Autosomal Dominant Pattern Research Articles

Case series of spontaneous bilateral absorbed cataracts running in a family

There are only a handful of case reports and studies available regarding spontaneously absorbed cataracts and their management, including the surgical techniques and results following the management. In our study, on retrospective analysis, after a thorough search of the concerned literature, we encountered a series of cases of bilateral spontaneous absorbed cataracts running in a family with no such documentation. This retrospective study included 11 patients (aged between 3 and 65 years and of either sex) of the same family having bilateral absorbed cataracts. All patients underwent best-corrected visual acuity (BCVA); a thorough eye examination; rubella titer estimation; intraocular lens (IOL) power calculation; lens aspiration with or without posterior capsulotomy, anterior vitrectomy (AV), or IOL implantation; and visual rehabilitation. All patients had bilateral absorbed cataracts, which were acquired in an autosomal dominant pattern. Preoperative BCVA distance: 22 eyes had either counting fingers close to the face or counting fingers at 1–2 feet. The presence of high-frequency mixed bilateral nystagmus was noted in four patients. Anterior continuous curvilinear capsulorhexis was possible. Cortical aspiration was uneventful. In the capsular bag, implantation was possible in the majority of cases. No postoperative inflammation was noted, and the IOL was well-centered in all patients. To the best of our knowledge, this is the first study to report a case series of bilateral absorbed cataracts running in an Indian family with no syndromic association, no history of mental retardation, or infection. Anatomic disorganization of the absorbed lens makes surgery in such cases challenging. By using appropriate surgical methods and good visual rehabilitation, satisfactory surgical and visual outcomes can be achieved.

Nocturnal enuresis in children

Nocturnal enuresis, defined as urinary incontinence during sleep at least twice weekly for three consecutive months in children over 5 years old, is a common childhood condition that significantly impacts both children and their families. This review examines the classification, etiology, pathophysiology, evaluation, and treatment options for nocturnal enuresis. The condition is classified as either monosymptomatic or non-monosymptomatic, and primary or secondary, with primary enuresis accounting for 80% of cases. The pathophysiology involves three main mechanisms: nocturnal polyuria, high arousal threshold, and bladder dysfunction. Genetic factors play a significant role, with a strong familial component following an autosomal dominant pattern. Evaluation includes detailed medical history, voiding diary, physical examination, and basic laboratory tests. Treatment approaches are divided into non-pharmacological (including behavioral modifications, motivational therapy, and alarm therapy) and pharmacological interventions (primarily desmopressin, tricyclic antidepressants, and anticholinergic drugs). While alarm therapy shows the highest long-term success rates (65-75%), combination therapy may be necessary for treatment-resistant cases. This review emphasizes the importance of individualized treatment approaches and family support in managing childhood nocturnal enuresis effectively.

Radiological Evaluation of Huntington’s Disease: A Case Report

Huntington’s Disease (HD) is a rare neurodegenerative condition inherited in an autosomal dominant pattern, where Gamma Amino Butyric Acid-ergic (GABAergic) neurons in the basal ganglia progressively deteriorate. Symptoms include subcortical dementia, behavioural changes, midlife psychosis, and involuntary choreoathetosis movements. Imaging techniques like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) show shrinkage of the caudate nucleus and putamen, alongside enlarged lateral ventricles. Diagnosis is confirmed through molecular analysis identifying the hallmark amplified Cytosine Adenine Guanine (CAG) triplet. The case report describes a 57-year-old female diagnosed with HD, presenting symptoms of accidental falls caused by involuntary jerky movements, along with behavioural changes and cognitive decline over three years. Initial Non Contrast Computed Tomography (NCCT) of the brain revealed bilateral basal ganglia and diffuse cerebral atrophy. Quantitative analysis indicated a decreased frontal horn width to intercaudate distance (FH/CC) ratio of 1.24 and an increased Intercaudate distance to inner table width (CC/IT) ratio of 0.30. Multivoxel Magnetic Resonance Spectroscopy (MRS) showed reduced N-Acetyl Alanine (NAA) and creatine (Cr) levels with an NAA/Cr ratio of 0.84. Magnetic Resonance Tractography and Diffusion Tensor Imaging (DTI) revealed elevated Fractional Anisotropy (FA) and diffusivity in the basal ganglia, and reduced FA with increased diffusivity in white matter tracts. Genetic analysis by Polymerase Chain Reaction (PCR) confirmed HD. Newer MRI like DTI allows early identification of disease and better assessment of disease progression and response to therapy. A multidisciplinary approach involving neurologists, psychiatrists, and other healthcare professionals is essential. Genetic counseling and psychosocial support are crucial for patients and their families. Early and accurate identification of HD is vital for timely interventions and improved symptom control.

Varijante u GATOR1 genima u fokalnoj epilepsiji

Significant genetic contributions to focal epilepsy have only recently been recognized, despite the well-established hereditary nature of other epilepsy syndromes. In 2013, the significant role of the DEPDC5 gene in a rare familial focal epilepsy syndrome was described, followed by the discovery of variants in NPRL2 and NPRL3 genes in patients with similar clinical features three years later. The genes listed above code the three subunits that comprise the GTPase-activating protein (GAP) activity towards Rags 1 (GATOR1) complex, a negative regulator of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). Loss of function of GATOR1 leads to constitutive mTORC1 activation that is linked to various malformations of cortical development (MCD), most notoriously focal cortical dysplasia (FCD), but has also been linked to epilepsy in the absence of overt MCD. Variants in GATOR1 genes have been detected in multiplex families with rare familial focal epilepsy syndromes where they demonstrate an autosomal dominant inheritance pattern with reduced penetrance. More recently, they have also been defined as major contributors in common nonacquired focal epilepsy in which they are detected in 3% of familial and 0.2% of sporadic cases and are particularly common in familial epilepsy associated with FCD where up to 11% of affected subjects carry gene variants. Clinical features of carriers include a propensity for nocturnal seizures, a poor response to antiseizure medication as well and an increased risk of sudden unexpected death in epilepsy, which is why other forms of treatment have been explored, including epilepsy surgery after which GATOR1 gene variant carriers have similar outcomes to other patients with focal epilepsy. A particularly promising avenue of exploration is the utilization of mTOR inhibitors like everolimus in epilepsy treatment, but further investigation into this option is warranted.

Exploring the impact of a KCNH2 missense variant on Long QT syndrome: insights into a novel gender-selective, incomplete penetrance inheritance mode.

Long QT syndrome (LQTS) is an inherited malignant arrhythmia syndrome that poses a risk of sudden death. Variants in the Potassium Voltage-Gated Channel Subfamily H Member 2 (KCNH2) gene are known to cause Long QT syndrome through an autosomal dominant inheritance pattern. However, as of now, there have been no reports of any KCNH2 variant leading to Long QT syndrome exhibiting incomplete penetrance that is influenced by gender. Whole-exome sequencing (WES) was conducted on the proband to identify pathogenic variants. Subsequently, Sanger sequencing was employed to validate the identified likely pathogenic variants in all family members. We analyzed a pedigree spanning three-generations afflicted by Long QT syndrome. WES revealed a novel KCNH2 missense variant (p.Val630Gly, c.1889T>G) as the causative factor for the family's phenotype. Within this family, all three male carriers of the KCNH2 variant carriers exhibited the Long QT syndrome phenotype: one experienced sudden death during sleep, another received an implantable cardioverter defibrillator (ICD), and a younger man displayed a prolonged QTc interval without any instances of syncope or malignant arrhythmia to date. Interestingly, the middle-aged female carrier showed no Long QT Syndrome phenotype. However, her offspring, diagnosed with Turner syndrome (45, X) and also a carrier of this variant, experienced frequent syncope starting at 12 years old and was diagnosed with Long QT syndrome, leading to an ICD implantation when she was 15 years old. These observations suggest that the manifestation of Long QT syndrome associated with this KCNH2 variant exhibits incomplete penetrance influenced by gender within this family, indicating potential protective mechanisms against the syndrome in females affected by this variant. Our investigation has led to the identification of a novel pathogenic KCNH2 variant responsible for Long QT syndrome within a familial context characterized by gender-selective, incomplete penetrance. This discovery highlights a unique pathogenic inheritance pattern for the KCNH2 gene associated with Long QT syndrome, and could potentially shed light on the distinct penetrance behaviors and patterns of the KCNH2 gene. This discovery broadens our exploration of the KCNH2 gene in cardiac arrhythmias, highlighting the intricate genetic dynamics behind Long QT syndrome.

A novel MAPT variant (E342K) as a cause of familial progressive supranuclear palsy.

MAPT variants are a known cause of frontotemporal dementia and Parkinsonian syndrome, of which progressive supranuclear palsy syndrome (PSP) is a rare manifestation. To report a novel MAPT variant in a PSP pedigree with autosomal dominant inheritance pattern, and to produce a literature review of PSP patients with MAPT variants. A comprehensive clinical, genetic, and molecular neuroimaging investigation was conducted on a 61 years-old female proband diagnosed with PSP. We also collected the clinical presentation data and history of the patient's pedigree, and performed further genetic analysis of 4 relatives, from two generations, with and without symptoms. The proband exhibited typical clinical manifestation of PSP. A cranial MRI revealed midbrain atrophy, and an FDG-PET scan suggested hypo-metabolic changes in caudate nucleus, left prefrontal lobe, both temporal poles, and midbrain. 18F-florzolo-tau-PET revealed tau-protein deposits in the thalamus and brainstem bilaterally. A gene test by whole-exome sequencing identified a novel MAPT variant [NM_005910.6, exon 11, c.1024G > A (p.E342K)], and the same variant was also identified in one affected relative and one asymptomatic relative, a probable pre-symptomatic carrier. The PSP pedigree caused by the novel MAPT (E342K) variant, expanded the mutational spectrum of MAPT.

Gain-of-Function KIDINS220 Variants Disrupt Neuronal Development and Cause Cerebral Palsy.

Kinase D-interacting substrate of 220 kDa (KIDINS220) is a multifunctional scaffolding protein essential for neuronal development. It has been implicated in neurological diseases with either autosomal dominant (AD) or autosomal recessive (AR) inheritance patterns. The molecular mechanisms underlying the AR/AD dual nature of KIDINS220 remain elusive, posing challenges to genetic interpretation and clinical interventions. Moreover, increased KIDINS220 exhibited neurotoxicity, but its role in neurodevelopment remains unclear. The aim was to investigate the genotype-phenotype correlations of KIDINS220 and elucidate its pathophysiological role in neuronal development. Whole-exome sequencing was performed in a four-generation family with cerebral palsy. CRISPR/Cas9 was used to generate KIDINS220 mutant cell lines. In utero electroporation was employed to investigate the effect of KIDINS220 variants on neurogenesis in vivo. We identified in KIDINS220 a pathogenic nonsense variant (c.4177C > T, p.Q1393*) that associated with AD cerebral palsy. We demonstrated that the nonsense variants located in the terminal exon of KIDINS220 are gain-of-function (GoF) variants, which enable the mRNA to escape nonsense-mediated decay and produce a truncated yet functional KIDINS220 protein. The truncated protein exhibited significant resistance to calpain and consequently accumulated within cells, resulting in the hyperactivation of Rac1 and defects in neuronal development. Our findings demonstrate that the location of variants within KIDINS220 plays a crucial role in determining inheritance patterns and corresponding clinical outcomes. The proposed interaction between Rac1 and KIDINS220 provides new insights into the pathogenesis of cerebral palsy, implying potential therapeutic perspectives. © 2023 International Parkinson and Movement Disorder Society.

Functional and structural analysis of a novel splice site HMBS variant in a Chinese AIP patient.

Background: Acute intermittent porphyria (AIP) is a rare metabolic disorder that results from mutations in the gene encoding hydroxymethylbilane synthase (HMBS), an enzyme involved in heme biosynthesis. AIP follows an autosomal dominant inheritance pattern, but most carriers are asymptomatic. The clinical manifestations of AIP include acute attacks of abdominal pain and neuropsychiatric disturbances. The pathogenicity of novel HMBS variants identified in Chinese patients has not been well established. Objective: The article aims to identify the pathogenic mutation in an AIP patient and prove its pathogenicity through in vitro experiments. Methods: A 22-year-old female diagnosed with AIP participated in the study. Variant screening of her HMBS gene was carried out through Sanger sequencing. To ascertain the consequences of the newly discovered variant, we conducted in vitro experimentation targeting HMBS gene expression and enzymatic function. Additionally, protein structure analysis was performed. Cycloheximide treatment and UPF1-specific siRNA knockdown were employed to assess the impact of the mutation on the mechanism of non-sense-mediated mRNA decay (NMD). Results: A novel splice site variant in the HMBS gene (c.648_651+1delCCAGG) was detected in the patient, which caused aberrant mRNA splicing. In vitro experiments demonstrated that this variant significantly decreased the expression of HMBS. Further investigation confirmed that this decrease was due to NMD. Additionally, structural analysis indicated that this variant would destabilize the HMBS protein and impair its catalytic activity. To gain a comprehensive understanding of HMBS mutations in the context of AIP, we conducted a literature search on PubMed using the keywords 'HMBS' and 'Acute intermittent porphyria' from 2013 to 2023. This search yielded 19 clinical case reports written in English, which collectively described 220 HMBS gene mutations worldwide. Conclusion: The study identified and proved the pathogenicity of a novel splice site HMBS variant for the first time. Our results elucidated the pathological mechanism by which this mutation causes AIP through reducing HMBS expression and activity. These findings provide theoretical guidance for the diagnosis, treatment and genetic counseling of AIP patients.

Clinical case of patient with Cryopyrin-associated Periodic Syndrome (Muckle-Wells syndrome) and systemic lupus erhythematodes

Muckle-Wells syndrome is a cryopyrin-associated periodic syndrome with an autosomal dominant transmission pattern. The disease characterized by episodes of step move. We present a clinical case a woman of 34-years old with cryopyrin-associated periodic syndrome (Muckle-Wells syndrome) and systemic lupus erhythematodes (SLE). Patient is a heterozygous carrier of a 3-nucleotide duplication in exon 3 of the NLRP3 gene (c.1315_1317dupGCG), inserting an alanine between amino acid positions 439 and 440 (p.Ala439dup). This mutation is a characteristic with Muckle-wells syndrome. From the clinical examination she has clinical symptoms of SLE with moderate activity from SLEDAI = 9 points (“malar rash”, arthritis, leucopenia with lymphopenia, elevated levels of ANA-antibodys and anti-dsDNA-antibodys). Patient was treatment with methylprednisolone 12 mg daily, methotrexate 15 mg weekly, colchicin 2 time of 0,5 mg daily. Over 3 months patient has partial improvement of symptoms without full reduction. On the moment patient lives in Germany and has treatment with Anakinra with excellent results and good quality of life. In the literature is not found other with connection between cryopyrin-associated periodic syndrome (Muckle-Wells syndrome) and connective tissue disease.

Homozygous missense variant F12 (Gly506Asp) associated with severe factor XII deficiency: a case report

BackgroundFactor XII deficiency can be related to either homozygous or compound heterozygous pathogenic variants in the F12 gene. The disease is commonly known as Hageman trait and is inherited in both autosomal recessive or dominant patterns. Clinically, factor XII deficiency is not associated with bleeding but conversely has been linked to thrombotic events, recurrent pregnancy loss, and hereditary angioedema. Molecular data of F12 deficiency are scarce and have revealed varying results between cases. However, most of the reported variants are missense mutations, gross deletions, or small insertion. Factor XII deficiency has been reported in the Saudi population in several studies, either as isolated case reports or included within the studies of rare bleeding factors deficiency. However, molecular data are lacking as no case report of genetic studies related to factor XII deficiency has been published in our local population, to the best of our knowledge.Case reportHerein we describe a homozygous missense variant involving exon 12 within F12 gene (5:176,830,269 G>A; p.Gly506Asp) in a 36-year-old Saudi multiparous female referred from the surgical clinic with significantly high activated partial thromboplastin time during preoperative assessment for sleeve gastrectomy. The patient had no history of bleeding episodes during the previous deliveries nor any tooth extractions. She had single event of spontaneous abortion during the 15th week of gestation without any bleeding complication. There was no history of thrombosis or skin manifestations, and she was not taking any medicines. There was no family history of bleeding or thrombosis. Family history revealed consanguinity as the parents are first-degree cousins. Physical examination was unremarkable. Upon investigation, the prolonged activated partial thromboplastin time was fully corrected by a 1:1 mixing study with normal pool plasma while lupus anticoagulant tests were negative. Factor assays and von Willebrand factor tests are all within normal ranges except for factor XII, which was severely deficient. A homozygous missense variant involving exon 12 within F12 gene (5:176,830,269 G>A; p.Gly506Asp) was identified.ConclusionF12 (5:176,830,269 G>A; p.Gly506Asp) variant is likely to be a pathogenic variant among homozygous factor XII-deficient patients. Genetic counseling and management of the patients and families should be based on clinical evaluation.

Family history and modifiable risk factors in early‐onset Alzheimer’s disease in southern Brazil.

AbstractBackgroundAlzheimer’s disease (AD) represents a burdensome health condition worldwide and has a highly clinical heterogeneity. In particular, the early‐onset presentations may be related to different risk factors and underlying pathological mechanisms. We aimed to compare the frequency of modifiable risk factors/family history of dementia in a sample of AD from a tertiary memory outpatient clinic in Southern Brazil.MethodWe reviewed the clinical data of patients clinically diagnosed with AD at the dementia outpatient clinic at the Hospital de Clínicas de Porto Alegre, Brazil, between 2014 and 2022. We collected sociodemographic, clinical, family history, and the presence of seven modifiable risk factors for dementia: hypertension, diabetes, alcohol abuse, tobacco use, traumatic brain injury, hearing loss and previous psychiatric illness. Differences between early (< 65 years) and late‐onset AD were analyzed by Chi squared and Mann‐Whitney tests, with significance defined as p<0.05. All analyses were made in the R.ResultsA total of 145 patients were evaluated, 96 (66.2%) female, mostly (80.7%) white and median (interquartile range, IQR) of 76 (69‐80) years in the first evaluation. Of these, 40 (27.6%) had early‐onset presentation, with age at onset of 59.3 (52.4 ‐ 63) years. The early‐onset group presented a higher frequency of family history of dementia with an autosomal dominant pattern, 7 (17.5%) vs 0 (p = 0.011), with two patients being diagnosed with PSEN1 mutations, and worse scores in Mini Mental State Examination (p = 0.034) at the first evaluation. The groups did not differ in years of formal education or disease duration at the first appointment. Except for a higher frequency of hypertension in the late‐onset group, 68 (64.8%) vs 18 (45%), p = 0.048, there was no difference in the other risk factors (Table 1).ConclusionIn our sample, the profile of risk factors was similar between early‐ and late‐onset AD presentations, but the early‐onset patients had a higher frequency of autosomal dominant dementia family history. Our results suggest that in our sample the genetic and modifiable risk factors are both associated with early‐onset presentations.

Cases of Digeorge Syndrome

Abstract DiGeorge syndrome is a primary immunodeficiency caused by the abnormal growth of the third and fourth pharyngeal pouches throughout prenatal development. It is typified by a triad: hypocalcemia due to hypoparathyroidism, some heart defects, and thymic hypoplasia or aplasia. This syndrome is associated with a microdeletion in the chromosomal region 22q11.2. DiGeorge syndrome together with other dysfunctions like velo-cardio-facial syndrome and Takao syndrome have overlapping traits. The symptoms are hidden under the name CATCH22. It describes signs like a cardiac defect, abnormal facies, thyme hypoplasia, cleft palate, hypocalcemia, and chromosome 22q11.2 deletions. Its incidence is estimated to be approximately 1:3000 live births. The disorder is inherited in an autosomal dominant pattern or arises from de novo mutation. 22q11.2 microdeletion is associated with an increased risk of developing mental diseases, including schizophrenia. In the general population, 1-2% of people suffer from schizophrenia. In DiGeorge syndrome this ratio is much higher, around 25-30%. Nowadays, the fluorescence in situ hybridization (FISH) is a gold standard method for the diagnosis of microdeletion syndrome. Currently, there is no effective therapy to prevent the development of the disease.

¿Frontotemporal dementia or Alzheimer’s disease? Phenotypic variability in a large family with neurodegenerative disorders

AbstractBackgroundThe frontal variant of Alzheimer’s disease is characterized by behavioral changes and executive deficits in the early stages. This phenotype is similar in the behavioral variant of frontotemporal dementia, hindering the clinical diagnosis. The aim of this study is to describe the profile of cognitive, behavioral and motor disorders in a family with an autosomal dominant inheritance pattern of early‐onset dementia.MethodFive cases of affected individuals of a Colombian family are presented. We conducted an interdisciplinary clinical evaluation involving different specialties including geriatric, neurology, psychiatry, neuropsychology, and genetics. After each individual evaluation, a consensus was reached among the specialists to define the diagnosis.ResultIn all cases, reported age of onset was before 60 years old. Three out of four cases met criteria for severe dementia and the remaining case presented Mild Cognitive Impairment (MCI). In two cases, the first symptoms reported were memory and planification problems that affected daily life activities. Nevertheless, at the formal evaluation, predominant changes at the executive functions and social cognition were found. In the other two cases, given the severity of the alterations, the evaluation was limited to the analysis of the clinical history, and it is suspected to be cases of linguistic variants of FTD.ConclusionIntrafamilial phenotypic variability was described in this family. This variability in the presentation of the disease phenotype could guide the clinical diagnosis.

Inheritance of the Epidermolysis Bullosa Subtypes

Epidermolysis bullosa (EB) is a group of inherited disorders that cause skin to blister and tear easily. The disease is caused by mutations in structural proteins that are key for maintaining the integrity of the skin’s basement membrane zone or dermoepidermal junction. EB can be inherited in two ways: autosomal dominant and autosomal recessive. The most common form of EB, epidermolysis bullosa simplex (EBS), as well as some forms of dystrophic epidermolysis bullosa (DEB) are inherited in an autosomal dominant pattern. This means they are passed down from an affected parent to half of his or her children. Other forms of EB, such as junctional epidermolysis bullosa (JEB) and some forms of DEB, are inherited in an autosomal recessive pattern. This means that two copies of the mutated gene, one from each parent, are required to develop the condition.

Bone Marrow Failure Associated with Short Telomeres and Digenic Variants of Uncertain Significance in Telomere Biology Genes

DISCUSSION Telomere Biology Disorders (TBD) are a group of heritable disorders characterized by abnormally short telomeres. There are at least 15 genes associated with TBD including ACD, CTC1, DKC1, NHP2, NOP10, PARN, POT1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53 NAF1 and ZCCHC8, which can be inherited in autosomal dominant (AD), autosomal recessive (AR), or X-linked recessive patterns. Genetic anticipation has been described in some families with more severe symptoms appearing in each successive generation. We report two patients that presented with bone marrow failure, who were subsequently identified to have short telomeres and variants of uncertain significance (VUS) in two different telomere genes inherited from their parents. These cases suggest a potential for digenic inheritance of TBD. CASE 1: At age 6, patient was diagnosed with stage 4 neuroblastoma. He was treated with chemotherapy, surgery, immunotherapy, and autologous stem cell rescue. At age 10, he developed frequent and severe epistaxis and was found to have pancytopenia. He underwent a bone marrow aspirate and biopsy which revealed a hypocellular marrow and der (1;7), which is associated with myelodysplastic syndrome (MDS). Genetic evaluation revealed one pathogenic variant in DNAJC21 (from father) and VUS in NAF1 (c.1375C>T) (from father) and RTEL1 (c.533T>C) (from mother). Because NAF1 and RTEL1 are related to AD or AR TBD, telomere length testing was performed. Patient was found to have low telomere length, < 1st percentile, in granulocytes, lymphocytes, memory T cells and NK cells (Figure 1). The patient's mother was found to have borderline low telomere length >=1 and <10 th percentiles in her lymphocytes, naïve T cells, memory T cells, and B cells, and low telomere length in her granulocytes. Father had borderline low telomere length >=1 and <10 th percentiles in granulocytes but normal telomere length in all other subsets. Neither parent reported any symptoms that would be consistent with TBD. We interpreted these findings as consistent with the patient having TBD and the patient's mother either also having TBD or being a carrier, and the potential that genetic anticipation may be involved. The NAF1 variant appears likely to be benign as father's telomeres were normal in length except for low telomere length in his granulocyte compartment. It is possible that the patient's prior treatment for neuroblastoma may have contributed to the shortened telomeres. Over the course of a year, patient developed worsening bone marrow failure. He then underwent reduced intensity conditioning using busulfan, fludarabine and anti-thymocyte globulin for a 4/6 matched cord stem cell transplant. He engrafted on day +10. CASE 2: A 15-year-old male presented with a depressed skull fracture and scalp hematoma following a sports-related head injury. He was incidentally found to have a platelet count of 69 x 10 3/microliter, mild anemia with macrocytosis, and mild leukopenia. Bone marrow biopsy revealed a hypocellular marrow with multilineage maturation, mild fibrosis, and no cytogenetic abnormalities. The patient's telomere lengths were low, below the 1 st percentile, in all 6 white blood cell subsets (Figure 2). He underwent clinical trio exome sequencing along with his parents. He was found to have VUSs in TERT (c.3158-80G>A) (from mother), TINF2 (c.814T>C) (from mother) and SRP72 (c.1928C>T) (from father). Mother was also found to have low telomere length (<1 st percentile) in all 6 subsets. Both parents have normal blood counts while patient continues to have pancytopenia and is transfusion independent. It is presently unclear which of the VUSs are contributing to the patient's phenotype as the TERT and TINF2 variants are both associated with bone marrow failure and heterozygous germline variants in SRP72 is associated with familial MDS. Genes that cause TBD can be inherited through various modes of inheritance. These two patients who presented with bone marrow failure, identified to have VUSs in more than one TBD-associated genes and functional evidence of shortened telomeres, highlight the potential for a digenic mode of inheritance underlying TBD. Synergy between two variants contributes to a penetrant phenotype and can result in earlier or more severe onset of disease. Our patients' parents were asymptomatic or mildly affected, compared to our patients. Larger cohort studies are needed to determine the prevalence of this mode of inheritance.

Basic and translational mechanisms in inflammatory arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a familial, nonischemic heart disease typically inherited via an autosomal dominant pattern (Nava et al., [1]; Wlodarska et al., [2]). Often affecting the young and athletes, early diagnosis of ACM can be complicated as incomplete penetrance with variable expressivity are common characteristics (Wlodarska et al., [2]; Corrado et al., [3]). That said, of the five desmosomal genes implicated in ACM, pathogenic variants in desmocollin-2 (DSC2) and desmoglein-2 (DSG2) have been discovered in both an autosomal-recessive and autosomal-dominant pattern (Wong et al., [4]; Qadri et al., [5]; Chen et al., [6]). Originally known as arrhythmogenic right ventricular dysplasia (ARVD), due to its RV prevalence and manifesting in the young, the disease was first described in 1736 by Giovanni Maria Lancisi in his book “De Motu Cordis et Aneurysmatibus” (Lancisi [7]). However, the first comprehensive clinical description and recognition of this dreadful disease was by Guy Fontaine and Frank Marcus in 1982 (Marcus et al., [8]). These two esteemed pathologists evaluated twenty-two (n = 22/24) young adult patients with recurrent ventricular tachycardia (VT) and RV dysplasia (Marcus et al., [8]). Initially, ARVD was thought to be the result of partial or complete congenital absence of ventricular myocardium during embryonic development (Nava et al., [9]). However, further research into the clinical and pathological manifestations revealed acquired progressive fibrofatty replacement of the myocardium (McKenna et al., [10]); and, in 1995, ARVD was classified as a primary cardiomyopathy by the World Health Organization (Richardson et al., [11]). Thus, now classifying ACM as a cardiomyopathy (i.e., ARVC) rather than a dysplasia (i.e., ARVD). Even more recently, ARVC has shifted from its recognition as a primarily RV disease (i.e., ARVC) to include left-dominant (i.e., ALVC) and biventricular subtypes (i.e., ACM) as well (Saguner et al., [12]), prompting the use of the more general term arrhythmogenic cardiomyopathy (ACM). This review aims to discuss pathogenesis, clinical and pathological phenotypes, basic and translational research on the role of inflammation, and clinical trials aimed to prevent disease onset and progression.

Screening saves sight: An unusual case of type-1 neurofibromatosis

Neurofibromatosis (NF), described by von Recklinghausen in 1882, consists of at least two distinct disorders: NF1 (von Recklinghausen's or peripheral neurofibromatosis) and NF2, formerly known as 'central neurofibromatosis." The prevalence of NF is approximately 1 in 4,000, and of NF2, 1 in 50,000. Neurofibromatosis type 1 is a multisystemic neurocutaneous disorder with an autosomal dominant hereditary pattern. Ocular manifestations include plexiform neurofibroma of eyelid, Lisch nodules in iris, optic nerve glioma, glaucoma, sphenoid wing dysplasia. Retinal and choroidal involvement are encountered less frequently. Unusual ocular findings include multiple choroidal nevi, combined hamartoma, choroidal Schwannoma, choroidal melanoma and vaso proliferative retinal tumors.Here we report a case of an 18 year old girl diagnosed with neurofibromatosis type 1 who on routine ocular examination was found to have high myopia in both eyes and on fundus examination had a macula ‘on’ inferior retinal detachment with retinal hole in right eye. Inferior retinal detachment is rarely reported in neurofibromatosis type 1. This case emphasizes the importance of conducting ocular examination even in asymptomatic patients with neurofibromatosis, so that early detection and treatment can prevent vision loss secondary to retinal detachment.

Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments.

Familial hypercholesterolemia (FH) is the most common monogenic disorder in humans. It affects millions of people globally, increasing the risk of developing cardiovascular disease (CVD) at a younger age due to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth. While effective traditional and novel treatments are available, the most significant challenge with FH is the lack of timely diagnosis. As a result, many patients remain undertreated leading to an increased risk of CVD. To mitigate risk, initiating early and aggressive LDL-C-lowering therapies is recommended. Moreover, given its autosomal dominant inheritance patterns, it is also recommended to perform cascade lipid and/or genetic testing of all first-degree relatives. This review highlights the importance of early FH diagnosis and available treatment options. Greater awareness and improved screening efforts can help diagnose and treat more individuals, ultimately reducing the CVD risk associated with FH.

The clinical significance of transthyretin gene variant homozygosity in variant ATTR-CM

Abstract Background Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a progressive condition characterised by the infiltration of the myocardial extracellular space resulting in progressive heart failure and mortality. Owing to advances in imaging and diagnostics, ATTR-CM is an increasingly recognised form of heart failure worldwide. ATTR-CM can be hereditary (hATTR) and associated with a pathogenic TTR gene variant which exhibits an autosomal dominant pattern of inheritance. Studies have shown that homozygosity in Mendelian diseases confers a more severe clinical phenotype. This has yet to be determined for hATTR-CM. Purpose To determine the clinical significance of TTR gene variant homozygosity in hATTR-CM. Methods All patients whom were diagnosed with hATTR-CM at a single UK national referral centre for amyloidosis were identified retrospectively. TTR gene zygosity, clinical, biochemical and echocardiographic parameters were obtained from patient clinical records. Results Only patients that were homozygous for the V122I TTR gene variant were identified in sufficient numbers for meaningful analysis. Twenty three patients with hATTR-CM whom were homozygous for the V122I variant were identified. Three hundred and ninety heterozygous V122I hATTR-CM patients were identified as a control group. There were no statistically significant differences in echocardiographic parameters (heterozygous vs homozygous means were as follows: IVSd 16.9mm v 16.6mm, LVEF 43.8% v 44.8%, stroke volume 30.7ml v 34.4ml, TAPSE 14.4mm v 15.3mm and GLS -9.7% vs -9.0%). Median NT-proBNP was lower in the homozygotes compared to heterozygotes (2480ng/L v 3179ng/L, p<0.05). Median survival from baseline was similar between the two groups (Figure 1), with homozygous and heterozygous patients having median survivals of 28.7 months and 24.5 months, respectively. However, homozygous patients were significantly younger at baseline diagnosis (mean age 66.4 years v 76.3 years, p<0.01) and therefore died at a much younger age (mean age at death 72.5 years v 79.9 years, p<0.01). Conclusions To our knowledge, this is the first study reporting outcomes in hATTR-CM patients whom are homozygous TTR gene variant carriers. Whilst the cardiac phenotype, natural history and length of survival were not substantially different between heterozygotes and homozygotes, the mean age at first diagnosis was substantially younger. Given the natural course of the disease was relatively similar between the groups, this resulted in a significantly younger age at death in hATTR patients whom are homozygous TTR variant carriers. Larger studies are required to confirm if this is applicable across all TTR variants. Nonetheless our study suggests that hATTR patients whom are homozygous carriers of TTR variants should be afforded closer clinical surveillance from a younger age than their heterozygous counterparts.Figure 1

Abstract 14665: Cybrid Analysis Delineates Nuclear and Mitochondrial Contributions to Oxidative Stress in Pulmonary Arterial Hypertension

Rationale : Heritable pulmonary arterial hypertension (HPAH) is a serious vasculopathy caused by remodeling of pulmonary arterioles. It is inherited in an autosomal dominant pattern with reduced penetrance, suggesting additional triggers are needed for disease development. Past study shows increased DNA damage and total reactive oxygen species (ROS) in lymphoblastoid cells (LCL) from PAH patients and unaffected relatives, indicating a potential genetic component. Hypothesis: Increased oxidative stress is an independent genetically-determined modifier of PAH susceptibility. Methods: LCL from patients, relatives and unrelated controls were analyzed for total and mitochondrial (mt) ROS and mt function (Seahorse). Untargeted metabolomics were performed by Metabolon. Nuclear vs mt gene contribution was studied using cybrids created by transferring the mitochondria from high (HC) and low ROS LCL (LC) to mt negative 143B Rho0 cells. Results: Metabolomics revealed significant differences between PAH and control LCL in the TCA cycle and glutathione metabolism relating to oxidative stress. HPAH LCL showed significant upregulation of both ROS species compared to controls. LCL from relatives clustered into two groups, one with increased mtROS, the other comparable to controls . Like PAH lung vascular cells, LCL with increased mtROS had reduced spare respiratory capacity (SRC) suggesting dysfunctional mitochondria, but no glycolytic switch. Cybrid analysis revealed that HCs had significantly higher basal respiration (p=0.02), with SRC trending higher compared to LCs, indicating a functional electron transport chain. These cells also had elevated mtROS (p=0.04), suggesting reduced antioxidants. Conclusions: HPAH is a complex disease, and mutation status alone doesn’t determine its susceptibility. Patient LCL recapitulate some of the metabolomic pathways dysregulated in lung vascular cells. Oxidative stress in LCL extends to some unaffected relatives, suggesting this is an independent genetic trait that modifies PAH risk. Our cybrid analysis, novel in PAH highlights the importance of nuclear-mt crosstalk. WGS is underway to identify nuclear variants that could affect the mt, and act as potential modifiers and second hits in PAH pathogenesis.