene Variant) and ICF3 (CDCA7 Variant) Syndrome.

Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF), is a rare disease with autosomal recessive inheritance. ICF syndrome. It has been reported that ICF syndrome is caused by mutations in the DNMT3B (ICF1), ZBTB24 (ICF2), CDCA7 (ICF3), and HELLS (ICF4) genes. As a result of literature research, there are no studies on transcription factor and cytokine expressions of helper T cell subsets in ICF syndrome. In the study; Th1 (TBET, STAT1, STAT4), Th2 (GATA3, STAT6), Th17 (RORgt, STAT3), Treg (FoxP3, STAT5) transcription factors and the major cytokines of these cells (Th1; IFNG, Th2; IL4, Th17; IL17A-21-22, Treg; IL10, TGFβ) expressions were aimed to be evaluated by qRT-PCR. Patients (ICF3: three patients; ICF2: two patients), six heterozygous individual and five healthy controls were included in the study. All patients had hypogammaglobulinemia. Except for the CD19 cells of P2 from patients diagnosed with ICF3, the CD3, CD4, CD8, and CD19 cells in the other ICF3 patients were normal. However, the rates of these cells were low in patients with ICF2 syndrome. Factors belonging to patients' Th1, Th17 and Treg cells were significantly lower than the control. Additionally, novel mutation was detected in ZBTB24 gene (c.1121-2A > T). Our study is the first molecular study on Th cell subsets in patients with ICF syndrome and a new mutation that causes ICF2 syndrome has been identified.

Genetic profile of progressive myoclonic epilepsy in Mali reveals novel findings.

Progressive myoclonic epilepsy (PME) is a group of neurological disorders characterized by recurrent myoclonic seizures with progressive neurological deterioration. We investigated the genetics of three unrelated patients with PME from Mali, a country in sub-Saharan Africa highly underrepresented in genetic and genomic research. Participants were carefully examined and phenotyped. DNA was obtained for genetic analysis including whole exome sequencing (WES). In silico prediction tools and ACMG criteria were used to assess the deleteriousness of putative candidate variants. Pedigree analysis suggests autosomal recessive inheritance patterns for one family and sporadic forms of PME for the two other cases. WES identified novel homozygous missense variants in all the three patients, one each for NHLRC1, EPM2A, and NEU1. The sequence variants segregated with PME in each family and in silico studies including protein 3D structures, CADD scores and ACMG criteria suggested that they were damaging. PME is a group of clinically heterogeneous neurological disorders. Most reported cases in the literature are from European background with only a few cases described in North Africa. We report here novel pathogenic variants in three different genes causing PME phenotypes in three unrelated Malian patients, suggesting that genetic studies of underrepresented populations may expand the genetic epidemiology of PME. These findings also emphasize the need for inclusive genetic research to ensure a more targeted diagnostic and therapeutic approaches for diverse patient populations.

McArdle's Disease: A Differential Diagnosis of Metabolic Myopathies.

McArdle's disease, also known as glycogen storage disease type V or McArdle syndrome, is a pure muscle myopathy with an autosomal recessive inheritance pattern. It is caused by mutations in the gene that encodes muscle phosphorylase. Symptoms typically begin in late adolescence or early adulthood, presenting as exercise intolerance. This review focuses on the diagnosis of McArdle's disease, initially manifesting as a clinical picture of rhabdomyolysis in an 18-year-old male patient with a history of minor thalassemia who had been followed in pediatric consultation since age three for failure to thrive. After excluding common causes such as alcohol consumption, drug use, traumatic muscle compression, and other conditions, the diagnosis of McArdle's disease was considered. The diagnosis was supported by laboratory tests showing myoglobinuria and elevated creatine kinase levels, as well as the absence of increased serum lactate following ischemic exercise. Genetic testing confirmed the presence of mutations in the PYGM gene, corroborating the diagnosis. Treatment includes administering a diet rich in slow-absorbing carbohydrates, regular low-intensity physical exercise, and, in some cases, supplementation with vitamin B6 and creatine. The prognosis is generally favorable with proper disease management, although vigorous exercise should be avoided to prevent complications such as severe muscle injury and rhabdomyolysis. Although McArdle's disease is a rare condition, it is likely underdiagnosed. Ideally, it should be considered in the differential diagnosis of rhabdomyolysis in all patients with symptoms of exercise intolerance and/or recurrent myoglobinuria.

Genetic Basis of Hearing Loss in Mongolian Patients: A Next-Generation Sequencing Study.

The genetic landscape of sensorineural hearing impairment (SNHI) varies across populations. In Mongolia, previous studies have shown a lower prevalence of GJB2 mutations and a higher frequency of variants in other deafness-related genes. This study aimed to investigate the genetic variants associated with idiopathic SNHI in Mongolian patients. We utilized the next-generation sequencing for investigating the causative mutations in 99 Mongolian patients with SNHI. We identified pathogenic variants in 53 of the 99 SNHI patients (54%), with SLC26A4 being the most frequently mutated gene. The c.919-2A>G variant in SLC26A4 was the most prevalent, accounting for 46.2% of the mutant alleles. In addition, we identified 19 other known and 21 novel mutations in a total of 21 SNHI genes in autosomal recessive or dominant inheritance patterns. Our findings expand the understanding of the genetic landscape of SNHI in Mongolia and highlight the importance of considering population-specific variations in genetic testing and counseling for SNHI.