Dominant Inheritance Research Articles

Genetic study of inherited peripheral neuropathy disease (Charcot–Marie Tooth) disease

Background Charcot-Marie-Tooth disease (CMT) is the most common hereditary neuromuscular disorder. Charcot-Marie-Tooth disease can be caused by mutations in many different genes. These genes provide instructions for making proteins involved in the functioning of the peripheral nerves of the feet, legs, and hands. Peripheral myelin protein 22 (PMP22) related neuropathies account for over 50% of inherited peripheral neuropathies. Agene copy variation results in CMT1A (duplication of 17p11.2.p12) and hereditary neuropathy with liability to pressure palsies (HNPP; single deletion). Point mutation comprise both phenotypes. The underlying pathological mechanisms are incompletely understood and biallilic mutations of PMP22 are very rare. Objective To study clinical characteristics of a cohort of Egyptian patients with CMT; frequency of PMP22 gene duplication and deletion by MLPA and molecular diagnosis. Methodology We applied our study on 97 Egyptian patients from 70 unrelated families with suspected CMT disease, patients were referred from different provinces to Ain Shams neuromuscular outpatient clinic. After an informed and written consent, all patients were examined neurologically and systemically. Diagnosis was based on clinical symptoms, electromyography and genetic study. Results Clinical classification of our patients revealed high incidence rate of AR CMT type patients (43.3%) and sporadic cases (39.3%), while AD CMT type represents (17.5%), the cause of the high rate of negative family history of same disease affection may be for many reasons mild subclinical expression in other family members, autosomal recessive inheritance, or a de novo heterozygous pathogenic variant in a gene associated with autosomal dominant inheritance. Neurophysiological classification according to median NCV shows that 53 patients (51.5%) have axonal sensory-motor affection with median NCV <38 m/s, 26 patients (26.8%) have demyelinating CMT type, and 19 patients (19.6%) have intermediate type (mixed axonal and demyelinating affection with median NCV range between 35 m/s to 45 m/s. Thus the commonest form is CMT 2 (axonal AR type) followed by CMT 4 (demyelinating AR type) with lower incidence of CMT 1 (demyelinating AD type). Conclusion from our study we concluded that (AR CMT type) is not uncommon in Egypt because of the high prevalence of consanguinity, and that PMP22 duplication is not a common cause of Egyptian inherited neuropathy disease.

LB1721 A novel pathogenic TPCN2 mutation detected for the first time in a Caucasian patient confirms the dominant inheritance of albinism

LB1721 A novel pathogenic TPCN2 mutation detected for the first time in a Caucasian patient confirms the dominant inheritance of albinism

Association between Eating Patterns and Quality of Life in Patients with Familial Hypercholesterolemia.

(1) Background: Familial hypercholesterolemia (FH) is a genetic disease that has autosomal dominant inheritance, being characterized by increased levels of low-density lipoproteins (LDLs) due to a decreased clearance of the circulant LDLs. Alimentation is a key factor in patients with FH. Implementing a restrictive diet may have a significant impact on their quality of life, besides the social and environmental factors. (2) Methods: We realized a prospective study that was conducted in the Cardiovascular Rehabilitation Clinic from the Clinical Rehabilitation Hospital and that included 70 patients with FH and 20 controls (adults with no comorbidities). We evaluated their lipid profile, their quality of life through the Short Form-36 Questionnaire, and their eating habits. (3) Results: Lower scores in the quality-of-life questionnaire were obtained in the FH group both in the case of the physical (73.06 vs. 87.62) and the mental component (75.95 vs. 83.10). Women had better physical function (85 vs. 75) and physical role than men (100 vs. 75). The group aged over 65 has the score lowest for all 10 components. Overeating was driven by boredom and was more frequent on weekends in the FH group. None of the patients in the control group felt loneliness or depression associated with overeating. (4) Conclusions: Overeating in patients with FH is associated with a lower quality of life. The complexity of these patients needs a multidisciplinary approach. Thus, the quality-of-life questionnaire should be implemented in their periodic follow-ups in order to increase their general status, paying special attention to geriatric patients.

Family and literature analysis demonstrates phenotypic effect of two variants in the calpain-3 gene

Both, recessive (LGMD R1) and dominant (LGMD D4) inheritance occur in calpain 3-related muscular dystrophy. We report a family with calpain-related muscular dystrophy caused by two known variants in the calpain 3 gene (CAPN3, NM_000070.3; (I) c.700G>A, p.Gly234Arg and (II) c.1746-20C>G, p.?). Three family members are compound heterozygous and exhibit a relatively homogeneous phenotype characterized by progressive proximal weakness starting in the third to fourth decade of life in the shoulder girdle and spreading to the legs. Two family members affected only by the p.Gly234Arg heterozygous missense variants show a different phenotype characterized by severe exertional myalgia without overt pareses. We conclude that in our family, the missense variant causes a severe myalgic phenotype without pareses that is aggravated by the second intronic variant and put these findings in the context of previous studies of the same variants.

Identification of novel variants in Turkish families with non-syndromic congenital cataracts using whole-exome sequencing.

The present study aimed to identify the molecular etiology of non-syndromic congenital cataract (CC) using whole-exome sequencing (WES) analysis. In the present study, ophthalmologic results and pedigree analysis of the families of 12 patients with non-syndromic CC were evaluated. WES analysis was conducted after DNA was isolated from peripheral blood samples obtained from the patients. Twelve non-syndromic probands (10 males and 2 females) with bilateral CC were included in the study. Patient age ranged between 1 and 11months. WES analysis showed pathogenic/likely pathogenic variant in 7 (58%) of the 12 families and variant of unknown significance (VUS) in 5 (42%) of them. All the 13 different variants detected in 9 different CC-related genes were co-segregated with the disease. Autosomal dominant inheritance was found in 7 (58%) of the families and autosomal recessive inheritance was found in 5 (42%) of them. To the best of our knowledge, the present research is one of the limited numbers of studies in the Turkish population in which genetically heterogeneous non-syndromic CC was investigated using WES analysis. Novel variants that we identified in DNMBP, LSS, and WFS1 genes, which are rarely associated with the CC phenotype, have contributed to the mutation spectrum of this disease. Identifying the relevant molecular genetic etiology allows accurate genetic counseling to be provided to the families.

A Novel Heterozygous TGFBI c.1613C>A Pathogenic Variant is Associated With Lattice Corneal Dystrophy in a Chinese Family

To investigate the gene mutations and relationship of clinical manifestation in a Chinese family with familial lattice corneal dystrophy (LCD). Single-family case-control study. A family with familial LCD was recruited for this study. A total of 10 affected and 13 healthy family members participated in this research. Clinical features were examined by slit-lamp examination and anterior segment optical coherence tomography (AS-OCT). Peripheral blood samples were collected from each participant, and genomic DNA was extracted. Whole-exome sequencing (WES) analysis was performed, and the pathogenic variants of LCD were identified using bioinformatics tools and confirmed by Sanger sequencing. Slit-lamp examination revealed diffuse grayish-white punctate, linear, and "lattice-like" opacities in the corneal epithelium and superficial corneal stroma. AS-OCT revealed an irregularly shaped cornea. The corneal epithelium and anterior corneal stroma showed high-reflective deposits and bulges. The clinical appearance of the patients fit the pattern and features of autosomal dominant inheritance of LCD type I (LCD I). A novel pathogenic variant of exon 12 in TGFBI was found by WES analysis, in which cytosine at position 1613 was substituted by adenine (c.1613C>A), and the amino acid was changed from threonine to lysine (p.T538K). Mutated genes and proteins were predicted to be deleterious. A novel heterozygous pathogenic variant (c.1613C>A) of TGFBI was identified in the Chinese family with LCD I.

CUKRZYCA MODY – PODŁOŻE MOLEKULARNE, CECHY KLINICZNE I POSTĘPOWANIE DIAGNOSTYCZNE

Maturity-onset diabetes of the young (MODY) is a monogenic disorder with autosomal dominant inheritance. MODY is a rarely diagnosed form of diabetes, its incidence, depending on the population, is estimated at 1-5% of children with diabetes. MODY diabetes currently includes 14 forms of diabetes with different etiology. Each of the MODY subtypes is conditioned by a mutation in one of the 14 identified genes: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, APPL1. The most frequently recognized subtypes of MODY are conditioned by mutations of the HNF1A (30-65%), GCK (30-60%), HNF4A (5-10%) and HNF1B (5%) genes. MODY is characterized by the following features: 1) mild fasting hyperglycemia, 2) onset of symptoms before the age of 25, 3) lack of autoantibodies against pancreatic beta-cell antigens and features typical of type 2 diabetes (insulin resistance, obesity). Individual subtypes of MODY diabetes are characterized by a different spectrum of clinical symptoms and different age of onset. GCK gene mutations cause mild, asymptomatic fasting hyperglycemia, usually not requiring appropriate treatment. HNF1A and HNF4A gene mutations are associated with progressive pancreatic β-cell dysfunction and hyperglycemia, which may lead to microvascular complications, in the HNF1B- MODY subtype there are concomitant developmental abnormalities. In the treatment of MODY, depending on the subtype, diet, sulfonylureas or other oral hyperglycemic agents are applied and insulin therapy may be required later in life and during pregnancy. Next-generation sequencing (NGS) technique using a commercial gene panel is used in the molecular diagnosis of MODY diabetes. The knowledge of the genetic etiology of diabetes and the determination of the MODY subtype is of significant practical importance in the prognosis of the course of the disease, it allows the selection of the optimal t reatment method, it is also the basis for screening of asymptomatic family members of the patient and genetic consueling.

An exploratory pharmacogenetic screening of SLC22A6, SLC22A8, ABCC4 and ABCC10 genes in a cohort of Ghanaian HBV patients

BackgroundOrganic anion transporters and efflux transporters are involved in the metabolism of drugs such as tenofovir disoproxil fumarate (TDF). Given the important role of organic anions and efflux transporters in drug disposition, genetic variations lead to interindividual differences in drug response. Variations in the SLC and ABC transporters have been associated with drug-induced renal dysfunction. Looking at the prevalence of HBV infection in our population and the use of drugs such as TDF in managing this condition, this study aimed to undertake an exploratory analysis of genetic variation in renal transporters SLC22A6, SLC22A8, ABCC10 and ABCC4 in a Ghanaian HBV infected cohort.MethodsWe genotyped 160 HBV infected patients for SNPs in SLC22A6 (rs12293966, rs4149170, rs6591722, rs955434), SLC22A8 (rs11568487), ABCC10 (rs700008, rs831311) and ABCC4 (rs9282570) genes. Clinicodemographic data was taken, and glomerular filtration rate (eGFR) was estimated using the CKD-EPI formula. Genotyping was undertaken using Iplex gold SNP genotyping protocol on the Agena MassARRAY® system. Statistical analysis was undertaken using packages in Stata SE (v17) and GraphPad prism. Hardy–Weinberg equilibrium, haplotype inference, and linkage disequilibrium (LD) were evaluated using web-based tools LDlink and Shesis.ResultsThe average eGFR was 79.78 ± 33.08 mL/min/1.73 m2 with 31% classified as stage 1 with normal or high GFR (eGFR > 90 mL/min/1.73 m2) and 45% with stage 2 CKD (> 60–89.99 mL/min/1.73 m2). All variants were in HWE except rs4149170, rs9282570 and rs700008 where p < 0.05. Strong LD was observed in the variants rs6591722, rs4149170, rs12293966, rs955434 and rs11568487. There was significant association between rs12293966 and eGFR stage under crude dominant inheritance model (OR 0.27, 95% CI 0.08–0.81; p = 0.019). Under crude model (OR 0.21, 95% CI 0.07–0.66; p = 0.008), adjusted model 1 (OR 76, 95% CI 0.39–7.89; p = 0.014) and adjusted model 2 (OR 0.30, 95% CI 0.12–0.78; p = 0.013) there was significant association observed between rs12293966 and eGFR stage in a codominant inheritance.ConclusionThe associations observed in this study point to the need for further evaluation with the population of HBV patients on TDF treatment in addition to other factors that would lead to unfavorable outcomes. This exploratory finding may require confirmation in a larger cohort with proper phenotyping to investigate the exact pharmacogenetic mechanisms.

Czech dysplasia mimicking rheumatoid arthritis: Case series andliterature review.

This study reported a family with most members affected by Czech dysplasia. We examined the patients' clinical, laboratory, and imaging characteristics and evaluated their functional capacity using the Stanford Health Assessment Questionnaire-Disability Index. The method used was case series description and literature review. This study showed that the pathogenic variant c.823C>T in the COL2A1 gene, which is a characteristic of Czech dysplasia, was found in 12 Brazilian individuals. Half of the patients in this family met the criteria for rheumatoid arthritis (RA) based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria. Patients had arthritis in their hand joints, synovitis detected by ultrasound, and alterations in inflammatory tests. The Stanford Health Assessment Questionnaire-Disability Index assessment revealed that all patients exhibited moderate-to-severe functional disability. What distinguish Czech dysplasia from RA are an autosomal dominant inheritance pattern, platyspondyly, sensorineural hearing loss, and shortening of the metatarsal bones. It is important to consider Czech dysplasia as a potential differential diagnosis for RA. This autosomal dominant skeletal dysplasia is associated with normal height, short metatarsals, platyspondyly, hearing loss, enlarged epiphyses, and precocious osteoarthritis. Inflammatory findings such as arthritis, synovitis, and alteration of inflammatory markers may also be present in individuals with Czech dysplasia.

RotaRod and acoustic startle reflex performance of two potential mouse models for Meniere's disease.

Meniere's disease (MD) is a disorder of the inner ear characterized by chronic episodes of vertigo, tinnitus, increased aural pressure, and sensorineural hearing loss. Causes of MD are unknown, but endolymphatic hydrops is a hallmark. In addition, 5%-15% of MD cases have been identified as familial. Whole-genome sequencing studies of individuals with familial MD identified DTNA and FAM136A as candidate genes for autosomal dominant inheritance of MD. Although the exact roles of these genes in MD are unknown, FAM136A encodes a mitochondrial protein, and DTNA encodes a cytoskeletal protein involved in synapse formation and maintenance, important for maintaining the blood-brain barrier. It is also associated with a particular aquaporin. We tested vestibular and auditory function in dtna and fam136a knockout (KO) mice, using RotaRod and startle reflex-based clicker tests, respectively. Three-factor analysis of variance (ANOVA) results indicated that sex, age, and genotype were significantly correlated with reduced mean latencies to fall ("latencies") for male dtna KO mice, while only age was a significant factor for fam136a KO mice. Fam136a KO mice lost their hearing months before WTs (9-11 months vs. 15-20 months). In male dtna KO mice, divergence in mean latencies compared with other genotypes was first evident at 4months of age, with older males having an even greater decrease. Our results indicate that fam136a gene mutations generate hearing problems, while dtna gene mutations produce balance deficits. Both mouse models should help to elucidate hearing loss and balance-related symptoms associated with MD.

Torsion dystonia type 30. Clinical observation. Case report

A 58-year-old patient with type 30 dystonia (OMIM619291) detected by genome-wide sequencing was described. A variant of rs778751388, not previously described in the literature, has been identified in the heterozygous state in exon 2 of 24 of the VPS16 gene, leading to the amino acid substitution of P.Cys36A4rg. DNA change (HG38)(protein change) 20:g.2859771TC ENST00000380445.8:c.106TC ENSP00000369810.3:p.Cys36Arg. The patient's disease began quite late, in the 4th decade of life, with spastic torticollis. Subsequently, the spread of the pathological process involving the muscles of the neck, the right upper limb, then the right lower limb, myoclonia of the right hand and tremor of the right lower limb was noted. Secondary mitochondrial disorders were revealed in the form of an increase in the level of lactate in the blood before and after loading with carbohydrates. A decrease in the activity of mitochondrial enzymes in peripheral blood lymphocytes was also revealed: succinate dehydrogenase, an enzyme of the mitochondrial respiratory chain complex II; -glycerophosphate dehydrogenase involved in mitochondrial fat metabolism; glutamate dehydrogenase (amino acid metabolism in mitochondria). The level of lactate dehydrogenase in peripheral blood lymphocytes in the patient was elevated. The identified secondary mitochondrial disorders may be an indication for the appointment of energotropic medicines along with levodopa drugs and dopaminergic receptor agonists. In the presented observation, it can be argued about autosomal dominant inheritance, since the patient has a characteristic clinical picture of the disease and a mutation in the heterozygous state in the VPS16 gene was detected.

Deep structured learning for variant prioritization in Mendelian diseases

Effective computer-aided or automated variant evaluations for monogenic diseases will expedite clinical diagnostic and research efforts of known and novel disease-causing genes. Here we introduce MAVERICK: a Mendelian Approach to Variant Effect pRedICtion built in Keras. MAVERICK is an ensemble of transformer-based neural networks that can classify a wide range of protein-altering single nucleotide variants (SNVs) and indels and assesses whether a variant would be pathogenic in the context of dominant or recessive inheritance. We demonstrate that MAVERICK outperforms all other major programs that assess pathogenicity in a Mendelian context. In a cohort of 644 previously solved patients with Mendelian diseases, MAVERICK ranks the causative pathogenic variant within the top five variants in over 95% of cases. Seventy-six percent of cases were solved by the top-ranked variant. MAVERICK ranks the causative pathogenic variant in hitherto novel disease genes within the first five candidate variants in 70% of cases. MAVERICK has already facilitated the identification of a novel disease gene causing a degenerative motor neuron disease. These results represent a significant step towards automated identification of causal variants in patients with Mendelian diseases.

Interpretation of SLC3A1 and SLC7A9 variants in cystinuria patients: The significance of the PM3 criterion and protein stability

Cystinuria is a genetic disorder caused by defects in the b0,+ transporter system, which is composed of rBAT and b0,+AT coded by SLC3A1 and SLC7A9, respectively. Variants in SLC3A1 and SLC7A9 follow autosomal recessive inheritance and autosomal dominant inheritance with reduced penetrance, respectively, which complicates the interpretation of cystinuria-related variants. Here, we report seven different SLC3A1 variants and six different SLC7A9 variants. Among these variants were two novel variants previously not reported: SLC3A1 c.223C > T and SLC7A9 c.404A > G. In silico analysis using REVEL correlated well with the functional loss upon SLC7A9 variants with scores of 0.8560–0.9200 and 0.4970–0.5239 for severe and mild decrease in transport activity, respectively. In addition, DynaMut2 was able to predict a decreased protein expression level resulting from the SLC7A9 variant c.313G > A with a ΔΔGStability −2.93 kcal/mol. Our study adds to the literature as additional cases of a variant allow applying the PM3 criterion with higher strength level. In addition, we suggest the clinical utility of REVEL and DynaMut2 in interpreting SLC3A1 and SLC7A9 variants. While a decreased protein expression level is not embraced in the current variant interpretation guidelines, we believe in silico protein stability predicting tools could serve as evidence of protein function loss.

Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse

Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.(Ala193Pro) variant in mice. The p.(Ala193Pro) variant was associated with ocular phenotypes in both mice and humans, with dominant inheritance in humans and recessive inheritance in mice. Unlike their human counterparts, p.(Ala193Pro) homozygous mutant mice had normal axial length, normal intraocular pressure, and structurally normal scleral collagen. However, in both homozygous mice and heterozygous humans, the p.(Ala193Pro) variant was associated with discrete white spots throughout the retinal fundus, with corresponding retinal folds on histology. This direct comparison of a TMEM98 variant in mouse and human suggests that certain nanophthalmos-associated phenotypes are not only a consequence of a smaller eye, but that TMEM98 may itself play a primary role in retinal and scleral structure and integrity.

Pathogenetic significance of polymorphic variants in the &lt;i&gt;TREM-1&lt;/i&gt; gene in the multiple organ failure risk after cardiac surgery

Introduction. Searching of highly specific, sensitive and easy-to-use markers of multiple organ failure (MOF) that will help to the early prognosis of this unfavorable condition, prevent complications and reduce mortality in the early postoperative period is very urgent for the modern medicine.Aim: To study the pathogenetic significance of the TREM-1 gene polymorphism in MOF in patients with coronary artery disease (CAD) in the early postoperative period.Material and methods. 592 CAD patients (564 patients with uncomplicated postoperative period and 28 MOF patients) were selected for the presented study. Genotyping polymorphic variants rs1817537, rs3804277, rs6910730, rs7768162, rs2234246, rs4711668, rs9471535 and rs2234237 in the TREM-1 gene was carried out by polymerase chain reaction.Results. It was found that the allele T (rs2234246), the allele G (rs1817537) and the allele T (rs3804277) in the TREM-1 gene were associated with an increased MOF risk after elective surgery according to the dominant inheritance model. TREM-1 polymorphic loci rs7768162 and rs4711668 were associated with a decreased MOF risk according to the additive inheritance model. We found no significant associations between polymorphic variants rs2234237, rs6910730, rs9471535, as well as inherited haplotype and MOF risk. Using the MDR analysis, three most significant models of gene-gene interactions of TREM-1 polymorphic loci associated with MOF risk in patients after cardiac surgery were identified.Conclusion. The obtained results demonstrate a significant contribution of polymorphic variants in the TREM-1 gene to the development of MOF in patients undergoing cardiac surgery.

&lt;i&gt;PIEZO2&lt;/i&gt; gene and its role in the development of distal arthrogryposis: A literature review

BACKGROUND:PIEZO1 and PIEZO2 are mechanosensitive ion channel proteins; in humans, they are encoded by genes with identical names. PIEZO proteins convert mechanical signals into biochemical cellular responses following transduction. Recent data highlight the importance of this family of ion channel proteins in the regulation of physiological processes; however, many mechanisms remain unknown. Modern studies have proven thatPIEZO2mutations lead to the development of various forms of distal arthrogryposis.&#x0D; AIM:To analyze publications containing information onPIEZO2gene and its role in the development of distal forms of arthrogryposis.&#x0D; MATERIALS AND METHODS:This study analyzed the results ofaliterature search in the open scientific literature databases of PubMed, Cochrane Library, and eLibrary. Consequently, 40 foreign, and domestic scientific sources were extracted from 1969 to 2022.&#x0D; RESULTS:This study showed the relationship betweenPIEZO2mutations and the development of the distal forms of arthrogryposis. The study also presented the types of distal arthrogryposis and their clinical manifestations depending on the mutation of this gene.PIEZO2mutations with decreased function cause distal arthrogryposis with impaired proprioception and taction (autosomal recessive type of inheritance).PIEZO2mutations with gain-of-function cause distal arthrogryposis of types 3 and 5 (autosomal dominant inheritance).&#x0D; CONCLUSIONS:Anintegrated approach to the diagnosis and molecular genetic study will allow us to choose the best techniques and treatment of patients with this pathology. The results are useful for doctors of various specialties.

Familial Cataracts: Profile of Patients and Their Families at a Child Eye Care Tertiary Facility in a Developing Country.

The aim of this study is to describe the clinical profile, pedigree charting, and management of children with familial cataracts at a child eye health tertiary facility in southwest Nigeria. The clinical records of children ≤16 years diagnosed with familial cataracts at the Pediatric Ophthalmology Clinic, University College Hospital Ibadan (Ibadan, Nigeria) from January 1, 2015, to December 31, 2019, were retrospectively reviewed. Information on demographic data, family history, visual acuity, mean refractive error (spherical equivalent), and surgical management was retrieved. The study included 38 participants with familial cataract. The mean age at presentation was 6.30 ± 3.68 years, with a range of 7 months to 13 years. Twenty-five patients (65.8%) were male. All patients had bilateral involvement. The mean duration from onset of symptoms to presentation at the hospital was 3.71 ± 3.20 years, with a range of 3 months to 13 years. In 16 of the 17 pedigree charts obtained, at least one individual was affected in each generation. The most common cataract morphology was cerulean cataract, observed in 21 eyes (27.6%). The most common ocular comorbidity was nystagmus which was observed in seven patients (18.4%). Sixty-seven eyes of 35 children underwent surgery within the period of the study. The proportion of eyes that had best-corrected visual acuity ≥6 / 18 before surgery was 9.1%; this proportion had increased to 52.7% at the last postoperative visit. Autosomal dominant inheritance appears to be the major pattern among our patients with familial cataract. The most common morphological type found in this cohort was cerulean cataract. Genetic testing and counseling services are vital for the management of families with childhood cataract.

Morphological and molecular genetic diagnosis of CADASIL: a rare clinical case

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary autosomal dominant vascular injury of the brain. Currently, the clinical diagnosis of CADASIL is based on the following criteria: the onset of the condition at a relatively young age (4050 years), recurrent lacunar infarcts, gradual progression of encephalopathy with the development of pseudobulbar syndrome and dementia, various emotional disorders, and autosomal dominant inheritance. Having a family history of relatives with similar symptoms. The diagnosis is verified on the basis of the results of the following studies: neuroimaging, instrumental, morphological, and laboratory. The presence of leukoaraiosis and multiple small bilateral infarctions in such anatomical structures as the basal ganglia and white matter of the cerebral hemispheres, visual tubercles and the pons, and brain stem during MRI diagnostics. Histologically, transmission electron microscopy reveals granular osmiophilic inclusions in the adventitial membrane of the blood vessels of the brain, and on the periphery in the adventitia of the vessels of skeletal muscles and somatic nerves and in vascular biopsies of skin flaps. A mutation in the Notch3 gene determines the clinic of the disease and morphological changes in blood vessels and is detected by a molecular genetic method. The article presents a clinical case, which was a manifestation of this rare hereditary microangiopathy. Clinical case description: A 43-year-old patient was admitted to the Department of Neurology of the Republican Clinical Hospital in Simferopol for ischemic stroke in the basin of the left middle cerebral artery. According to the anamnesis, the patient suffered from migraine without aura from a young age and lacunar strokes; examination revealed a decrease in cognitive function, and MRI showed signs of microangiopathy of cerebral vessels. For final diagnosis, the patient underwent an intravital pathomorphological examination of the biopsy of the musculoskeletal flap; the results obtained made it possible to make a reliable diagnosis of CADASIL. Conclusion: Understanding and knowledge of such a rare pathology as CADASIL is crucial for the rapid recognition of a characteristic clinical picture for further appointment and interpretation of the results of morphological and molecular genetic diagnostics, making it possible to make the correct diagnosis and treatment.

Alu Retrotransposition Event in SPAST Gene as a Novel Cause of Hereditary Spastic Paraplegia.

To diagnose the molecular cause of hereditary spastic paraplegia (HSP) observed in a four-generation family with autosomal dominant inheritance. Multiplex ligation-dependent probe amplification (MLPA), whole-exome sequencing (WES), and RNA sequencing (RNA-seq) of peripheral blood leukocytes were performed. Reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing were used to characterize target regions of SPAST. A 121-bp AluYb9 insertion with a 30-bp poly-A tail flanked by 15-bp direct repeats on both sides was identified in the edge of intron 16 in SPAST that segregated with the disease phenotype. We identified an intronic AluYb9 insertion inducing splicing alteration in SPAST causing pure HSP phenotype that was not detected by routine WES analysis. Our findings suggest RNA-seq is a recommended implementation for undiagnosed cases by first-line diagnostic approaches. © 2023 International Parkinson and Movement Disorder Society.

Case report – A rare syndromic association (Goldenhar syndrome)

ABSTRACT Goldenhar syndrome is a diverse and poorly understood continuum of disorders of unknown etiology. It is a complex of developmental disorders (face, ears, eyes, spine, etc.), varying in severity in each patient. The estimated incidence of the syndrome ranges from 1 in 3500 to 5600 live births. The male-to-female ratio is approximately 3:2. Most cases of Goldenhar syndrome occur sporadically, although several case reports have documented occurrences in successive generations that require consideration of autosomal recessive, dominant, or multifactorial inheritance. Since there are other syndromes with similar features, there is still confusion regarding which cases should be classified specifically as Goldenhar syndrome. Goldenhar syndrome is a malformation complex of varying severity, involving the structures arising from the first and second branchial arches, the first pharyngeal pouch, the first branchial cleft and the primordia of the temporal bone. We are presenting a rare case of 2 ½ months old male, with asymmetry of the frontonasal area, left auricle anotia, preauricular tags, epicanthus, and left facial nerve palsy. The child had thoracic hemivertebra and fused right ectopic kidney on left side with grade IV VUR. The child had H type trachea esophageal fistula which was confirmed on CT thorax which was a cause of recurrent chest infections in child.