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Background: A complex inheritance has been suggested in families with colorectal-, gastric- and prostate cancer. Therefore, we conducted a genome-wide association study (GWAS) in colorectal cancer patients, who's relatives had prostate-, and/or gastric cancer. Methods: The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model. Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case–control study. Results: Candidate loci/genes on ten chromosomal regions were suggested with odds ratios between 1.71–3.62 and p-values < 5 × 10–8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of DNA from 122 colorectal cancer patients with gastric- and/or prostate cancer in their families was performed to search for candidate variants in the haplotype regions. The identified candidate variants were tested in a nested case–control study of similar colorectal cancer cases and controls. There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested. Conclusions: This study demonstrated a proof of principle strategy to identify risk variants found by GWAS, and identified ten candidate loci that could be associated with colorectal, gastric- and prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Thrombophilias are characterized by excessive venous and arterial thrombosis at regular or unusual sites. It may result from inherited, acquired, or a combination. Hereditary thrombophilia (HT) is detected in 30–40% of patients with thromboembolism. Venous/arterial thrombosis is considered a multifactorial disorder, some patients may have more than one risk factor which may be transient or permanent. Objectives: Assess the clinical characteristics of patients with unprovoked thromboembolic events and the role of inherited thrombophilia as a causative or additive risk factor. Methods: 210 consecutive adult patients with unprovoked thromboembolic events were reviewed in hematology units at three tertiary Egyptian centers between September 2022 and September 2023. The diagnosis of thromboembolic events was confirmed by clinical and radiological findings. Laboratory screening for thrombophilia-associated. Results: Among our patients, 53(25.2%) patients presented with isolated DVT, followed by portal vein thrombosis, 32(15.2%) had a pulmonary embolism, and sagittal sinus thrombosis was developed in 23(10.9%) patients. Conclusion: Younger people who experience spontaneous thromboembolism run the chance of having hereditary thrombophilia; the more mutations discovered, the higher the risk of thrombosis; the lower leg and deep vein thrombosis were the most common sites. Lastly, MTHFR C677T was the most common polymorphism in Egyptians, detected in almost half of the cases. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor 1 (FGFR1) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l−1, follicle-stimulating hormone (FSH) levels were 1.0 IU l−1, and testosterone levels were 1.3 nmol l−1. In contrast, the de novo group had LH levels of 0.2 IU l−1, FSH levels of 0.5 IU l−1, and testosterone levels of 0.9 nmol l−1, indicating milder hypothalamus–pituitary–gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations.

Background Neurological inherited disorders are rare in domestic animals. Cerebellar cortical degeneration remains amongst the most common of these disorders. The condition is defined as the premature loss of fully differentiated cerebellar components due to genetic or metabolic defects. It has been studied in dogs and cats, and various genetic defects and diagnostic tests (including magnetic resonance imaging (MRI)) have been refined in these species. Cases in cats remain rare and mostly individual, and few diagnostic criteria, other than post-mortem exam, have been evaluated in reports with multiple cases. Here, we report three feline cases of cerebellar cortical degeneration with detailed clinical, diagnostic imaging and post-mortem findings. Case presentation The three cases were directly (siblings, case #1 and #2) or indirectly related (same farm, case #3) and showed early-onset of the disease, with clinical signs including cerebellar ataxia and tremors. Brain MRI was highly suggestive of cerebellar cortical degeneration on all three cases. The relative cerebrospinal fluid (CSF) space, relative cerebellum size, brainstem: cerebellum area ratio, and cerebellum: total brain area ratio, were measured and compared to a control group of cats and reference cut-offs for dogs in the literature. For the relative cerebellum size and cerebellum: total brain area ratio, all affected cases had a lower value than the control group. For the relative CSF space and brainstem: cerebellum area ratio, the more affected cases (#2 and #3) had higher values than the control group, while the least affected case (#3) had values within the ranges of the control group, but a progression was visible over time. Post-mortem examination confirmed the diagnosis of cerebellar cortical degeneration, with marked to complete loss of Purkinje cells and associated granular layer depletion and proliferation of Bergmann glia. One case also had Wallerian-like degeneration in the spinal cord, suggestive of spinocerebellar degeneration. Conclusion Our report further supports a potential genetic component for the disease in cats. For the MRI examination, the relative cerebellum size and cerebellum: total brain area ratio seem promising, but further studies are needed to establish specific feline cut-offs. Post-mortem evaluation of the cerebellum remains the gold standard for the final diagnosis.

Background: Disease-causing variants in the KCNV2 gene are associated with "cone dystrophy with supernormal rod responses," a rare autosomal recessive retinal dystrophy. There is no previous report of hypomorphic variants in the disease. Material and Methods: Medical history, genetic testing, ocular examination, high-resolution retinal imaging including adaptive optics scanning light ophthalmoscopy (AOSLO), and functional assessments. Results: A 16-year-old male with mild cone-rod dystrophy presented with reduced central vision and photophobia. Genetic testing showed two variants in KCNV2, c.614_617dupAGCG (p.207AlafsTer166) and c.854T>G (p.Met285Arg), the latter which was previously considered benign. Electrophysiological assessment revealed the pathognomic electroretinogram waveforms associated with KCNV2-retinopathy. Optical coherence tomography showed discrete focal ellipsoid zone disruption, while fundus autofluorescence was normal. Non-waveguiding cones corresponding to areas of loss of photoreceptor integrity were visible on adaptive optics scanning light ophthalmoscopy. Retinal sensitivity and fixation were relatively preserved, with a demonstrable deterioration after 14 months of follow-up. Conclusions: We provide functional and structural evidence that the variant M285R is disease-causing if associated with a loss-of-function variant. To the best of our knowledge, this is the first hypomorphic allele reported in KCNV2. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor 1 (FGFR1) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l−1, follicle-stimulating hormone (FSH) levels were 1.0 IU l−1, and testosterone levels were 1.3 nmol l−1. In contrast, the de novo group had LH levels of 0.2 IU l−1, FSH levels of 0.5 IU l−1, and testosterone levels of 0.9 nmol l−1, indicating milder hypothalamus–pituitary–gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations. [ABSTRACT FROM AUTHOR]

Background: Neurological inherited disorders are rare in domestic animals. Cerebellar cortical degeneration remains amongst the most common of these disorders. The condition is defined as the premature loss of fully differentiated cerebellar components due to genetic or metabolic defects. It has been studied in dogs and cats, and various genetic defects and diagnostic tests (including magnetic resonance imaging (MRI)) have been refined in these species. Cases in cats remain rare and mostly individual, and few diagnostic criteria, other than post-mortem exam, have been evaluated in reports with multiple cases. Here, we report three feline cases of cerebellar cortical degeneration with detailed clinical, diagnostic imaging and post-mortem findings. Case presentation: The three cases were directly (siblings, case #1 and #2) or indirectly related (same farm, case #3) and showed early-onset of the disease, with clinical signs including cerebellar ataxia and tremors. Brain MRI was highly suggestive of cerebellar cortical degeneration on all three cases. The relative cerebrospinal fluid (CSF) space, relative cerebellum size, brainstem: cerebellum area ratio, and cerebellum: total brain area ratio, were measured and compared to a control group of cats and reference cut-offs for dogs in the literature. For the relative cerebellum size and cerebellum: total brain area ratio, all affected cases had a lower value than the control group. For the relative CSF space and brainstem: cerebellum area ratio, the more affected cases (#2 and #3) had higher values than the control group, while the least affected case (#3) had values within the ranges of the control group, but a progression was visible over time. Post-mortem examination confirmed the diagnosis of cerebellar cortical degeneration, with marked to complete loss of Purkinje cells and associated granular layer depletion and proliferation of Bergmann glia. One case also had Wallerian-like degeneration in the spinal cord, suggestive of spinocerebellar degeneration. Conclusion: Our report further supports a potential genetic component for the disease in cats. For the MRI examination, the relative cerebellum size and cerebellum: total brain area ratio seem promising, but further studies are needed to establish specific feline cut-offs. Post-mortem evaluation of the cerebellum remains the gold standard for the final diagnosis. [ABSTRACT FROM AUTHOR]

Clouding of the transparent eye lens, or cataract(s), is a leading cause of visual impairment that requires surgical replacement with a synthetic intraocular lens to effectively restore clear vision. Most frequently, cataract is acquired with aging as a multifactorial or complex trait. Cataract may also be inherited as a classic Mendelian trait—often with an early or pediatric onset—with or without other ocular and/or systemic features. Since the early 1990s, over 85 genes and loci have been genetically associated with inherited and/or age-related forms of cataract. While many of these underlying genes—including those for lens crystallins, connexins, and transcription factors—recapitulate signature features of lens development and differentiation, an increasing cohort of unpredicted genes, including those involved in cell-signaling, membrane remodeling, and autophagy, has emerged—providing new insights regarding lens homeostasis and aging. This review provides a brief history of gene discovery for inherited and age-related forms of cataract compiled in the Cat-Map database and highlights potential gene-based therapeutic approaches to delay, reverse, or even prevent cataract formation that may help to reduce the increasing demand for cataract surgery. [ABSTRACT FROM AUTHOR]

Abstract Background In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). Hypothesis/Objectives To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. Animals Twelve neurologically affected QH foals and the dams. Methods Genomic DNA was isolated and pedigrees were manually constructed. Results All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma‐glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0–18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. Conclusions and Clinical Importance EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs

Abstract Background Equine neuroaxonal dystrophy/degenerative myeloencephalopathy (eNAD/EDM) is a neurodegenerative disease that primarily affects young, genetically predisposed horses that are deficient in vitamin E. Equine NAD/EDM has not previously been documented in Gypsy Vanner horses (GVs). Objectives To evaluate: (1) the clinical phenotype, blood vitamin E concentrations before and after supplementation and pedigree in a cohort of GV horses with a high prevalence of neurologic disease suspicious for eNAD/EDM and (2) to confirm eNAD/EDM in GVs through postmortem evaluation. Animals Twenty‐six GVs from 1 farm in California and 2 cases from the Midwestern U.S. Methods Prospective observational study on Californian horses; all 26 GVs underwent neurologic examination. Pre‐supplementation blood vitamin E concentration was assessed in 17‐ GVs. Twenty‐three were supplemented orally with 10 IU/kg of liquid RRR‐alpha‐tocopherol once daily for 28 days. Vitamin E concentration was measured in 23 GVs after supplementation, of which 15 (65%) had pre‐supplementation measurements. Two clinically affected GVs from California and the 2 Midwestern cases had necropsy confirmation of eNAD/EDM. Results Pre‐supplementation blood vitamin E concentration was ≤2.0 μg/mL in 16/17 (94%) of GVs from California. Post‐supplementation concentration varied, with a median of 3.39 μg/mL (range, 1.23‐13.87 μg/mL), but only 12/23 (52%) were normal (≥3.0 μg/mL). Normalization of vitamin E was significantly associated with increasing age (P = .02). Euthanized horses (n = 4) had eNAD/EDM confirmed at necropsy. Conclusions and Clinical Importance GVs could have a genetic predisposition to eNAD/EDM. Vitamin E supplementation should be considered and monitored in young GVs.

Background: Equine neuroaxonal dystrophy/degenerative myeloencephalopathy (eNAD/EDM) is a neurodegenerative disease that primarily affects young, genetically predisposed horses that are deficient in vitamin E. Equine NAD/EDM has not previously been documented in Gypsy Vanner horses (GVs). Objectives: To evaluate: (1) the clinical phenotype, blood vitamin E concentrations before and after supplementation and pedigree in a cohort of GV horses with a high prevalence of neurologic disease suspicious for eNAD/EDM and (2) to confirm eNAD/EDM in GVs through postmortem evaluation. Animals: Twenty‐six GVs from 1 farm in California and 2 cases from the Midwestern U.S. Methods: Prospective observational study on Californian horses; all 26 GVs underwent neurologic examination. Pre‐supplementation blood vitamin E concentration was assessed in 17‐ GVs. Twenty‐three were supplemented orally with 10 IU/kg of liquid RRR‐alpha‐tocopherol once daily for 28 days. Vitamin E concentration was measured in 23 GVs after supplementation, of which 15 (65%) had pre‐supplementation measurements. Two clinically affected GVs from California and the 2 Midwestern cases had necropsy confirmation of eNAD/EDM. Results: Pre‐supplementation blood vitamin E concentration was ≤2.0 μg/mL in 16/17 (94%) of GVs from California. Post‐supplementation concentration varied, with a median of 3.39 μg/mL (range, 1.23‐13.87 μg/mL), but only 12/23 (52%) were normal (≥3.0 μg/mL). Normalization of vitamin E was significantly associated with increasing age (P =.02). Euthanized horses (n = 4) had eNAD/EDM confirmed at necropsy. Conclusions and Clinical Importance: GVs could have a genetic predisposition to eNAD/EDM. Vitamin E supplementation should be considered and monitored in young GVs. [ABSTRACT FROM AUTHOR]

Background: In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). Hypothesis/Objectives: To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. Animals: Twelve neurologically affected QH foals and the dams. Methods: Genomic DNA was isolated and pedigrees were manually constructed. Results: All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma‐glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0–18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. Conclusions and Clinical Importance: EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs <1 month of age in North America that is etiologically distinct from other clinically similar neurological disorders. Once the causative variant for EJSCA is validated, carriers can be identified through genetic testing to inform breeding decisions. [ABSTRACT FROM AUTHOR]

Hereditary colorectal cancer has been an area of focus for research and public health practitioners due to our ability to quantify risk and then act based on such results by enrolling patients in surveillance programs. The wide access to genetic testing and whole-genome sequencing has resulted in identifying many low/moderate penetrance genes. Above all, our understanding of the family component of colorectal cancer has been improving. Polygenic scores are becoming part of the risk assessment for many cancers, and the data about polygenic risk scores for colorectal cancer is promising. The challenge is determining how we incorporate this data in clinical care. [ABSTRACT FROM AUTHOR]

Background: Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life‐limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND. Methods: We undertook a UK‐based interview study with 35 individuals, including: 7 people living with genetically‐mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners. Results: We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open‐ended, tailored support and information provision. Conclusions: Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken‐for‐granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public‐facing resource on the healthtalk.org website. Patient or Public Contribution: People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel. [ABSTRACT FROM AUTHOR]

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes. [ABSTRACT FROM AUTHOR]

Background: The CRX-associated autosomal dominant retinopathies suggest a possible pathogenic mechanism of gene haploinsufficiency. However, based on reported human patient cases and studies with mouse models, it is hard to confirm the specific weight of haploinsufficiency in pathogenesis due to the interspecies gaps between gene expression and function. Methods: We created monoallelic CRX by replacing one allele with tdTomato in human embryonic stem cells (hESCs) and subsequently dissect pathogenesis in hESCs-derived retinal organoids. We used transcriptome and immunofluorescence analyses to dissect phenotypic differences between CRX-monoallelic knockout and control wildtype organoids. For location analysis of CRX+ cells, a CRX-expression-tracing system was constructed in control hESCs. We implemented long-term live-cell imaging to describe the translocation of CRX+ cells between two groups in early organoid differentiation. The expression pattern of these dynamic differences was validated using RNA-seq and immunofluorescence assays. Results: We identified delayed differentiation of outer nuclear layer (ONL) stratification along with thinner ONL, serious loss of photoreceptor outer segments, as well as downregulated expression of gene for phototransduction and inner/outer segment formation. By live-cell imaging and immunostaining, we observed the overtension of actomyosin network and the arrested translocation of monoallelic CRX+ cells in the early stage of retinal differentiation. Conclusions: We confirmed that gene haploinsufficiency is the mechanism for the dominant pathogenicity of CRX and discovered that CRX regulated postmitotic photoreceptor precursor translocation in addition to its specification of photoreceptor cell fates during human retinal development. These findings revealed a new underlying mechanism of CRX dominant pathogenesis and provided a new clue for the treatment of CRX-associated human retinopathies. [ABSTRACT FROM AUTHOR]

To describe the largest, most phenotypically and genetically diverse cohort of patients with inherited retinal disease (IRD)-related Coats-like vasculopathy (CLV). Multicenter retrospective cohort study. A total of 67 patients with IRD-related CLV. Review of clinical notes, ophthalmic imaging, and molecular diagnosis from 2 international centers. Visual function, retinal imaging, management, and response to treatment were evaluated and correlated. The prevalence of IRD-related CLV was 0.5%; 54% of patients had isolated retinitis pigmentosa (RP), 21% had early-onset severe retinal dystrophy, and less frequent presentations were syndromic RP, sector RP, cone-rod dystrophy, achromatopsia, PAX6 -related dystrophy, and X-linked retinoschisis. The overall age of patients at CLV diagnosis was 30.7 ± 16.9 years (1–83). Twenty-one patients (31%) had unilateral CLV, and the most common retinal features were telangiectasia, exudates, and exudative retinal detachment (ERD) affecting the inferior and temporal retina. Macular edema/schisis was observed in 26% of the eyes, and ERD was observed in 63% of the eyes. Fifty-four patients (81%) had genetic testing, 40 of whom were molecularly solved. Sixty-six eyes (58%) were observed, 17 eyes (15%) were treated with a single modality, and 30 eyes (27%) had a combined approach. Thirty-five eyes (31%) were "good responders," 42 eyes (37%) were "poor responders," 22 eyes (19%) had low vision at baseline and were only observed, and 12 eyes (11%) did not have longitudinal assessment. Twenty-one observed eyes (62%) responded well versus 14 (33%) treated eyes. Final best-corrected visual acuity was significantly worse than baseline (P = 0.002); 40 patients (60%) lost 15 ETDRS letters or more over follow-up in 1 or both eyes, and 21 patients (31%) progressed to more advanced stages of visual impairment. Inherited retinal disease–related CLV is rare, sporadic, and mostly bilateral; there is no gender predominance, and it can occur in diverse types of IRD at any point of the disease, with a mean onset in the fourth decade of life. Patients with IRD-related CLV who have decreased initial visual acuity, ERD, CLV changes affecting 2 or more retinal quadrants, and CRB1 - retinopathy may be at higher risk of a poor prognosis. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Background: Rare coagulation factor deficiencies and disorders of fibrinolysis (defined as rare bleeding disorders [RBDs]) present with a heterogeneous bleeding phenotype, and bleeding severity is difficult to predict. Objectives: Describe underlying rare genetic variants in the Dutch RBD population and investigate the relationship between genotype, laboratory phenotype, and clinical phenotype. Methods: The Rare Bleeding Disorders in the Netherlands is a cross-sectional, nationwide study conducted between October 1, 2017, and November 30, 2019. Bleeding scores and blood samples were collected during a single study visit. Coagulation factor levels were measured centrally, and targeted exome analysis was performed on 156 genes involved in thrombosis and hemostasis. Pathogenicity was assigned according to the Association for Clinical Genetic Science guidelines. Results: Rare genetic variants specific to the diagnosed RBD were found in 132 of 156 patients (85%). Of the 214 rare genetic variants identified, 57% (n = 123) were clearly pathogenic, 19% (n = 40) were likely pathogenic, and 24% (n = 51) were variants of unknown significance. No explanatory genetic variants were found in patients with plasminogen activator inhibitor type 1 deficiency or hyperfibrinolysis. A correlation existed between factor activity levels and the presence of a genetic variant in the corresponding gene in patients with rare coagulation factor deficiencies and alpha-2-antiplasmin deficiency. Co-occurrence of multiple genetic variants was present in a quarter of patients, but effect on phenotype remains unclear. Conclusion: Targeted exome analysis may offer advantages over single-gene analysis, emphasized by a number of combined deficiencies in this study. Further studies are required to determine the role of co-occurring hemostasis gene variants on the bleeding phenotype in RBDs.

Abstract Background Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life‐limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND. Methods We undertook a UK‐based interview study with 35 individuals, including: 7 people living with genetically‐mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners. Results We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open‐ended, tailored support and information provision. Conclusions Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken‐for‐granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public‐facing resource on the healthtalk.org website. Patient or Public Contribution People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel.

Chromosomal inversions are usually balanced structural chromosomal rearrangements that do not have an impact on the clinical phenotype of a carrier. The main clinical consequence of inversions is the risk for unbalanced gametes and offspring with severe phenotypes. Rarely though, inversions are associated with a phenotype, mainly due to submicroscopic Copy Number Variants (CNVs) or disruption at the breakpoints of a functionally important gene and/or genomic elements. In this study, a paracentric inversion of chromosome 16 [inv(16)(q22.3q24.1)] was identified in a three-generation family with discordant phenotypes with/without epilepsy and/or intellectual impairment, as well as with an unaffected carrier. This finding was confirmed by fluorescence in situ hybridization (FISH). Genetic investigation, initially with chromosomal microarray (CMA), did not reveal any copy number variants. Finally, Clinical Exome Sequencing (CES), detected the presence of a pathogenic nonsense variant (rs797044912) in the Chromodomain Helicase DNA-binding protein 2 (CHD2) gene [NM_001271.4:c.5035C>T p.(Arg1679Ter)]. CHD2 pathogenic variants have been associated with Developmental and Epileptic Encephalopathy-94 (DEE-94), a rare yet severe condition, characterized by developmental delay, seizures with an early onset, intellectual impairment, autism spectrum disorder, and sometimes behavioral issues. Family testing showed that the variant segregated with phenotypic heterogeneity in the affected individuals and appears to be causative. To the best of our knowledge, this is the first CHD2 pathogenic variant segregating in a three-generation family and the fourth familial case reported. These results further support our previous findings that familial, balanced rearrangements with discordant phenotypes in the same family are, in the vast majority, coincidental.

IntroductionA family history is impacting the individual’s risk perception. The objective of this systematic review was to describe inherited risk perceptions of type 2 diabetes from the citizen’s viewpoint. The aim was to summarize and increase understanding so that the increased knowledge could be used effectively in type 2 diabetes risk communication in health care.MethodsWe conducted a systematic review using CINAHL, Medline, and Scopus databases for hereditary, risk, perception, and diabetes related concepts, within the date range of 1.1.2017 to 2.8.2022. Eligible articles were English, peer-reviewed, and addressed the research question: how is hereditary risk of type 2 diabetes perceived? Returns were viewed independently by two authors, and evaluated using the appraisal criteria of the Joanna Briggs Institute. A thematic analysis was used for the synthesis of the data, yielding three themes describing perceptions of inherited risk in type 2 diabetes.ResultsA total of 32 articles were included, of which 23 were quantitative, 5 qualitative, and 4 were mixed-methods studies. The extracted themes were (1) Identifying heredity as a risk factor, (2) Diversity of hereditary risk, and (3) Perception of the magnitude of personal risk.DiscussionThe perception towards hereditary risk can vary from a desire to actively make a lifestyle change, to the view that diabetes is inevitable regardless of lifestyle. A positive family history increases the risk perception of type 2 diabetes, but the perceived magnitude of the risk may vary from person to person. The findings have the potential to be applied in healthcare’s risk communication.

Introduction: Inherited bleeding disorders (IBD) are genetic conditions that affect blood clotting, leading to complications such as prolonged or spontaneous bleeding into muscles or joints. Early identification and treatment are crucial to prevent complications and improve outcomes. However, effective patient outreach and identification programs for IBD face significant challenges globally. Aim: This study aimed to identify successful patient outreach initiatives for IBD, barriers encountered during implementation, and approaches used to overcome them. Methods: The World Federation of Haemophilia (WFH) conducted a survey of its national member organizations and other patient associations, totalling 153 organizations, to identify common strategies, barriers to their implementation, and solutions for outreach and the identification of people with IBD. The survey consisted of both closed‐ended and open‐ended questions, and the data were analysed using descriptive statistics and thematic analysis. Results: Common challenges included resource and sustainability‐related aspects such as financial constraints, limited lab equipment for diagnosis, and inadequate government commitment. Significant barriers also encompassed physical/geographical challenges like difficulty accessing remote areas, and inadequate logistical support and transportation. Seven themes emerged to enhance patient outreach: resource mobilization; awareness‐raising and advocacy; knowledge and capacity building; collaboration and partnership; decentralization of services; improved logistical support and infrastructure; utilization of technology and innovation; and financial aid and incentives. Conclusion: Multistakeholder collaboration, coupled with secured government commitment, is crucial for improving global outreach, diagnosis rates, and access to care for individuals with IBD. Customized outreach programs should consider regional contexts, financial constraints, and prioritize innovation. [ABSTRACT FROM AUTHOR]

Diagnosis and risk stratification of rare genetic heart diseases remains clinically challenging. In many cases, there are few data and insufficient numbers to support randomized controlled trials. While implantable cardioverter defibrillator (ICD) use is vital to protect higher-risk individuals from life-threatening ventricular arrhythmias, low-risk individuals also require protection from unnecessary ICDs and their associated complications. Once an ICD has been implanted, appropriate device programming is essential to ensure maximal protection while balancing the risks of inappropriate therapy. [ABSTRACT FROM AUTHOR]

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD. [ABSTRACT FROM AUTHOR]

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies. [ABSTRACT FROM AUTHOR]

Abstract Background Carers of people living with rare diseases report heavy burden and a plethora of unmet needs. A previous parental supportive care needs framework has described the needs of parents of children living with rare diseases, but it is not specific to rare inherited diseases (RIDs) and does not include non-parental carers. We conducted a targeted literature review to: (1) ascertain the burden/supportive care needs of informal carers of people living with RIDs, (2) understand the burden/supportive care needs unique to these carers, and (3) develop a conceptual model based on the findings. Methods A targeted literature review searching Embase and Medline between 2000 and 2020 was conducted to identify journal articles describing the burden/supportive care needs of all types of informal carers of people living with RIDs. Thematic analysis was conducted on the articles to develop a conceptual model. Results After screening and quality appraisal, 31 journal articles were analysed, representing 70 RIDs (including bleeding, bone, central nervous system, multisystem and inherited metabolic disorders). Most articles (74%) focused on parent carer samples. The conceptual model has three overarching domains, encompassing 13 themes: (1) Living with Rare Inherited Disease (Being a Carrier of Rare Disease, Carer Perceptions, Disease Severity); (2) Carer Needs/Burden (Social/Community, Well-being, Information, Practical); and (3) Carer Coping Strategies (Acceptance, Support Systems, Gratitude and Hope, Faith, Quest for Knowledge, Establish a Routine). Our conceptual model uniquely describes carers’ transmission guilt, clinically relevant depression and anxiety, worry about future family members living with the RID, and challenging decisions about having more children. Carers often implemented psychological, structural, practical, and social coping strategies to manage their burdens. Conclusions The identified burdens underscore the need for the provision of information and social support to these carers. Future research should focus on the (1) potential mediators/moderators of carers’ burden, (2) needs of carers within the wider family including siblings and grandparents, (3) needs of carers of adults living with RIDs, including spouses and children, and (4) biopsychosocial effect on carers living with a RID themselves. Our conceptual model offers a potential tool for healthcare professionals to utilise during the provision of support to carers.

Inherited Dystrophic Epidermolysis Bullous (DEB) is a rare disease, a subtype of Epidermolysis Bullous (EB) due to mutations in collagen VII, COL7A1. The clinical features of DEB were mucocutaneous blisters, hemorrhagic bullous, and secondary erosions due to minor mechanical trauma. Oral manifestations of DEB can affect the patient's Quality of Life (QoL). The objective of this case report is to describe the oral manifestation of DEB and its management to improve the QoL in a pediatric patient. A 12-year-old girl was referred to Oral Medicine Clinic with a chief complaint of pain throughout the oral mucosa. Based on the OHIP-14 assessment, the patient's QoL was categorized as poor with a score of 46. Extraoral examination revealed clear fluid-filled hemorrhagic bullous lesions and multiple erosive lesions over mostvof the body. Intraoral examination revealed hemorrhagic bullae on the left side of the buccal mucosa and erosive lesions on the mucobuccal folds. Hyperkeratotic lesions were found on the dorsum of the tongue that could not be scraped off. Diagnosis of DEB was established based on histopathology from the left-thigh skin which showed acantholysis with blister formation in the subepidermal layer. The patient was given systemic and topical corticosteroids, antiseptic mouthwash, and multivitamins. Oral lesions were improved after 5 weeks of treatment. Improvement of oral mucosal lesions appeared to be a particularly successful management intervention in improving the QoL for a pediatric patient with DEB. [ABSTRACT FROM AUTHOR]

Purpose: Inherited macrothrombocytopenia is an underdiagnosed condition and may result in misdiagnosis and inappropriate management. This research was done to study this condition in a hospital setting. Materials and Methods: This study was conducted over 6 months in a teaching hospital. Patients whose complete blood count (CBC) samples were sent to the hematology laboratory were included. Patients were suspected to have inherited macrothrombocytopenia according to pre-defined criteria. Demographic information, automated CBC and peripheral smear examination was carried out. Seventy five healthy individuals and 50 patients with secondary thrombocytopenia were also analyzed. Results: Likely inherited macrothrombocytopenia was identified in 75 patients. Automated platelet count in these patients ranged from 26 × 10^9/L to 106 × 10^9/L while MPV ranged from 11.0 to 13.6 fL. There was significant difference (p <.001) in mean platelet volume (MPV) and platelet large cell ratio (P-LCR) amongst patients with likely inherited macrothrombocytopenia, those with secondary thrombocytopenia and the control group. Mean platelet diameter was significantly higher (3.5 ± 1.1μm) in patients with likely inherited macrothromboctopenia compared to those with secondary thrombocytopenia (2.4 ± 0.7μm) and control group (1.9 ± 0.7μm). All patients with suspected inherited macrothrombocytopenia showed abnormal platelet histograms with descending limb in the high volume and red cell zone. Four distinct histogram patterns were identified. Conclusion: Inherited macrothrombocytopenia is an underdiagnosed condition. The patient's history, clinical examination, judicious use of automated CBC data including platelet histograms and careful review of the peripheral blood smear are useful tools to suspect this condition. [ABSTRACT FROM AUTHOR]

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GATA1 is required for normal erythropoiesis. Exonic/intronic GATA1 mutations causes Diamond-Blackfan Anemia (DBA)-like disease. Herein, we present a case of a 5-year-old boy with anemia of unknown etiology. Whole-exome sequencing revealed a de novo GATA1 c.220 + 1G>C mutation. The reporter gene assay revealed that such mutations did not affect on GATA1 transcriptional activity. The normal transcription of GATA1 was disturbed, as evidenced by increased expression of the shorter GATA1 isoform. RDDS prediction analysis revealed that abnormal GATA1 splicing might be the underlying mechanism disrupting GATA1 transcription, thereby impairing erythropoiesis. Prednisone treatment significantly improved erythropoiesis, evidenced by increased hemoglobin and reticulocyte counts. [ABSTRACT FROM AUTHOR]

Inherited retinal dystrophies (IRDs) are a global problem that is largely unaddressed, especially in Africa. Black indigenous Africans are rarely represented in research that develops genetic tests and genetic therapies for IRDs, yet their genomes are more diverse. The aim of this literature review is to synthesize information on the IRD genetic research conducted among indigenous black Africans to identify challenges and opportunities for progress. PubMed was searched to identify empirical publications reporting the genetic analysis of IRDs among indigenous Africans. A total of 11 articles were selected for the review. Based on the information in the articles, the main genetic testing methods in use include next-generation, whole exome, and Sanger sequencing. The main IRDs characterized by the genetic tests include retinitis pigmentosa, Leber Congenital Amaurosis, Stagardt disease, and cone dystrophy. Examples of implicated genes include MERTK, GUCY2D, ABCA4, and KCNV2 for the four IRDs, respectively. Research activities on the genetics of IRDs are generally scanty in Africa. Even in South Africa and North Africa where some research activities were noted, only a few indigenous black Africans were included in the study cohorts. There is an urgent need for genetic research on IRDs, especially in East, Central, and West Africa. [ABSTRACT FROM AUTHOR]

For most health professionals who have chosen the challenging path of comprehending classical homeopathy, the theory of miasms is the most intriguing part of our science and is an area where much misunderstanding, criticism and controversy prevails. There are now a large number of opposing ideas and opinions on the subject of miasms, with various classifications, many of which we believe to be erroneous and which confuse many homeopaths and result in incorrect prescriptions. Here we clarify the main postulates of Hahnemann's miasm theory and analyse how his followers transformed his ideas over the next century in the light of medical discoveries. This allows us to understand the limited relevance of miasm theory to modern day prescribing and offer a new and precise definition of the term miasm in relation to modern diseases such as cancer and autoimmune diseases. How we apply this theory to the health challenges of the 21 st century, such as increasing environmental pollution and other toxins, may play an important role in the future wellbeing of the human population. [ABSTRACT FROM AUTHOR]

Study Aim. At the moment of people's increasingly satisfied material and cultural life, how to meet the spiritual and cultural life has become problematic in rural areas. The original ecological villages have become one of the choices for the people to satisfy spiritual and cultural life. They can improve their physical fitness through the physical exercise of the original ecological villages. They can also learn traditional cultural knowledge, cultivate sentiment, and enhance the inheritance and development of traditional national sports culture. Material and Methods. Therefore, the use of qualitative analysis and quantitative research to describe the current status of the development of the Longlin De 'e Climbing rod, Through literature, field surveys, questionnaire interviews and oral history, and other research methods take the Longlin De 'e Climbing rod as an example to study the status of sports protection in the original ecological village. Results. The conclusion is that the lack of support from government departments in the original ecological village, the weakening of the villagers' sense of recognition of the national culture, and the change in a local social structure made inheritance unsustainable. Conclusions. Therefore, it is recommended that the government should respond to the improvement of the support of the original ecological villages, formulate corresponding measures, enhance the sense of identity in the sports culture of the original ecological village, change the traditional inheritance model, and create a good development and inheritance environment for the sports of the original ecological villages, to achieve the nation Protection of traditional sports culture. [ABSTRACT FROM AUTHOR]

Background: Carers of people living with rare diseases report heavy burden and a plethora of unmet needs. A previous parental supportive care needs framework has described the needs of parents of children living with rare diseases, but it is not specific to rare inherited diseases (RIDs) and does not include non-parental carers. We conducted a targeted literature review to: (1) ascertain the burden/supportive care needs of informal carers of people living with RIDs, (2) understand the burden/supportive care needs unique to these carers, and (3) develop a conceptual model based on the findings. Methods: A targeted literature review searching Embase and Medline between 2000 and 2020 was conducted to identify journal articles describing the burden/supportive care needs of all types of informal carers of people living with RIDs. Thematic analysis was conducted on the articles to develop a conceptual model. Results: After screening and quality appraisal, 31 journal articles were analysed, representing 70 RIDs (including bleeding, bone, central nervous system, multisystem and inherited metabolic disorders). Most articles (74%) focused on parent carer samples. The conceptual model has three overarching domains, encompassing 13 themes: (1) Living with Rare Inherited Disease (Being a Carrier of Rare Disease, Carer Perceptions, Disease Severity); (2) Carer Needs/Burden (Social/Community, Well-being, Information, Practical); and (3) Carer Coping Strategies (Acceptance, Support Systems, Gratitude and Hope, Faith, Quest for Knowledge, Establish a Routine). Our conceptual model uniquely describes carers' transmission guilt, clinically relevant depression and anxiety, worry about future family members living with the RID, and challenging decisions about having more children. Carers often implemented psychological, structural, practical, and social coping strategies to manage their burdens. Conclusions: The identified burdens underscore the need for the provision of information and social support to these carers. Future research should focus on the (1) potential mediators/moderators of carers' burden, (2) needs of carers within the wider family including siblings and grandparents, (3) needs of carers of adults living with RIDs, including spouses and children, and (4) biopsychosocial effect on carers living with a RID themselves. Our conceptual model offers a potential tool for healthcare professionals to utilise during the provision of support to carers. [ABSTRACT FROM AUTHOR]

Abstract Objective This study was designed to determine if CEACAM mutations are associated with inherited risk of colorectal cancer. Recently, protein-truncating mutations in the CEACAM gene family were associated with inherited breast cancer risk. That discovery, along with aberrant expression of CEACAM genes in colorectal cancer tumors and that colorectal cancer and breast cancer share many risk factors, including genetics, inspired our team to search for inherited CEACAM mutations in colorectal cancer cases. Specifically utilizing The Cancer Genome Atlas (TCGA) blood-derived whole-exome sequencing data from the colorectal cancer cohort, rare protein-truncating variants and missense variants were investigated through single variant and aggregation analyses in European American and African American cases and compared to ethnic-matched controls. Results A total of 34 and 14 different CEACAM variants were identified in European American and African American colorectal cancer cases, respectively. Nine missense variants were individually associated with risk, two in African Americans and seven in European Americans. No identified protein-truncating variants were associated with CRC risk in either ethnicity. Gene family and gene-specific aggregation analyses did not yield any significant results.

Abstract Background Dog breeds are known for their distinctive body shape, size, coat color, head type and behaviors, features that are relatively similar across members of a breed. Unfortunately, dog breeds are also characterized by distinct predispositions to disease. We explored the relationships between inbreeding, morphology and health using genotype based inbreeding estimates, body weight and insurance data for morbidity. Results The average inbreeding based on genotype across 227 breeds was Fadj = 0.249 (95% CI 0.235–0.263). There were significant differences in morbidity between breeds with low and high inbreeding (H = 16.49, P = 0.0004). There was also a significant difference in morbidity between brachycephalic breeds and non-brachycephalic breeds (P = 0.0048) and between functionally distinct groups of breeds (H = 14.95 P

Pigment production and distribution is controlled through multiple genes, resulting in a wide range of coat color phenotypes in dogs. Dogs that produce only the pheomelanin pigment vary in intensity from white to deep red. The Poodle breed has a wide range of officially recognized coat colors, including the pheomelanin-based white, cream, apricot, and red coat colors, which are not fully explained by the previously identified genetic variants involved in pigment intensity. Here, a genome-wide association study for pheomelanin intensity was performed in Poodles which identified an association on canine chromosome 18. Whole-genome sequencing data revealed an SNN retrocopy insertion (SNNL1) in apricot and red Poodles within the associated region on chromosome 18. While equal numbers of melanocytes were observed in all Poodle skin hair bulbs, higher melanin content was observed in the darker Poodles. Several genes involved in melanogenesis were also identified as highly overexpressed in red Poodle skin. The most differentially expressed gene however was GPR22, which was highly expressed in red Poodle skin while unexpressed in white Poodle skin (log2 fold change in expression 6.1, P <0.001). GPR22 is an orphan G-protein-coupled receptor normally expressed exclusively in the brain and heart. The SNNL1 retrocopy inserted 2.8 kb upstream of GPR22 and is likely disrupting regulation of the gene, resulting in atypical expression in the skin. Thus, we identify the SNNL1 insertion as a candidate variant for the CFA18 pheomelanin intensity locus in red Poodles. [ABSTRACT FROM AUTHOR]

Background: Emerging treatments are being developed for inherited retinal diseases, requiring a clear understanding of natural progression and a database of potential participants for clinical trials. This article describes the rationale, study design and methodology of the Victorian Evolution of inherited retinal diseases NaTUral history REgistry (VENTURE), including data from the first 150 participants enrolled. Methods: VENTURE collects retrospective and prospective data from people with inherited retinal diseases. Following registration, participants are asked to attend a baseline examination using a standardised protocol to confirm their inherited retinal disease diagnosis. Examination procedures include (i) retinal function, using visual acuity and perimetry; (ii) retinal structure, using multimodal imaging and (iii) patient‐reported outcomes. Participants' molecular diagnoses are obtained from their clinical records or through targeted‐panel genetic testing by an independent laboratory. Phenotype and genotype data are used to enrol participants into disease‐specific longitudinal cohort sub‐studies. Results: From 7 July 2020 to 30 December 2021, VENTURE enrolled 150 registrants (138 families) and most (63%) have a rod‐cone dystrophy phenotype. From 93 participants who have received a probable molecular diagnosis, the most common affected genes are RPGR (13% of all registrants), USH2A (10%), CYP4V2 (7%), ABCA4 (5%), and CHM (5%). Most participants have early to moderate vision impairment, with over half (55%) having visual acuities of better than 6/60 (20/200) at registration. Conclusions: The VENTURE study will complement existing patient registries and help drive inherited retinal disease research in Australia, facilitating access to research opportunities for individuals with inherited retinal diseases. [ABSTRACT FROM AUTHOR]

Introduction: At a population level, there is a poor understanding of the incidence and pre‐disposing risk factors of postpartum haemorrhage (PPH) among women with inherited bleeding disorders (IBD). Aim: To determine the incidence of PPH, and identify maternal factors associated with risk of PPH among women with IBD. Methods: We conducted a retrospective cohort study using data housed within ICES (formerly known as the Institute for Clinical Evaluative Sciences). The cohort included women with an in‐hospital, live or stillborn delivery, between January 2014 and December 2019. The primary outcome was PPH (identified by ICD‐10 code O72). PPH incidence and risk factors were compared between women with and without IBD. Temporal trends were assessed using the Cochrane‐Armitage test. Between group differences were assessed using standardised differences (std. difference). Results: Total 601,773 women were included; 2002 (.33%) had an IBD diagnosis. PPH incidence was 1.5 times higher (7.3 vs. 4.9 cases/100 deliveries, std. difference.1) among women with IBD compared to women without. Women with IBD were slightly older (31.7 vs. 30.7 years), had higher rates of hypertension, previous PPH, and induction of labour. Women with IBD were more frequently diagnosed with anaemia (4.8% vs. 1.8%; std difference.17) and had lower haemoglobin levels at admission for delivery compared to women without IBD. Conclusions: This study contributes to the literature regarding obstetric bleeding among women with IBD, showing that anaemia at delivery may be an important risk factor for PPH. Given their predisposition to anaemia, clarifying this relationship will optimise management and outcomes. [ABSTRACT FROM AUTHOR]

Rationale & Objective: The identification of pathogenic variants in genes associated with chronic kidney disease can provide patients and nephrologists with actionable information to guide diagnoses and therapeutic plans. However, many nephrologists do not use genetic testing despite costs decreasing over time and more widespread availability. Study Design: We conducted a survey to uncover the perceptions of general adult nephrologists about the utility of and barriers to genetic testing in clinical practice. Setting & Participants: The online survey was administered to board-certified nephrologists (n = 10,054) in the United States. Analytical Approach: We analyzed demographic characteristics of the survey respondents and their responses in the context of their use of genetic testing in routine clinical practice. Results: A total of 149 nephrologists completed the survey, with 72% (107 of 149) reporting genetic test use in their practice. On average, tests were ordered for 3.8% of their patient population. Thirty-five percent of responses from nephrologists without a history of genetic test use ranked perceived barriers as “extremely significant” compared with 23% of responses from those who had previously used genetic tests. However, both users and nonusers of genetic tests indicated high cost (users: 46%, 49 of 107; nonusers 69%, 29 of 42) and poor availability or lack of ease (users: 33%, 35 of 107; nonusers: 57%; 24 of 42) of genetic testing as the most significant perceived barriers to implementation. Limitations: The survey used in this study was not previously validated; additionally, because of the relatively small number of responses, there might have been a selection bias among the responders. Conclusions: Although most nephrologists reported using genetic tests in clinical practice, high costs and poor availability or the lack of ease of use were perceived as the most important barriers to routine adoption. These observations indicate that educational programs that cover a range of topics, from genetics of chronic kidney disease to selection of the test, may help mitigate these barriers and enhance the use of genetic testing in nephrology practice.

Hereditary uterine cancer (UC) is traditionally associated with pathogenic/likely pathogenic germline variants (PGVs) in Lynch syndrome genes or PTEN ; however, growing evidence supports a role for other genes that may reveal new clinical management options. In this study we assessed the prevalence and potential clinical impact of PGVs identified in UC patients referred for comprehensive germline genetic testing that combined testing for Lynch syndrome, PTEN , and other cancer predisposition genes. Prevalence of PGVs in patients referred to a single clinical lab for germline genetic testing with an indication of uterine or endometrial cancer were retrospectively assessed and compared by syndrome type, patient age at testing, and self-reported ancestry. Potential clinical actionability of PGVs was based on established guidelines for clinical management, targeted therapies, and clinical trial eligibility. PGVs were detected in 13.6% of the cohort (880/6490). PGVs were most frequently observed in Lynch syndrome genes (60.4%) and PTEN (1.5%), with 38.1% in another cancer predisposition gene (i.e., CHEK2, BRCA1/BRCA2). PGV prevalence was similar for patients <50 years and those ≥50 years (15.1% vs 13.2%). Nearly all PGVs (97.2%) were associated with guideline-recommended management, including cascade testing; 60.5% were associated with FDA-approved therapies; and 35.2% were associated with clinical trials. Focusing germline testing on Lynch syndrome genes and PTEN and limiting testing to patients <50 years of age at diagnosis may overlook a substantial proportion of UC patients who harbor actionable PGVs. Universal comprehensive genetic testing of UC patients could benefit many patients and at-risk family members. • Pathogenic or likely pathogenic germline variants (PGVs) were found in 13.6% of uterine cancer patients tested. • Nearly 40% of PGVs were found outside of Lynch syndrome genes and PTEN. • The prevalences of PGVs in patients <50 years and ≥ 50 years at the time of testing were similar (15.1% vs 13.2%). • Sixty percent of PGVs were associated with FDA-approved therapies and 35% with precision therapy clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Nearly 85%-90% of osteogenesis imperfecta (OI) cases are caused by autosome dominant mutations of COL1A1 and COL1A2 genes, of which de novo mutations cover a large proportion, whereas their characteristics remain to be elucidated. This study aims to compare the differences in clinical and genetic characteristics of de novo and inherited COL1A1/COL1A2 mutations of OI, assess the average paternal and maternal age at conception in de novo mutations, and research the rate of nonpenetrance in inherited mutations. Materials and Methods: A retrospective comparison between de novo and inherited mutations was performed among 135 OI probands with COL1A1/COL1A2 mutations. Mutational analyses of all probands and their family members were completed by Sanger sequencing. A new clinical scoring system was developed to assess the clinical severity of OI quantitatively. Results: A total of 51 probands (37.78%) with de novo mutations and 84 probands (62.22%) with inherited mutations were grouped by the results of the parental gene verification. The proportion of clinical type III (P<0.001) and clinical scores (P<0.001) were significantly higher in de novo mutations. Missense mutations covered a slightly higher proportion of de novo COL1A1 mutations (46.34%) compared with inherited COL1A1 mutations (33.33%), however, lacking a significant difference (P=0.1923). The mean BMD Z/T-score at the lumbar spine in de novo mutations was -2.3 ± 1.5, lower than inherited mutations (-1.7 ± 1.8), but lacking statistical significance (P=0.0742). There was no significant difference between the two groups in OI-related phenotypes (like fracture frequency, blue sclera, and hearing loss) and biochemical indexes. In de novo mutations, the average paternal and maternal age at conception was 29.2 (P<0.05) and 26.8 (P<0.0001), respectively, which were significantly younger than the average gestational age of the population. Additionally, 98.04% of pedigrees (50/51) with de novo mutations were spontaneous conception. The rate of nonpenetrance of parents with pathogenic variants in the inherited mutation group was 25.64% (20/78). Conclusions: Our data revealed that the proportion of clinical type III and clinical scores were significantly higher in de novo mutations than in inherited mutations, demonstrating that de novo mutations are more damaging because they have not undergone purifying selection. [ABSTRACT FROM AUTHOR]

To avoid acquired variants found in the blood, cultured skin fibroblasts are a recommended DNA source for germline genetic testing in patients with hematologic disorders, but data are lacking regarding practicality and limitations. We conducted a retrospective cohort study of 350 subjects with hematologic disorders who underwent skin fibroblast culture for germline genetic testing. We analyzed next‐generation sequencing data from the targeted capture of 144 inherited cancer and bonemarrow failure genes to identify variants at heterozygous and subclonal variant allele frequencies. Sixteen (5%) biopsies failed to culture. Culture failure was more likely in samples with delays in culture initiation (OR = 4.3; p < 0.01) or a pathogenic variant in a telomere gene (OR = 42.6; p < 0.01). Median culture time was 28 days (IQR 22−29 days). Culture time was longer for subjects with prior allogeneic stem cell transplantation (+10.7%; p = 0.02) and shorter in subjects with a heterozygous pathogenic variant (−11.9%; p < 0.01), larger biopsy size (−10.6%; p < 0.01), or lymphoid malignancy (−8.4%; p < 0.01). Subclonal variants were identified in 10 (4%) and confirmed in five (56%) of eight with alternate samples available. Subclonal and discordant variants illustrate that germline testing from cultured skin fibroblasts requires phenotypic correlation and, in rare cases, follow‐up studies for optimal interpretation. [ABSTRACT FROM AUTHOR]

Syncope is a common clinical syndrome with rapid onset and numerous pathogenesis. Among all the types of syncope, patients with cardiovascular disease related syncope have the worst prognosis. Rapid identification, early diagnosis, and accurate evaluation and treatment are vital. This paper briefly reviews the etiology, evaluation, diagnosis and treatment of syncope related to cardiovascular diseases from the perspectives of clinical diagnosis and treatment management. [ABSTRACT FROM AUTHOR]

The etiology of obesity is complex and idiosyncratic—with inherited, behavioral, and environmental factors determining the age and rate at which excessive adiposity develops. Moreover, the etiologic status of an obese phenotype (how and when it developed initially) strongly influences both the short-term response to intervention and long-term health trajectories. Nevertheless, current management strategies tend to be 'one-size-fits-all' protocols that fail to anticipate the heterogeneity of response generated by the etiologic status of each individual's phenotype. As a result, the efficacy of current lifestyle approaches varies from ineffective and potentially detrimental, to clinically successful; therefore, we posit that effective management strategies necessitate a personalized approach that incorporates the subtyping of obese phenotypes. Research shows that there are two broad etiologic subtypes: 'acquired' and 'inherited'. Acquired obesity denotes the development of excessive adiposity after puberty—and because the genesis of this subtype is behavioral, it is amenable to interventions based on diet and exercise. Conversely, inherited obesity subsumes all forms of excessive adiposity that are present at birth and develop prior to pubescence (pediatric and childhood). As the inherited phenotype is engendered in utero, this subtype has irreversible structural (anatomic) and physiologic (metabolic) perturbations that are not susceptible to intervention. As such, the most realizable outcome for many individuals with an inherited subtype will be a 'fit but fat' phenotype. Given that etiologic subtype strongly influences the effects of intervention and successful health management, the purpose of this 'perspective' article is to provide a concise overview of the differential development of acquired versus inherited obesity and offer insight into subtype-specific management. [ABSTRACT FROM AUTHOR]

Abstract Chromosomal copy number variants (CNVs) are an important cause of congenital malformations and mental retardation. This study reported a large Chinese pedigree (4-generation, 76 members) with mental retardation caused by chromosome microduplication/microdeletion. There were 10 affected individuals with intellectual disability (ID), developmental delay (DD), and language delay phenotypes. SNP array analysis was performed in the proband and eight patients and found all of them had a microduplication of chromosome 4p16.3p15.2 and a microdeletion of chromosome 8p23.3p23.2. The high-resolution karyotyping analysis of the proband had unbalanced karyotype [46, XY, der(8)t(4;8)(p15.2;p23.1)mat], his mother had balanced karyotype [46, XX, t(4;8) (p15.2;p23.1)], whereas his father had normal karyotype [46,XY]. Fluorescence in situ hybridization (FISH) analysis further confirmed that the proband’s mother had a balanced translocation between the short arm terminal segment of chromosome 4 and the short arm end segment of chromosome 8, ish t(4;8)(8p + ,4q + ;4p + ,8q +). In conclusion, all the patients inherited chromosomes 8 with 4p16.3p15.2 duplication and 8p23.3p23.2 deletion from their parental balanced translocation, which might be the cause of the prevalence of intellectual disability. Meanwhile, 8p23.3p23.2 deletion, rather than 4p16.3p15.2 duplication might cause a more severe clinical syndrome.

Benign familial fleck Retina is a rare inherited retinal disease first reported by Sabel Aish and Dajani in 1980. It is an autosomal recessive condition associated with a distinctive retinal appearance with no apparent visual or electrophysiological deficits. Fundus photography, autofluorescence and enhanced depth optical coherence tomography B-scan imaging modalities aid in the diagnosis. We present a case report of a 19-year-old female diagnosed with benign familial fleck retina which belongs to a heterogeneous group of flecked retina syndromes, and should be considered in patients with yellowish-white retinal lesions sparing the macula.

Introduction: Heritable lung cancer may occur in the context of germline TP53 mutations (Li-Fraumeni syndrome). Limited cases of intrafamily tumor genomic characteristics have been reported. Main concerns, Important Clinical Findings, Primary Diagnoses, Interventions, Outcomes: A 40-year-old woman with no smoking history or known environmental exposure risk was incidentally found to have stage II (T2N1) NSCLC harboring an EGFR exon 19 p.Glu746_Ala750 deletion. Family history was notable for an identical twin sister with colorectal cancer (diagnosed at age 31 y) and a mother with stage I NSCLC harboring an EGFR exon 21 c.2573T>G (p.Leu858Arg) mutation (diagnosed at age 69 y). Genetic testing revealed a germline TP53 c.542G>A (p.Arg181His) mutation in the patient, her mother, and her sister, consistent with Li-Fraumeni syndrome. No germline EGFR mutations were detected. Conclusion: Shared germline TP53 mutations may be associated with distinct NSCLC somatic EGFR mutations within families with Li-Fraumeni syndrome. Further understanding of the association between genetic cancer syndromes and lung cancer risk may improve early lung cancer detection in populations not otherwise meeting screening eligibility.