Autosomal Dominant Inheritance Research Articles

Genetic Insights and Epidemiological Models in Understanding Primary Open Angle Glaucoma

Primary open-angle glaucoma (POAG) is a multifactorial chronic optic neuropathy with significant genetic heterogeneity. The pathogenesis of POAG involves an imbalance between the production and drainage of aqueous humor (AH). Genetic theories suggest that transgenic mice demonstrating the GLU50LYS mutation in optineurin (OPTN) experience retinal ganglion cell apoptosis, while mutant myocilin (MYOC) proteins induce endoplasmic reticulum (ER) stress, leading to an unfolded protein response (UPR) and subsequent apoptosis of trabecular meshwork cells (TMC). Furthermore, the interaction between MYOC and mitochondria in the trabecular meshwork (TM) and astrocytes may lead to mitochondrial membrane depolarization and calcium channel dysregulation, contributing to POAG. Overexpression of MYOC variants (P370L, Q368X) is also implicated, as are epigenetic modifications and signaling pathways such as histone and DNA modification. POAG has been associated with autosomal dominant inheritance, with mutations in MYOC and OPTN being prominent causative factors, although many cases involve multiple genetic loci. Currently, over 20 genetic loci have been linked to POAG, with 14 chromosomal loci (GLC1A to GLC1N) identified, 5 of which contribute to juvenile-onset open-angle glaucoma (JOAG). Of these loci, MYOC, OPTN, WD repeat domain 36 (WDR36), and neurotrophin-4 (NTF4) are the most studied causative genes. The ongoing study of molecular genetics offers potential pathways for future therapeutic advances in the treatment of POAG.

MUC5B Promoter Variant and Survival in Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Investigate the association between the MUC5B rs35705950 promoter variant and survival in RA-associated interstitial lung disease (RA-ILD). We studied participants in the Veteran Affairs Rheumatoid Arthritis (VARA) registry with validated ILD diagnoses. Participants were followed until death or end of study period. The MUC5B rs35705950 promoter variant was measured using an Infinium genotyping array, assuming autosomal dominant inheritance. Survival and cause of death were determined from VA death records and the National Death Index. Associations of the MUC5B promoter variant with survival were tested in Cox regression models adjusting for potential confounders. Among 263 participants with RA-ILD (mean age 69 years, 95% male, 73% white race, 85% smoking history), the MUC5B promoter variant was present in 33.5%. Mortality rate was similar between those with (12.2/100PY [95% CI: 9.4, 15.8]) and without (11.1/100PY [95% CI: 9.1, 13.5]) the variant. MUC5B status was not significantly associated with survival overall (aHR 0.97 [95% CI: 0.68, 1.37]) or when stratified by ILD pattern (clinical usual interstitial pneumonia [UIP] aHR 0.86 [95% CI: 0.55, 1.35]; clinical non-UIP aHR 1.15 [95% CI: 0.63, 2.09]). Further, MUC5B status was not significantly associated with respiratory-related (aHR 0.83 [95% CI: 0.42, 1.66]) or non-respiratory causes of death (aHR 1.08 [95% CI: 0.72, 1.62]). While associated with RA-ILD risk, the MUC5B promoter variant was not predictive of survival among RA-ILD patients in this multicentre cohort. Further studies are needed to identify other genetic and non-genetic prognostic factors in RA-ILD to inform disease management.

Craniosynostosis in Siblings, an Extremely Rare Occurrence: A Case Report.

Craniosynostosis (CS) is the premature fusion of skull sutures, with all sutures except the metopic suture typically fusing in adulthood. Premature fusion constrains brain growth, leading to abnormal skull shape and potential neurocognitive or neurological issues, along with syndromic features in some cases. While CS is rare, its occurrence in siblings is exceptionally uncommon and holds significant academic importance. We report a case of CS in siblings: a 13-month-old boy and his five-and-a-half-year-old sister. Neither parent exhibits craniofacial dysmorphism or signs of increased intracranial pressure (ICP). The younger sibling presents with dolichocephaly and normal neurological, cognitive, and motor development, while the elder sibling exhibits proptosis, midface hypoplasia, and normal developmental milestones. Neither sibling displays limb or systemic anomalies. Imaging studies, including multislice plain CT brain with 3D skull reconstruction and MRI, revealed multiple suture closures. The younger sibling has complete sagittal suture closure with partial closure of other sutures, while the elder sibling shows multisutural CS. Ophthalmologic evaluations and developmental assessments excluded increased ICP and systemic issues. Most CS cases follow an autosomal dominant inheritance pattern, making this case particularly significant. CT with 3D skull reconstruction remains the diagnostic gold standard. Management aims to preserve cosmetic appearance and prevent complications from increased ICP. Treatment options range from conservative follow-up to surgical interventions, including endoscopic suturectomy, open craniotomy, and distraction osteogenesis, depending on the presence of neurocognitive issues or elevated ICP. Both siblings currently show normal neurological, cognitive, and motor development without increased ICP, emphasizing the need for ongoing monitoring to identify new developments or recurrence after treatment. Differential diagnoses, such as deformational plagiocephaly, must also be considered in such cases.

Genetic Contributions to Alzheimer's Disease and Frontotemporal Dementia in Admixed Latin American Populations.

Latin America's diverse genetic makeup, shaped by centuries of admixture, presents a unique opportunity to study Alzheimer's disease dementia (AD) and frontotemporal dementia (FTD). Our aim is to identify genetic variations associated with AD and FTD within this population. The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) recruited 2,162 participants with AD, FTD, and healthy controls from six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, and Peru). All participants underwent array, exome, and/or whole-genome sequencing. Population structure was analyzed using Principal Component Analysis and ADMIXTURE, projecting the ReDLat population onto the 1000 Genomes Project database. To identify genes associated with autosomal dominant, autosomal recessive, or X-linked forms of adult-onset dementia, we searched the Online Mendelian Inheritance in Man database and analyzed pedigree information. Variant interpretation followed guidelines from the American College of Medical Genetics and Genomics, and the Guerreiro algorithm was applied for the PSEN1 and PSEN2 genes. Global ancestry analysis of the ReDLat cohort revealed a predominant mix of American, African, and European ancestries. Uniquely, Brazil displayed an additional East Asian component accurately reflecting the historical admixture patterns from this region. We identified 17 pathogenic variants, a pathogenic C9orf72 expansion, and 44 variants of uncertain significance. Among our cohort, 70 families exhibited autosomal dominant inheritance of neurodegenerative diseases, with 48 families affected by AD and 22 by FTD. In families with AD, We discovered a novel variant in the PSEN1 gene, c.519G>T (p.Leu173Phe), along with other previously described variants seen in the region, such as c.356C>T (p.Thr119Ile). In families with FTD, the most commonly associated gene was GRN, followed by MAPT. Notably, we identified a patient meeting criteria for FTD who carried a pathogenic variant in SOD1, c.388G>A (p.Phe21Leu), which had previously been reported in another FTD patient from the same geographical region. This study provides the first snapshot of genetic contributors to AD and FTD in a multisite cohort across Latin America. It will be critical to evaluate the generalizability of genetic risk factors for AD and FTD across diverse ancestral backgrounds, considering distinct social determinants of health and accounting for modifiable risk factors that may influence disease risk and resilience across different cultures.

Congenital Radioulnar Synostosis Review: Recommendations and Treatment Outcomes.

Background/Objectives: Congenital radioulnar synostosis (CRS) is a rare congenital disorder of the elbow joint caused by the abnormal fusion of the radius and ulna during fetal development, leading to limited forearm rotation and functional impairment. This narrative review aims to summarize the key aspects of diagnostic suspicion, treatment options, and lifestyle management strategies for individuals affected by CRS. Relevant sections: While CRS often occurs sporadically, there are familial cases with an autosomal dominant inheritance pattern. The diagnosis is established through a combination of clinical evaluation and radiological imaging, which confirms the presence and extent of the synostosis. Identifying the specific type and severity of CRS is critical for management decisions. Surgical interventions are considered based on factors such as the patient's age, level of functional limitation, and symptom severity, while conservative treatment may be appropriate for cases with mild impairment. Discussion: Various surgical techniques have been described, but derotation osteotomy has emerged as a preferred option due to its predictable improvement in forearm function. Nevertheless, surgical treatment poses challenges, including potential complications like nerve injury and recurrence of deformity. Cultural and individual considerations, such as the desired forearm position, must be addressed to achieve optimal outcomes aligned with the patient's lifestyle and needs. Conclusions: Managing CRS requires a nuanced and individualized approach, recognizing the unique challenges each patient presents. This review highlights the importance of continuous research to refine diagnostic and therapeutic strategies, ultimately aiming to enhance functional outcomes and quality of life for CRS patients.

A systematic review and meta-analysis to determine the biological sex ratio in monogenic genetic and non-genetic dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) is characterised by left ventricular or biventricular systolic dysfunction and dilatation, in the absence of abnormal loading conditions or coronary artery disease (1). Up to 30% of cases have an identified monogenic cause, usually with autosomal dominant (AD) inheritance (2). The disease appears to be twice as common in males, suggesting either a sex specific penetrance or a potential difference in expressivity. This sex ratio has not been systematically evaluated for genetic forms of DCM. Purpose To assess the sex ratio in patients with all-cause DCM compared to genetic (monogenic) and gene-elusive subtypes, defined by the presence or absence of a pathogenic variant in DCM-associated genes. Methods A literature search was conducted to identify cohorts of DCM patients with identifiable sex ratios. Exclusion criteria were patients with syndromic, X-linked, mitochondrial, or autosomal recessive (AR) DCM. Studies with a small cohort size (n<100), a paediatric population, unidentifiable sex ratio, or ischaemic and peripartum DCM were excluded. 98 studies with a total of 36,662 participants were included in this study. A random-effects meta-analysis generated a pooled proportion of female participants with a 95% confidence interval (95% CI) for an overall DCM cohort as well as for the subtypes – all genetic DCM, individual gene level for 10 key DCM genes (including titin, TTN, and lamin, LMNA), and gene elusive DCM. Results The overall DCM cohort had a 0.30 female proportion (95% CI: 0.28-0.32; Figure 1). This corresponds to a male:female (M:F) ratio of 2.38:1. This ratio did not significantly change in patients with an identified causative DCM variant (0.31 [95% CI 0.26-0.36]; M:F ratio of 2.22:1; p=0.563). There was also no significant difference when compared to patients who had been genetically tested with no identified variant (0.30 [95% CI 0.24-0.37]; M:F ratio of 2.29:1; p=0.814). Furthermore, the ratio within participants with AD gene variants was not significantly different for the specific genes of TTN (0.28 [95% CI 0.22-0.36]; M:F ratio of 2.51:1) and LMNA (0.35 [95% CI 0.27-0.44]; M:F ratio of 1.84:1). Overall, the sex ratio amongst patients with these AD gene variants was similar to the all-cause group (0.34 [95% CI 0.28-0.40]; M:F ratio of 1.98:1; p=0.18); Figure 2. Conclusions This meta-analysis suggests that DCM is twice as prevalent in males than females, even in pooled monogenic genetic subtypes with an equally prevalent genetic risk factor, indicating a difference in penetrance between the sexes. Further studies are required to determine the drivers of this sex specific penetrance.Forest plots: overall DCM cohortForest plots: gene-specific DCM cohort

Proposing GLMN, encoding glomulin, as a novel gene for Dowling-Degos disease.

Dowling-Degos disease (DDD) is a rare hyperpigmentation disorder with autosomal-dominant inheritance. To date, work by our group and others has identified a total of four DDD sub-phenotypes, which arise secondary to variants in KRT5, POFUT1, POGLUT1, and PSENEN. We postulate that GLMN is a novel fifth gene for DDD that contributes to a hitherto unrecognized DDD sub-phenotype.

A Novel Pathogenic Mutation in WNK1 Gene Causing HSAN Type II in Three Siblings.

Hereditary sensory and autonomic neuropathy (HSAN) is a rare genetic disorder that primarily affects the peripheral nervous system, leading to a progressive loss of the ability to perceive pain, temperature, and touch. This condition can result in severe complications, including injuries and infections due to the inability to feel pain. HSAN is classified into nine types, with types I and VII exhibiting autosomal dominant inheritance, while the others follow an autosomal recessive pattern. In this study, we examined three affected brothers of Turkish Azeri descent, aged 20, 23, and 25 years. They presented symptoms such as a lack of temperature and pain sensation, frequent wounds and infections, self-harm, and hyperkeratosis. To identify the genetic cause of their condition, whole-exome sequencing (WES) was performed, followed by Sanger sequencing to confirm the findings. The results revealed a homozygous likely pathogenic nonsense mutation, c.2971C > T (p.Arg991Ter), in exon 9 of the WNK1 gene. This mutation results in the truncation of three isoforms of the WNK1 protein, which are essential for pain perception. This discovery enhances our understanding of HSAN and highlights the importance of genetic testing for accurate diagnosis and future screening.

Epidermolytic Hyperkeratosis Type 1 with a New Heterozygous Mutation in KRT1 Gene: A Case Report

Background: Epidermolytic hyperkeratosis (EHK) formerly known as bullous ichthyosiform erythroderma, is a rare autosomal dominant inheritance condition with a prevalence ranging from 1:200,000 to 1:300,000. The underlying etiology of which is a mutation in the genes responsible for keratin proteins synthesis, primarily in KRT1 and KRT10 genes, cataloged under OMIM number 113800. Clinicopathological presentations include blistering in the neonatal period followed by ichthyotic hyperkeratosis in childhood and adolescence, characterized by the hallmark features of generalized dry skin, scaling, hyperkeratosis, and frequently associated with erythroderma. EHK may present with or without palmoplantar keratoderma involvement, depending on the keratin gene variant. Case report: A 24-year-old male of Arab descent was born with diffuse skin hyperkeratotic plates featuring erythematous fissures, covering his entire body, resembling a collodion baby. His birth was full-term via cesarean section without complications, although he later developed developmental dysplasia of the hip. By the time he started primary school, he began experiencing severe thickening of the skin around his joints, reducing flexibility and leading to contractures and significant disfigurement. He is undergoing treatment with acitretin. Genetic testing using Next-Generation Sequencing (NGS) was performed to identify the responsible gene, revealing a novel heterozygous variant in the KRT1 gene (OMIM 139350), while no variant was detected in the KRT10 gene. Conclusion: EHK type 1 manifests with a new heterozygous variant in the KRT1 gene. This rare disorder, associated with variant in genes related to keratin production such as KRT1 and KRT10, results in distinctive skin features present from birth, as well as joint problems and fungal foot infections. Genetic testing has confirmed the presence of a variant in the KRT1 gene.

Hereditary multiple exostoses

Hereditary multiple exostoses is a rare congenital condition with autosomal dominant inheritance. It consists of formation of osteocartilaginous exostoses, most commonly from the metaphysis of long bones. Surgery is the main treatment as there is no available medical treatment. Clinical follow-ups with orthopaedic specialists are important, both in childhood and adulthood. In childhood, focus is on managing symptoms and removing symptomatic exostoses, while in adulthood, MRI is performed to rule out malignant transformation, as argued in this review.

Hereditary heart diseases

This review outlines the workflow for patients and relatives with suspected inherited cardiovascular disease, diagnostic criteria, inheritance patterns, and »red flags« for selected conditions. Evaluation for inherited cardiovascular disease typically includes the index patient (proband) and relatives, emphasizing the importance of assessment at specialized clinics. Most inherited cardiovascular conditions have an autosomal dominant inheritance, but other patterns are seen.

Research progress on GSDME-mediated cell pyroptosis resulting in GSDME type hearing loss

Pyroptosis is a novel mode for programmed cell death discovered and confirmed in recent years. The Gasdermins (GSDMs) family is a key effector molecule mediating pyroptosis. As an important cause of extensive inflammatory damage and side effects of conventional chemotherapy drugs, anomalous pyroptosis has also been associated with hearing loss, tumor, and disorders of the immune system. The GSDME protein, encoded by the GSDME (DFNA5) gene, belongs to the GSDMs family and is a key factor mediating pyroptosis. Gain-of-function variants of the GSDME gene can lead to GSDME-related hearing loss, which shows an autosomal dominant inheritance. This article has reviewed the role of GSDME-mediated pyroptosis in the pathogenesis of GSDME-related hearing loss, with an aim to provide insights into the treatment of GSDME-related hearing loss.

C9orf72 Gene-Associated Frontotemporal Dementia Mimicking Autoimmune Pathology.

The C9orf72 mutation can manifest in diverse clinical ways, including rapid cognitive decline, parkinsonism, or late-life neuropsychiatric symptoms, sometimes mimicking autoimmune encephalitis. A 64-year-old female presented to the autoimmune neurology clinic with rapidly progressive dementia (RPD) associated with episodes of headache, confusion, auditory hallucinations, and abnormal electroencephalogram. She was treated empirically at an outside hospital for possible autoimmune encephalitis with intravenous methylprednisolone, but there was no improvement, and rapid cognitive decline continued. Family history was notable for RPD with akinetic mutism in her sister, sudden severe depression followed by parkinsonism with progressive dementia in her father in his 60s, and late-life gradually progressive dementia in her mother. Additional testing revealed a low titer positive contactin-associated protein-like 2 (CASPR2) immunoglobulin G (IgG) in the serum and elevated CSF 14-3-3 protein. CSF CASPR2 IgG and real-time quaking-induced conversion for Creutzfeldt-Jakob disease were negative. Brain MRI showed normal parenchymal volume. Genetic testing was conducted, which identified a heterozygous pathogenic hexanucleotide tandem repeat expansion in the C9orf72 gene. This case underscores the phenotypic variability of C9orf72 mutation and the importance of a detailed family history exploring young or atypical deaths and neuropsychiatric symptoms or behavioral changes. Genetic etiologies are crucial to consider in those with a family history concerning autosomal dominant inheritance patterns of early-onset dementia, parkinsonism, or late-onset psychiatric disease. Emphasis is placed on considering alternative etiologies early, particularly when there is no response to first-line immunomodulation for suspected autoimmune dementia.

A novel variant in the 3′ UTR of the TCF4 gene likely causes Pitt-Hopkins syndrome: a case report

BackgroundPitt–Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder that results from variants of TCF4 gene. PTHS follows an autosomal dominant inheritance pattern and the underlying pathological mechanisms of this disease are still unclear.MethodsWhole-genome sequencing (WGS) was conducted to screen for potential pathogenic variant in a boy highly suspected of having a genetic disorder. PCR and Sanger sequencing were used to verify the effects of the variant. Serum TCF4 levels were measured by ELISA.ResultsWe present a 4-year and 3-month-old Chinese boy clinically and molecularly diagnosed with PTHS. The proband experienced global development delay, and the preliminary clinical diagnosis was cerebral palsy. WGS identified a de novo heterozygous variant: c.*1A > G in the 3’UTR of the TCF4 gene as a potential cause of his condition. The variant was verified to cause aberrant mRNA splicing by PCR and the aberrant splicing was confirmed by Sanger sequencing.ConclusionThe study identified and demonstrated the pathogenicity of a novel 3’UTR site TCF4 variant for the first time. This research enhances understanding of pathogenetic mechanisms of PTHS and aids genetic counseling and diagnosis.

7316 A Unique Presentation of Diabetes Mellitus in an 8-Year-Old Male Positive For 3 Different Mutations Related to MODY

Abstract Disclosure: R. Senguttuvan: None. A. Pamfil: None. Background: Maturity-Onset Diabetes of the Young (MODY) is the most common form of inherited non-autoimmune diabetes mellitus, characterized by autosomal dominant inheritance, young age at onset and beta cell dysfunction. There are at least 14 MODY mutations and we present a pediatric case not meeting criteria for type 1[T1DM] or type 2 diabetes mellitus[T2DM], who tested positive for mutations in 3 different genes known to cause MODY. Case: An 8-year-old male, born full term, 2776 grams and 48.3 cm, without history of neonatal hypoglycemia or hyperglycemia, was referred for new onset diabetes mellitus management. While undergoing evaluation for abdominal pain and constipation, he was found to have a fasting glucose of 126 mg/dL (7 mmol/L) and hemoglobin A1C of 6.5%. He endorsed polyuria, but no polydipsia. He had no clinical signs of insulin resistance (e.g., acanthosis nigricans) and a BMI of 23.65 kg/m2, at the 97th percentile. Family history is positive for diabetes mellitus requiring insulin, in father (diagnosed at 11 years) and paternal grandmother and T2DM in paternal aunt. Laboratory evaluation was negative for all 5 antibodies (GAD, IA-2, Anti-islet cell antibody, Zinc Transporter 8 and Insulin antibodies) and revealed an insulin level of 15.9 uIU/mL (RR: <2.0-13.0) and C peptide: 2.3 ng/mL (RR: 1.1-4.4). Lacking diagnostic criteria for T1DM or T2DM, genetic testing was performed. Patient tested heterozygous for mutations in 3 genes known to cause MODY: GCK [(c.350 G>T p. (G117V)], ABCC8 [(c.2270 C>G p.(T757R)], and HNF1B [(c.68A>G p.(K23R)], all variant of uncertain significance. Over an 8-month period, patient's weight decreased from 98 lbs. (44.9 kg) to 90 lbs. (41.1 kg) after meeting with our dietician and implementing healthy dietary changes, and his beta cell function markers improved from diagnosis: Fasting insulin (4.5 uIU/mL), C peptide (1.3 ng/mL), and glucose 119 mg/dL; Hemoglobin A1C remained relatively stable at 6.1%. A kidney ultrasound was normal. No medical intervention were started yet, and patient is being monitored clinically and biochemically every 3-4 months. Discussion: Clinical monitoring over time, genetic testing in the parents, are critical in this patient’s long-term treatment plan and prognosis. To our knowledge, this may be the first case of diabetes mellitus in a pediatric patient, positive for mutations in 3 different genes known to cause MODY. South Texas has one of the highest incidences of T2DM in the USA. In addition to screening for genetic forms of diabetes, in patients with negative T1DM antibodies and atypical phenotype for T2DM, we should consider genetic screening in mildly obese pediatric and young adult patients without significant acanthosis nigricans, who were already diagnosed as T2DM. Presentation: 6/1/2024

7328 A case of Adrenal Calcifications in a Patient with Familial Cerebral Cavernous Malformations

Abstract Disclosure: R.I. Dorin: None. L.E. Aguirre: None. M. Bomgardner: None. Background: Familial syndromes of cerebral cavernous malformation (fCCM) having autosomal dominant inheritance and variable penetrance and expression have been linked to loss of function mutations at three genetic loci. The association of small focal adrenal calcifications with fCCM was only recently recognized in a New Mexican cohort of subjects predominately carrying the founder common Hispanic mutation in the CCM1 locus (stop codon Q455X in the Krev1 interaction trapped gene 1 [KRIT1]). We report a case of bilateral, focal adrenal calcifications in a patient affected by fCCM. Clinical Case: A 72-year-old Hispanic male with past medical history of intracranial CCM was referred for osteoporosis and hyperthyroidism due to multinodular goiter. Small focal calcifications of the adrenal glands were incidentally noted on prior imaging studies. There was no history of anticoagulant use, adrenal hemorrhage, or systemic/adrenal infection. The patient was without clinical manifestations of adrenal insufficiency, morning cortisol and plasma ACTH concentrations were normal, and exam was negative for hyperpigmentation or cutaneous vascular malformations. Brain MRI revealed the presence of over 100 parenchymal CCM lesions. A family history of CCM was reported in multiple family members, including 7/10 siblings. Conclusion: In addition to cutaneous malformations, small focal adrenal calcifications are now recognized as one of the extra-neurological manifestations of fCCM, particularly in patients harboring the common Hispanic CCM1/KRIT1 mutation. Whether adrenal calcifications are observed in fCCM patients having other mutations of KRIT1 or other genetic loci of fCCM (CCM2 or PDCD10) remains to be determined. The focal adrenal calcifications are believed to be result of dyssynchronous, subclinical hemorrhagic events related to vascular malformations in the adrenal gland. These findings implicate a role for KRIT1 in endothelial development in the adrenal gland in addition to established role in CNS, spinal cord, and skin. Our patient appeared had normal adrenocortical function, as expected for the focal nature of the adrenal lesions. Though adrenal function has not been evaluated in fCCM patients, there are no reports of primary adrenal insufficiency in fCCM in the literature. Adrenal calcifications may be considered to represent an imaging biomarker for fCCM, and fCCM should be included in the differential diagnosis of adrenal calcifications. The incidental recognition of characteristic small, focal adrenal calcifications in either bilateral or unilateral adrenal glands should prompt evaluation for fCCM.

The membrane curvature-inducing REEP1-4 proteins generate an ER-derived vesicular compartment.

The endoplasmic reticulum (ER) is shaped by abundant membrane curvature-generating proteins that include the REEP family member REEP5. The REEP1 subfamily, consisting of four proteins in mammals (REEP1-4), is less abundant and lack a N-terminal region. Mutations in REEP1 and REEP2 cause Hereditary Spastic Paraplegia, but the function of these four REEP proteins remains enigmatic. Here we show that REEP1-4 reside in a unique vesicular compartment and identify features that determine their localization. Mutations in REEP1-4 that compromise curvature generation, including those causing disease, relocalize the proteins to the bulk ER. These mutants interact with wild-type proteins to retain them in the ER, consistent with their autosomal-dominant disease inheritance. REEP1 vesicles contain the membrane fusogen atlastin-1, but not general ER proteins. We propose that REEP1-4 generate these vesicles themselves by budding from the ER, and that they cycle back to the ER by atlastin-mediated fusion. The vesicles may serve to regulate ER tubule dynamics.

7850 Developmental ZNHIT3 expression in mice embryos in Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome related organs

Abstract Disclosure: D. Kira: None. B. Eroglu, MS, PhD: None. Z. Hawkins: None. L.P. Chorich: None. S. Brakta: None. L.C. Layman: None. Introduction: MRKH is a severe form of the Mullerian duct (MD) anomaly where the upper 2/3 of the vagina and the uterus fail to develop. Individuals with MRKH still have normally functioning ovaries and normal chromosomes. MRKH may be isolated Mullerian aplasia (type 1) or associated with renal, skeletal, cardiac, and/or auditory dysfunction (type 2). The etiology of MRKH syndrome remains unknown for most probands, although a genetic contribution is likely. Most evidence suggests autosomal dominant inheritance with incomplete penetrance. WNT4 and HNF1B pathogenic variants have been identified in some MRKH individuals. Recently, our lab identified heterozygous (HTZ) ZNHIT3 loss of function variants in persons with MRKH, Both variants predict functional changes in the ZNHIT3 C-terminus and impair protein expression in vitro. Previously, other investigators found biallelic variants in the N-terminus of ZNHIT3 in individuals with PEHO syndrome, a severe autosomal recessive neurodevelopmental disorder characterized by extreme cerebellar atrophy. We are currently characterizing a novel Znhit3 knockout (KO) mouse model, in which homozygous KO mice exhibit embryonic lethality. We have demonstrated ZNHIT3 RNA expression in the human uterus, heart, kidney, and skeleton, but developmental expression of ZNHIT3 in wild type (WT) animals has not been studied. In the WT mouse embryo, the kidney forms between E8.0 and E11, while the MDs form through invagination of epithelium ∼E11.5 and extend along the Wolffian duct until reaching the cloaca at ∼E13.5. Hypothesis: We hypothesize that ZNHIT3 is involved in MD development and expressed in the urogenital system and MRKH-related organs during embryonic development of WT mice. Method: Timed mating of WT mice produced embryos for analysis. Embryos were dissected out at E11.5, 12.5 and 13.5, fixed in 4% PFA, embedded in paraffin, and sectioned sagittally at 5mm thickness. H&E staining was done to identify sections showing kidney, genital tubercle, skeleton and cerebellum. Immunohistochemistry was also done using a ZNHIT3 antirabbit antibody and DAPI as nuclear counter stain. Imaging was performed using the Keyence fluorescence microscope (BZ-X800) at 10x and 40x magnification. Results: At all 3 time points, ZNHIT3 protein expression was observed in the developing urogenital organs including kidneys and bipotential gonads, as well as in vertebral bones and cerebellum. Heart protein expression studies are ongoing. Conclusion: ZNHIT3 protein expression is seen as early as E11.5 and is present in MRKH-related organs, suggesting it may play a role in the development of urogenital and MRKH-related organs. These findings provide the basis to compare expression in the Znhit3 KO mouse, a mouse model for MRKH. Presentation: 6/2/2024

Psychosocial impact on individuals who received negative test results from predictive testing for Huntington's disease: Anexploratory qualitative study.

Huntington's disease (HD) is a neurodegenerative disease with autosomal dominant inheritance, and no radical cure for HD has been established. Qualitative studies are necessary to investigate the psychological state of individuals who underwent predictive testing for HD, because the psychosocial impact on noncarriers remains unclarified in Japan. Herein, we elucidated the psychosocial impact on the noncarriers for HD and the role of genetic counseling for predictive testing and follow-up after testing by examining their experiences with predictive testing. We conducted semi-structured interviews with eight individuals participating in this study. Interview data were transcribed verbatim and evaluated according to thematic analysis. As a result, 4 themes were generated from 21 categories of 46 codes: (1) Diversity of perceptions concerning the test results, (2) Views on life as a noncarrier, (3) Changes in feelings toward and relationships with family members, and (4) Sharing information within the family. After receiving the negative results, the noncarriers felt not only relief but also surprise, doubt, relief from tension, and regret. It was shown that noncarriers felt survivor's guilt toward many unspecified individuals, which was not only a sense of guilt but also a sense of mission or responsibility. Additionally, they conducted altruistic behavior as members of their family and society, that may be related to the Japanese collectivism. Some participants were concerned about sharing information with their siblings. Noncarriers for HD can experience complex psychological states, and Japanese people who prefer high-context communication may find it difficult to express their feelings and thoughts. It is important to understand their true feelings before and after the predictive genetic testing, reconsider the impact of being a noncarrier and whether it is a burden for them from both subjective and objective perspectives, and conduct long-term follow-up as needed.

Evaluation of the clinical features of an outpatient cohort with Marfan syndrome

Marfan syndrome is a connective tissue disease with autosomal dominant inheritance and variable clinical presentation. The main clinical manifestations recognition could contribute to early diagnosis and cardiovascular complication prevention. We aimed to evaluate the clinical profile of a Marfan syndrome outpatient cohort. MethodsRetrospective cross-sectional study was carried out with outpatients over 12 years of age whose electronic medical records contained the clinical information and complementary exams necessary for study inclusion. Data were analyzed using descriptive statistics and comparisons were performed using student's t-test and chi-square or Fisher's exact test. P-values<0.05 were considered statistically significant. Results75 patients (29.5 ± 13.4 years) were included and 43(57 %) were female. Positive family history for the syndrome was observed in 55(73 %) patients and ectopia lentis in 37(49 %). Positive systemic score (≥7) was identified in 60(80 %) individuals and the most frequent score components were: skin striae in 64(85 %), scoliosis in 59(79 %), wrist and thumb sign in 45(60 %), moderate or severe myopia in 43(57 %) and plain flat foot in 40(53 %). Cardiovascular symptoms occurred in 17(23 %) patients: dyspnea in 10(13 %) and palpitations in 6(8 %). Mitral valve prolapse was observed in 32(43 %) participants and aortic root dilation (z-score ≥ 2) in 53(71 %), without significant difference between the groups with or without these alterations concerning sex, age, or symptom presence. ConclusionClinical profile of a Marfan syndrome outpatient cohort includes adolescents and young adults, most without cardiovascular symptoms and with a high incidence of skeletal, ophthalmological, and cardiovascular involvement. Recognizing these clinical signs could contribute to early disease diagnosis in the general population.