Autosomal Recessive Pattern Of Inheritance Research Articles

First report of Mycobacterium chimaera infection in a patient with chronic granulomatous disease

Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI). NADPH oxidase is an enzyme complex that produces various reactive oxygen species, such as superoxide anions and hydrogen peroxide. Pathogenic variants in cytochrome B (CYB)-B, CYBA, CYBC1, neutrophil cytosolic factor (NCF)-1, NCF2, and NCF4 genes of the NADPH oxidase enzyme complex are responsible for the clinical phenotype of CGD [1]. CGD has an X-linked or autosomal recessive inheritance pattern [1]. Patients with CGD present with various inflammatory and infectious diseases [1]. They are susceptible to fungal and bacterial infections, including mycobacterial infections [1]. Mycobacterium tuberculosis infections have been observed in Bacillus Calmette–Guérin (BCG)-vaccinated patients with CGD [2]. Mycobacterial infections in CGD are commonly observed in countries with a high prevalence of these microorganisms, such as those receiving the BCG vaccination at birth or those with a high prevalence of tuberculosis [2]. Nontuberculous mycobacterial (NTM) infections are rare in CGD [2]. Here, we described the first M. chimaera infection in a female patient with autosomal recessive CGD caused by a pathogenic variant in CYBA.

Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance.

NOTCH3 variants are known to be linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, some null NOTCH3 variants with homozygous inheritance cause neurological symptoms distinct from CADASIL. The aim of this study was to expand the clinical spectrum of this distinct condition and provide further evidence of its autosomal recessive inheritance. Whole exome sequencing (WES) was performed on a proband who exhibited livedo racemosa, ataxia, cognitive decline, seizures, and MRI white matter abnormalities without anterior temporal pole lesions. Segregation analysis was conducted with Sanger sequencing. WES of the proband identified a novel homozygous NOTCH3 null variant (c.2984delC). The consanguineous parents were confirmed as heterozygous variant carriers. In addition, three heterozygous NOTCH3 null variants were reported as incidental findings in three unrelated cases analyzed in our center. The findings of this study suggest an autosomal recessive inheritance pattern in this early-onset leukoencephalopathy, in contrast to CADASIL's dominant gain-of-function mechanism; which is a clear example of genotype-phenotype correlation. Comprehensive genetic analysis provides valuable insights into disease mechanisms and facilitates diagnosis and family planning for NOTCH3-associated neurological disorders.

Modelling of a RYR2-associated left ventricular non-compaction and sudden cardiac death overlap syndrome in hiPSC-EHTs

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ESC training grant; DZHK Background Genetic cardiomyopathies contribute to a significant proportion of morbidity and mortality among young people. Over the past decades, a wide range of underlying molecular mechanisms has been discovered. The current project arose from the clinical observation of a left ventricular non-compaction and sudden cardiac death overlap syndrome in a large family in northern Italy. Whole exome sequencing performed on family members of different generations revealed a single nucleotide polymorphism in the RYR2 gene (RYR2 c.5654G>A homozygous – RyR2 p.G1885E - exon37:missense) with an autosomal-recessive inheritance pattern. The mutation is localized in the DR3 region of the RyR2 protein, adjacent to the FKBP12.6 binding site, a protein that is known to stabilize RyR2, preventing aberrant activation of the channel. Methods and Results Patient-derived, human induced pluripotent stem cells (hiPSCs), carrying the variant homo- and heterozygously, were generated by reprogramming patient-derived peripheral blood mononuclear cells using a non-integrative Sendai virus protocol. The lines were fully characterized and expressed high levels of pluripotency markers at the RNA and protein level. Patient lines were all able to efficiently differentiate into cardiomyocytes. Subsequently, 3D strip-format, force-generating Engineered Heart Tissues (EHTs) were cast and structurally and functionally characterized. Contraction analysis over 60 days showed differences in force development of the patient-derived lines. In particular, the EHTs carrying the homozygous pathogenic variant showed progressive reduction in both beating rate and force over time, increased spontaneous arrhythmogenicity and reduced inotropic response after exposure to isoprenaline, compared to the heterozygous line and unrelated healthy controls. Starting from day 30 after casting, patient-derived EHTs developed morphological changes with areas of marked cellular overgrowth and reduced troponin expression. Transcriptomic and proteomic analysis at 30 and 60 days after EHTs generation, as well as in 2D cardiomyocytes, complement the phenotyping and provide molecular insights into the underlying pathophysiology. To directly evaluate pathogenicity of the genetic variant identified, we generated isogenic homo- and heterozygously corrected hiPSCs, using CRISPR/ Cas9 technology, starting from the homozygous patient-line. The characterization of these corrected clones is currently ongoing. The genetically corrected 3D tissue models will be critical not only in defining the role of the novel RyR2 variant in the familial phenotype described, but also to unveil mechanistic roles of ryanodine receptor in cardiac disease. Conclusion We describe a novel recessive RYR2 variant associated with a left ventricular non- compaction and sudden cardiac death overlap syndrome. 3D cardiac tissue modelling based on patient-derived hiPSCs uncovered a proarrhythmic and structural phenotype of the mutated lines.

Cystic fibrosis in childhood and adulthood

Cystic fibrosis (CF, or mucoviscidosis) is one of the rare diseases with a fatal course and with the highest prevalence. Formerly known as apurely childhood disease, this multisystemic disease follows an autosomal recessive inheritance pattern and results in amalfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, leading to the production of viscous secretions. The prognosis and outcome of CF are determined by the severity of the involvement of the lungs. Other typically affected organs include the pancreas, liver and intestines. This article reviews the clinical presentation and evolution of CF with afocus on the new era of the highly effective CFTR modulator treatment. An overview of the current state of knowledge on the care for CF patients is presented. The introduction of the CF newborn screening, the increased understanding of the disease and the development of novel treatment options have substantially increased the quality of life and life expectancy of people with CF. As aresult, more than half of CF patients in Germany are now older than 18years of age and the complications of a chronic disease as well as organ damage due to the intensive treatment are gaining in importance. The highly effective CFTR modulator treatment results in a significant improvement in CFTR function, lung function, body mass index and quality of life and is available to approximately 90% of patients in Germany, based on the genotype. Nevertheless, further research including the development of causal treatment, e.g., gene therapy, targeting the underlying defect in the remaining 10% of CF patients, is urgently needed. Even in adult patients, CF with a mild course or aCFTR-related disease should be considered, e.g., in cases of bronchiectasis and/or recurrent abdominal complaints.

Understanding Pediatric Hemoglobinopathies: Epidemiology, Genetics, and Management Strategies

Children's hemoglobinopathies, such as thalassemias and sickle cell disease (SCD), present a diverse range of symptoms and complex genetic causes, which provide significant challenges for therapy. This website provides comprehensive information on the genetics, prevalence, and many treatment options available for baby hemoglobinopathies. Research in global epidemiology suggests that individuals suffer from a diverse array of ailments. Therefore, it is crucial to prioritize targeted screening programs and medicines. Understanding the fundamental concepts of basic genetics, such as autosomal recessive inheritance patterns and specific gene mutations, is crucial for developing precise diagnostic tools and personalized treatment strategies. Comprehensive management strategies encompass several approaches such as providing supportive care, utilizing pharmaceutical therapy, and implementing advanced techniques like gene therapy for treating disorders. Due to continuous research that enhances our comprehension of hemoglobinopathies, we should expect improved results and an enhanced standard of living for individuals affected by them. The purpose of this study is to enhance our comprehension of pediatric hemoglobinopathies and our approach to therapy by gathering the perspectives of epidemiology, genetics, and clinical practice.

Syndromic Retinitis Pigmentosa: A 15-Patient Study.

Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic conditions. This study reviewed the clinical data of 15 patients with syndromic retinitis pigmentosa from a Rare Disease Reference Center in Brazil and the results of their next-generation sequencing tests. Five males and ten females participated, with the mean ages for ocular disease onset, fundoscopic diagnosis, and molecular evaluation being 9, 19, and 29 years, respectively. Bardet-Biedl syndrome (n = 5) and Usher syndrome (n = 3) were the most frequent diagnoses, followed by other rare conditions. Among the patients, fourteen completed molecular studies, with three negative results and eleven revealing findings in known genes, including novel variants in MKKS (c.432_435del, p.Phe144Leufs*14), USH2A (c.(7301+1_7302-1)_(9369+1_9370-1)del), and CEP250 (c.5383dup, p.Glu1795Glyfs*13, and c.5050del, p.Asp1684Thrfs*9). Except for Kearn-Sayre, all presented an autosomal recessive inheritance pattern with 64% homozygosity results. The long gap between symptom onset and diagnosis highlights the diagnostic challenges faced by the patients. This study reaffirms the clinical heterogeneity of syndromic retinitis pigmentosa and underscores the pivotal role of molecular analysis in advancing our understanding of these diseases.

Carnitine palmitoyltransferase II (CPT II) deficiency responsible for refractory cardiac arrhythmias, acute multiorgan failure and early fatal outcome

BackgroundCarnitine palmitoyltransferase II (CPT II) deficiency is a rare inborn error of mitochondrial fatty acid metabolism with autosomal recessive pattern of inheritance. Its phenotype is highly variable (neonatal, infantile, and adult onset) on the base of mutations of the CPT II gene. In affected subjects, long-chain acylcarnitines cannot be subdivided into carnitine and acyl-CoA, leading to their toxic accumulation in different organs. Neonatal form is the most severe, and all the reported patients died within a few days to 6 months after birth. Hereby, we report on a male late-preterm newborn who presented refractory cardiac arrhythmias and acute multiorgan (hepatic, renal, muscular) injury, leading to cerebral hemorrhage, hydrocephalus, cardiovascular failure and early (day 5 of life) to death. Subsequently, extended metabolic screening and target next generation sequencing (NGS) analysis allowed the CPT II deficiency diagnosis.Case presentationThe male proband was born at 36+ 4 weeks of gestation by spontaneous vaginal delivery. Parents were healthy and nonconsanguineous, although both coming from Nigeria. Family history was unremarkable. Apgar score was 9/9. At birth, anthropometric measures were as follows: weight 2850 g (47th centile, -0.07 standard deviations, SD), length 50 cm (81st centile, + 0.89 SD) and occipitofrontal circumference (OFC) 35 cm (87th centile, + 1.14 SD). On day 2 of life our newborn showed bradycardia (heart rate around 80 bpm) and hypotonia, and was then transferred to the Neonatal Intensive Care Unit (NICU). There, he subsequently manifested many episodes of ventricular tachycardia, which were treated with pharmacological (magnesium sulfate) and electrical cardioversion. Due to the critical conditions of the baby (hepatic, renal and cardiac dysfunctions) and to guarantee optimal management of the arrythmias, he was transferred to the Pediatric Cardiology Reference Center of our region (Sicily, Italy), where he died 2 days later. Thereafter, the carnitines profile evidenced by the extended metabolic screening resulted compatible with a fatty acid oxidation defect (increased levels of acylcarnitines C16 and C18, and low of C2); afterwards, the targeted next generation sequencing (NGS) analysis revealed the known c.680 C > T p. (Pro227Leu) homozygous missense mutation of the CPTII gene, for diagnosis of CPT II deficiency. Genetic investigations have been, then, extended to the baby’s parents, who were identified as heterozygous carriers of the same variant. When we meet again the parents for genetic counseling, the mother was within the first trimester of her second pregnancy. Therefore, we offered to the couple and performed the prenatal target NGS analysis on chorionic villi sample, which did not detect any alterations, excluding thus the CPT II deficiency in their second child.ConclusionsCPTII deficiency may be suspected in newborns showing cardiac arrhythmias, associated or not with hypertrophic cardiomyopathy, polycystic kidneys, brain malformations, hepatomegaly. Its diagnosis should be even more suspected and investigated in cases of increased plasmatic levels of creatine phosphokinase and acylcarnitines in addition to kidney, heart and liver dysfunctions, as occurred in the present patient. Accurate family history, extended metabolic screening, and multidisciplinary approach are necessary for diagnosis and adequate management of affected subjects. Next generation sequencing (NGS) techniques allow the identification of the CPTII gene mutation, essential to confirm the diagnosis before or after birth, as well as to calculate the recurrence risk for family members. Our report broads the knowledge of the genetic and molecular bases of such rare disease, improving its clinical characterization, and provides useful indications for the treatment of patients.

Screening of Spinal Muscular Atrophy Carriers and Prenatal Diagnosis in Pregnant Women in Yancheng, China.

Spinal muscular atrophy (SMA) is a neuromuscular disorder with an autosomal recessive inheritance pattern. Patients with severe symptoms may suffer respiratory failure, leading to death. The homozygous deletion of exon 7 in the SMN1 gene accounts for nearly 95% of all cases. Population carrier screening for SMA and prenatal diagnosis by amniocentesis for high-risk couples can assist in identifying the risk of fetal disease. We provided the SMA carrier screening process to 55,447 pregnant women in Yancheng from October 2020 to December 2022. Among them, 8185 participated in this process, with a participation rate of around 14.76% (95% CI 14.47-15.06%). Quantitative real-time polymerase chain reaction (qPCR) was used to detect deletions of SMN1 exons 7 and 8 (E7, E8) in screened pregnant women. 127 were identified as carriers (111 cases of E7 and E8 heterozygous deletions, 15 cases of E7 heterozygous deletions, and 1 case of E7 heterozygous deletions and E8 homozygous deletions), resulting in a carrying rate of around 1.55% (95% CI 1.30-1.84%). After genetic counseling, 114 spouses of pregnant women who tested positive underwent SMA carrier screening; three of them were screened as SMA carriers. Multiplexed ligation-dependent probe amplification (MLPA) was used for the prenatal diagnosis of the fetuses of high-risk couples. Two of them exhibited two copies of SMN1 exon 7 (normal), and the pregnancy was continued; one exhibited no copies of SMN1 exon 7 and exon 8 (SMA patient), and the pregnancy was terminated. Analyzing SMN1 mutations in Yancheng and provide clinical evidence for SMA genetic counseling and birth defect prevention. Interventional prenatal diagnosis for high-risk families can promote informed reproductive selection and prepare for the fetus's early treatment.

A novel homozygous missense mutation in the RPE65 gene in an Iranian family with retinitis pigmentosa

Hereditary retinal dystrophies such as retinitis pigmentosa (RP) are genetically and phenotypically heterogeneous and result in total blindness. One of the key genes causing RP is RPE65. In 2017, a gene therapy drug, voretigene neparvovec-rzyl, for RP associated with RPE65 mutations, received Food and Drug Administration approval. So, identification of RPE65 gene mutations in affected patients which may be amenable to genetic treatment is critical. Here, we examine three related Iranian patients with RP which have not been previously described in the population. Whole exome sequencing (WES) using next-generation Illumina sequencing was utilized to identify the disease-causing mutation in the proband. Subsequently, Sanger sequencing was performed to confirm the identified mutation in the patients and their family members. Finally, the possible effect of the reported mutation on the target protein was also evaluated using bioinformatics tools. WES identified a novel homozygous missense mutation c.T170C: p.F57S in exon 3 of the RPE65 gene. Sanger sequencing confirmed the mutation found in the patients and their healthy family members. This mutation segregated with the autosomal recessive inheritance pattern of RP disorder. Furthermore, the pathogenic nature of the identified mutation was confirmed by in silico approaches and genotype-phenotype correlation analysis. Our findings revealed a novel missense mutation c.T170C: p.F57S in the RPE65 gene and could expand the pathogenic mutations spectrum of the RPE65 gene. Additionally, such studies can aid to conduct genetic counseling, prenatal diagnosis, clinical management and even genetic treatment more accurately for all affected patients with RPE65 gene mutations.

Novel compound heterozygous variants in LTBP2 associated with relative anterior microphthalmos.

Relative anterior microphthalmos (RAM) is a rare congenital defect associated with severe vision impairment that is primarily caused by genetic alterations. The purpose of this study was to identify the causative genetic variants in two Chinese families with RAM with an autosomal recessive inheritance pattern. DNA samples were obtained from two probands and their family members. Targeted next-generation sequencing (NGS) was used to screen 425 genes associated with inherited eye diseases to identify possible disease-causing variants in the two patients. Sanger sequencing was subsequently used to validate the results in both families. The targeted NGS panel identified potentially causative novel variants of the latent transforming growth factor beta binding protein 2 (LTBP2) gene in the two RAM families: a missense variant (c.2771C > T; p.Ala924Val) and an intronic variant (c.4582 + 9A > G) in Family A and a different missense variant (c.5239C > A; p.Arg1747Ser) and a synonymous variant (c.951G > A; p.Pro317Pro) in Family B. These four novel variants all cosegregated with the disease phenotype. To our knowledge, this is the first study to report novel LTBP2 gene variants related to RAM. Considering the importance of LTBP2 in ocular development, we provide initial insights into the potential pathogenic mechanisms of LTBP2 in RAM.

A bird’s eye view on the use of whole exome sequencing in rare congenital ophthalmic diseases

Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and classification of diseases. Over the last decade, genomic research has indeed boosted our understanding in the molecular basis of ASD and genes associated with both autosomal dominant and recessive patterns of inheritance have been described with a wide range of expressivity. Here we describe the molecular characterization of a cohort of 162 patients displaying isolated or syndromic congenital ocular dysgenesis. Samples were analyzed with diverse techniques, such as direct sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing (WES), over 20 years. Our data reiterate the notion that PAX6 alterations are primarily associated with ASD, mostly aniridia, since the majority of the cohort (66.7%) has a pathogenic or likely pathogenic variant in the PAX6 locus. Unexpectedly, a high fraction of positive samples (20.3%) displayed deletions involving the 11p13 locus, either partially/totally involving PAX6 coding region or abolishing its critical regulatory region, underlying its significance. Most importantly, the use of WES has allowed us to both assess variants in known ASD genes (i.e., CYP1B1, ITPR1, MAB21L1, PXDN, and PITX2) and to identify rarer phenotypes (i.e., MIDAS, oculogastrointestinal-neurodevelopmental syndrome and Jacobsen syndrome). Our data clearly suggest that WES allows expanding the analytical portfolio of ocular dysgenesis, both isolated and syndromic, and that is pivotal for the differential diagnosis of those conditions in which there may be phenotypic overlaps and in general in ASD.

Autosomal Recessive Non-Syndromic Deafness: Is AAV Gene Therapy a Real Chance?

The etiology of sensorineural hearing loss is heavily influenced by genetic mutations, with approximately 80% of cases attributed to genetic causes and only 20% to environmental factors. Over 100 non-syndromic deafness genes have been identified in humans thus far. In non-syndromic sensorineural hearing impairment, around 75-85% of cases follow an autosomal recessive inheritance pattern. In recent years, groundbreaking advancements in molecular gene therapy for inner-ear disorders have shown promising results. Experimental studies have demonstrated improvements in hearing following a single local injection of adeno-associated virus-derived vectors carrying an additional normal gene or using ribozymes to modify the genome. These pioneering approaches have opened new possibilities for potential therapeutic interventions. Following the PRISMA criteria, we summarized the AAV gene therapy experiments showing hearing improvement in the preclinical phases of development in different animal models of DFNB deafness and the AAV gene therapy programs currently in clinical phases targeting autosomal recessive non syndromic hearing loss. A total of 17 preclinical studies and 3 clinical studies were found and listed. Despite the hurdles, there have been significant breakthroughs in the path of HL gene therapy, holding great potential for providing patients with novel and effective treatment.

Peripheral Blood Film Patterns in Thalassemia and Hemoglobinopathy Carrier

Thalassemia and hemoglobinopthies are the commonest genetic disorders of hemoglobin. The disease has autosomal recessive pattern of inheritance. Screening of thalassemia and hemoglobinopathy carriers is a burning issue to prevent new cases. Thalassemia and hemoglobinopathies can be prevented by genetic testing followed by genetic counseling, if we can detect carriers of thalassemia or hemoglobinopathies by an easy method. The objective of this study was to see the peripheral blood film pattern among the carriers of thalassemia and hemoglobinopathies. It was a cross-sectional study conducted from September 2015 to November 2015. A total of 437 random specimens were collected from three tribal groups. Two mL of venous blood were collected in EDTA tube. Hemoglobin variants were studied by HPLC method using Variant Hemoglobin Testing System (Variant II Beta Thalassemia Short Program). Statistical analysis was carried out using SPSS statistical package (version 23.0). Data were analyzed by frequency distribution. In this study, total 437 respondents were examined for blood test. Male to female ratio was 1:1. The study included cases from 2 years to 82 years where mean age was 18.3±12.0 years. In clinical analysis, Hb ranged from 8.5 to 19.0 gm/dL and 187 cases were found normochromic, 110 cases anisochromic 140 cases hypochromic. Among them, 38.2% were normal individuals, Hb E Trait were 34.8%, Hemoglobin E disease were 21.7% and Beta Thalassemia trait were 5.3%.Peripheral blood film and hemoglobin status may give an idea about thalassaemia and hemoglbinopathy trait or carrier. In the suspected cases, High Performance Liquid Chromatography (HPLC) may be done to confirm the diagnosis.
 Bangladesh J Med Biochem 2019; 12(2): 23-30

Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity.

Short-chain enoyl-CoA hydratase deficiency (ECHS1D) is a rare congenital metabolic disorder that follows an autosomal recessive inheritance pattern. It is caused by mutations in the ECHS1 gene, which encodes a mitochondrial enzyme involved in the second step of mitochondrial β-oxidation of fatty acids. The main characteristics of the disease are severe developmental delay, regression, seizures, neurodegeneration, high blood lactate, and a brain MRI pattern consistent with Leigh syndrome. Here, we report three patients belonging to a consanguineous family who presented with mitochondrial encephalomyopathy. Whole-exome sequencing revealed a new homozygous mutation c.619G > A (p.Gly207Ser) at the last nucleotide position in exon 5 of the ECHS1 gene. Experimental analysis showed that normal ECHS1 pre-mRNA splicing occurred in all patients compared to controls.Furthermore, three-dimensional models of wild-type and mutant echs1 proteins revealed changes in catalytic site interactions, conformational changes, and intramolecular interactions, potentially disrupting echs1 protein trimerization and affecting its function. Additionally, the quantification of mtDNA copy number variation in blood leukocytes showed severe mtDNA depletion in all probands.

Gelatinous Drop-Like Corneal Dystrophy in an Acehnese Family: Serial Cases.

Introduction : Gelatinous drop-like dystrophy (GDLD) is a rare type of corneal dystrophy with an autosomal recessive inheritance pattern. Although the prevalence in Japan is approximately 1 in 33,000, it is much less common in other nations. Lamellar or penetrating keratoplasty is needed for most patients to alleviate the symptoms. This case series aims to provide knowledge regarding rare cases of GDLD and its management.
 Case Illustration : Three male siblings from consanguineous marriage were found to have corneal dystrophy, characterized by a white-yellow nodular lesion with a kumquat-like appearance on the corneal surface. The visual acuity of each patient was light perception with good projection. To treat the condition, all patients underwent full-thickness penetrating keratoplasty. One month after the procedure, their visual acuity had improved to 3/60, 2/60, and 2/60, respectively.
 Discussion : GDLD is a genetic disease with gelatinous amyloid deposits in the cornea that typically manifests within the first decades of life. GDLD can present in three different phenotypes, including band keratopathy, mulberry, and kumquat-like appearance. In the case of these siblings, they have developed the severe kumquat-like phenotype. Detection by examining family involvement and the cornea's clinical presentation can help diagnose GDLD. Full-thickness penetrating keratoplasty can be an option for managing severely impaired visual acuity caused by GDLD.
 Conclusion : GDLD is a rare corneal dystrophy that can lead to severe visual impairment. The objective of treating GDLD is to enhance vision and prevent its progression. Vision loss can be alleviated througha surgical procedure such as full-thickness penetrating keratoplasty.

Novel mutation as a cause of anterior segment dysgenesis leading to blindness in progeny: the genetics decoded!

BackgroundAnterior segment dysgenesis (ASD) disorders comprises of spectrum of developmental conditions affecting the structures of angle of anterior chamber including cornea, iris, and lens. These conditions are characterized by both autosomal dominant and recessive patterns of inheritance often with incomplete penetrance/variable expressivity. A significant overlap among phenotypes attributed to mutations in different ASD genes is well recognized.Case presentationWe present a case involving a 29-year-old pregnant woman referred for genetic screening and counseling. She had a 7-year-old male child with congenital bilateral corneal opacity, and his elder sister also exhibited similar findings. Exome sequencing identified a novel variant in the CYP1B1 gene in a homozygous state, which was associated with anterior segment dysgenesis. Both parents were found to be carriers of the same variant, while the sister had the same variant in a homozygous state. Genotype–phenotype correlation was performed, and it was concluded that the novel variant could be responsible for the eye changes in both siblings. The parents sought prenatal diagnosis for the current pregnancy, which was deemed possible.ConclusionsThis case underscores the importance of genetic testing in such rare diseases, as it can assist in early diagnosis, management, and prognosis. It also aids clinicians and parents in making decisions regarding the continuation of the pregnancy at the appropriate time.

Hereditary Syndromes Associated with Brain Tumors. Literature Review.

Tumors of the central nervous system (CNS) represent 2% of all neoplasms. Low-prevalence hereditary syndromes constitute only a small proportion of all cases of primary tumors of the central nervous system. Most of these syndromes have autosomal-dominant inheritance, except in the case of Turcot syndrome type 1 which has an autosomal recessive inheritance pattern. It is important in daily neurosurgical practice to be able to recognize these hereditary syndromes in order to apply the best therapeutic alternative in these patients.

P-10 A rare case of Triple A Syndrome with familial involvement

Abstract Introduction Alacrimia, achalasia cardia, and adrenocorticotrophic hormone (ACTH)-resistant adrenal insufficiency make up the triple-A syndrome. It is an uncommon disease with an autosomal recessive inheritance pattern. The AAAS gene, which codes for the ALADIN protein and is located on chromosome 12q13, is the cause of Allgrove syndrome. The initial and typical symptoms are achalasia cardia and adrenal insufficiency. The majority of neurological disorders have autonomic signs, and they typically show in later life. The other typical neurological conditions are polyneuropathy, amyotrophy, and optic atrophy. Clinical Case A 25-year-old female patient presented to our clinic with complaints of weakness, dizziness, and hyperpigmentation of the skin. Her medical history revealed a recent intensive care unit (ICU) stay due to hypotension, during which her condition was managed with steroid therapy. However, she did not continue the steroid treatment after discharge. Notably, the patient had a family history of achalasia with operative intervention in all three siblings. The patient and her family members were also under the care of a gastroenterology specialist. Additionally, the patient reported experiencing dry eyes, for which she was using artificial tears. Physical examination revealed hyperpigmentation of tongue, gums and buccal mucosa. Upon examination, her baseline investigations revealed a hemoglobin of 11.4 g/dL, sodium 137 mmol/L and potassium 4.0 mmol/L. The patient's adrenocorticotropic hormone (ACTH) level was measured at 1250 pg/ml, with a basal cortisol level of 0.5 ug/dL, leading to the diagnosis of adrenal insufficiency. Hydrocortisone treatment was initiated at a dosage of 2×10mg, resulting in a decline of the ACTH level to 31. Given the combination of symptoms including achalasia, alacrima, and adrenal insufficiency, genetic testing was conducted. Both alleles revealed a homozygous c.1432C>T (p.Arg478*) mutation, confirming the diagnosis of Triple A Syndrome. Following the genetic diagnosis, a familial investigation was initiated. This investigation revealed the presence of the homozygous positive mutation in two siblings and two cousins. The constellation of symptoms and the genetic findings confirmed the occurrence of Triple A Syndrome within this family. Conclusion This case highlights the significance of recognizing Triple A Syndrome as an underlying cause of adrenal insufficiency in the presence of achalasia, alacrima, and a suggestive clinical history. In order to confirm the diagnosis and identify any affected family members, genetic testing is crucial. To avoid potential complications brought on by adrenal insufficiency and other systemic Triple A Syndrome manifestations, early identification and treatment are crucial.

A novel pathogenic variant in the carnitine transporter gene, SLC22A5, in association with metabolic carnitine deficiency and cardiomyopathy features

BackgroundPrimary carnitine deficiency (PCD) denotes low carnitine levels with an autosomal recessive pattern of inheritance. Cardiomyopathy is the most common cardiac symptom in patients with PCD, and early diagnosis can prevent complications. Next-generation sequencing can identify genetic variants attributable to PCD efficiently.ObjectiveWe aimed to detect the genetic cause of the early manifestations of hypertrophic cardiomyopathy and metabolic abnormalities in an Iranian family.MethodsWe herein describe an 8-year-old boy with symptoms of weakness and lethargy diagnosed with PCD through clinical evaluations, lab tests, echocardiography, and cardiac magnetic resonance imaging. The candidate variant was confirmed through whole-exome sequencing, polymerase chain reaction, and direct Sanger sequencing. The binding efficacy of normal and mutant protein-ligand complexes were evaluated via structural modeling and docking studies.ResultsClinical evaluations, echocardiography, and cardiac magnetic resonance imaging findings revealed hypertrophic cardiomyopathy as a clinical presentation of PCD. Whole-exome sequencing identified a new homozygous variant, SLC22A5 (NM_003060.4), c.821G > A: p.Trp274Ter, associated with carnitine transport. Docking analysis highlighted the impact of the variant on carnitine transport, further indicating its potential role in PCD development.ConclusionsThe c.821G > A: p.Trp274Ter variant in SLC22A5 potentially acted as a pathogenic factor by reducing the binding affinity of organic carnitine transporter type 2 proteins for carnitine. So, the c.821G > A variant may be associated with carnitine deficiency, metabolic abnormalities, and cardiomyopathic characteristics.

Multifocal electroretinogram in the diagnosis of Stargardt disease

Aims/Purpose: Electrophysiological vision tests have been a key method in the diagnosis and monitoring of inherited retinal dystrophies (IRD). With the development of mfERG, the clinical applications of these tests have expanded to cone dystrophies such as Stargardt disease, which is the most common cone‐IRD. This disease is typically associated with an autosomal recessive inheritance pattern, primarily, although not exclusively, due to mutations in the ABCA4 gene. The introduction of different diagnostic techniques such as Optical Coherence Tomography (OCT), OCT Angiography (OCTA), autofluorescence (FAF) and microperimetry has diminished the importance of fluorescein angiography (FA). These techniques have been joined by the diagnostic role of mfERG.The aim of this study is to evaluate functional changes in patients with Stargardt disease using mfERG.Methods: Eighteen eyes of patients with Stargardt disease were included. The disease was previously confirmed by genotyping with homozygous ABCA4 mutations or heterozygous PROM1 mutations. The patients were evaluated using mfERG, using the standardized international ISCEV guidelines. Electrical density and implicit time of each first‐order response (K1) in the five concentric rings centered on the fovea were measured and analysed.Results: Mean best‐corrected visual acuity (BCVA) was 0.5 (0.12–1.0). First‐order responses (K1) showed a decreased electrical density, predominantly in central rings, along with minimally prolonged latencies of the P1. FAF showed central atrophy in 6 patients, atrophy with flecks within or beyond the vascular branches in 8 and 4 patients respectively.Conclusions: Stargardt disease involves cones and is characterized by a significant decrease in foveal and central response in mfERG, even in early stages when BCVA remains relatively preserved and fundus findings are minimal. Flash ERG may show normal results or minimal abnormalities.