Autosomal Dominant Pattern Of Inheritance Research Articles

Molecular basis of hereditary cardiomyopathy: A systematic review

Hereditary cardiomyopathies include a diverse spectrum of myocardial disorders characterized by mechanical and electrical abnormalities, among which hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are distinguished. This paper dives into the genetic foundations of these conditions, with a focus on mutations in genes encoding sarcomere proteins, thin filament proteins, and calcium homeostasis regulators. The familial aggregation of cardiomyopathies underscores the substantial genetic component, with autosomal dominant inheritance patterns predominant in some cases. Genetic testing and counseling emerge as pivotal tools for early diagnosis, risk assessment, and the formulation of personalized treatment strategies. The integration of genetic insights into clinical management holds promise for improving patient outcomes and reducing disease burden. Further analysis of the molecular mechanisms underlying hereditary cardiomyopathies is critical for identifying novel therapeutic targets and advancing precision medicine approaches. By comprehensively exploring the genetic underpinnings of cardiomyopathies, this paper contributes to our understanding of these complex diseases and highlights the potential for innovative interventions to enhance patient care in the field of cardiovascular medicine.

#2259 Preimplantation genetic testing in inherited kidney diseases

Abstract Background and Aims Identifying the underlying genetic cause in individuals with monogenic kidney disease allow counselling to provide prognosis and therapeutic options. In addition, discussions may extend to assessing the risk of having affected children and exploring family planning alternatives. Pre-conception counselling covers a wide range of considerations, including the expected pregnancy outcome for both mother and child, the risk of recurrence, invasive prenatal diagnosis, and the option of pre-implantation genetic testing (PGT). In this study we provide a clinical overview of PGT for monogenic kidney disease in our centre. Methods This is a retrospective cohort study of individuals with monogenic kidney disease counselled on our fertility clinic for PGT, in the Fundació Puigvert—Hospital de Sant Pau, Barcelona-Spain from January 2016 to 2023. Results During the study period, 751 visits were made to the fertility clinic, of which 8.3% (63/751) had a monogenic inherited kidney disease (IKD). Regarding the baseline characteristics of individuals with monogenic conditions, most were females (70%; 44/63). The mean age of the women was 33 years, most had no history of pregnancy prior to the first visit (73%). The mean anti-Mullerian hormone (AMH) level was 2.67 ng/ml, with 22% having levels below 1.1 ng/ml. Most cases (84%; 53/63) showed an autosomal dominant pattern of inheritance, with autosomal dominant polycystic kidney disease (ADPKD) being the primary cause in 66% of cases (42/63), followed by tuberous sclerosis complex in 8% (5/63). Autosomal recessive and X-linked disorders were each present in 8% (5/63). Table 1 shows the complete list of genetic kidney disease cases that consulted the fertility clinic. In terms of renal function, affected women had a mean renal function measured by estimated glomerular filtration rate (eGFR) of 90 mil/min/1.73 m2, with 74% having chronic kidney disease (CKD) category G1. Affected male had mean eGFR of 65 mL/min/1.73 m2, with only 38% (6/19 patients) having CKD-G1. Two (13%; 2/19) of the affected men had received a kidney transplant. Of the 63 couples who were counseled, 51% (32/63) agreed to proceed with PGT; 81% (26/32) underwent at least one cycle of ovarian stimulation, in vitro fertilization, and PGT. Fifty per cent (13/26) had a live birth child and 19% (5/26) are currently pregnant. Six couples (10%; 6/32) have pending tests. Among patients who decided not to proceed with PGT (31/63), the main reason for not doing so was that they had a spontaneous pregnancy before the first PGT cycle (35%; 11/31). Low ovarian reserve and couple´s refusal to proceed with PGT were the second most common reasons, each accounting for 22.5% of cases. In 10% (3/31) of cases, the indication for PGT was not yet approved in Spain (mainly because these patients already had a healthy living child). Maternal age over 40 years and the age of the prospective father were the reasons for not performing PGT in 6% and 3% respectively. Of note, a patient with ADPKD presented with a ruptured hepatic cyst after ovarian hormone stimulation. Therefore, PGT was discontinued after two cycles. Conclusion Women with IKD are most likely to request PGT than affected males. The most frequent condition is, by far, ADPKD. Once the technique is explained less than 50% of couples keep wishing to undergo PGT. Low ovarian reserve (which correlates quite well with age) is an important reason that impedes to go through PGT. Larger international studies are needed to understand the patient's uptake of PGT for IKD as well as the access to this technique depending on the country.

Rare dermatosis is disseminated actinic superficial porokeratosis

Porokeratoses are a very rare group of dermatoses, acquired or hereditary, of unknown etiology, characterized by a violation of keratinization. The disease is manifested by one or more atrophic spots, each of which is surrounded by a characteristic hyperkeratotic, ridge-like border called a "horny plate". There are several forms of this pathology, among which there are sporadic cases and family variants with an autosomal dominant pattern of inheritance of various penetrance. This article presents a clinical case of the occurrence of superficial disseminated actinic porokeratosis in a 59-year-old woman after prolonged exposure to the sun. The eruptions were represented by small spots, rounded, pinkish-yellow-brown in color with an atrophic center, surrounded by a raised narrow roller with a groove on the surface, have no tendency to merge, symmetrically arranged. Screening for diseases that cause immunosuppression (human immunodeficiency virus, hematological malignancies) and renal insufficiency did not reveal pathology. Histological examination showed a typical well-limited plume of parakeratotic cells (horn plate), hypogranulosis, dyskeratotic cells or vacuolated keratinocytes, which made it possible to make a final diagnosis. Considering that insolation in this case is a causally significant factor and the likelihood of malignant neoplasms against the background of dermatosis remains, it is extremely important for such patients to use sunscreens with a high degree of protection as part of complex therapy, as well as regular skin examinations.

Genetic analysis of a Chinese pedigree affected with Brachydactyly type B1 due to a novel variant of ROR2 gene

To explore the genetic basis for a Chinese pedigree affected with Brachydactyly type B1 (BDB1) through whole exome sequencing (WES). A BDB1 pedigree admitted to the Affiliated Women and Children's Hospital of Qingdao University on June 25, 2021 was selected as the study subject. Clinical data of the pedigree was collected with informed consent. WES was carried out for the proband, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. WES and Sanger sequencing had identified a heterozygous c.2257delT variant in the ROR2 gene of the proband and his affected father, which has conformed to an autosomal dominant pattern of inheritance. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified to be likely pathogenic (PVS1_Strong+PM2 Supporting+PP4). The c.2257delT variant of the ROR2 gene was unreported previously and is strongly correlated with the BDB1-like phenotype in this pedigree. Above finding has enriched the mutational spectrum of the ROR2 gene and facilitated the diagnosis and genetic counseling for this pedigree.

B-cells absence in patients diagnosed as inborn errors of immunity: a registry-based study.

Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton's agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5-10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in BTK. Three novel mutations in the BTK gene include c.115T > C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (IGHM) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (CD79A) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (TCF3) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern,which includesa missense variant in PIK3CD, a novel missense variant in PIK3R1 and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (RASGRP1) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases.

Blau Syndrome With Delayed Cutaneous Manifestations: A Case Report.

Blau syndrome is a rare familial autoinflammatory disorder characterized by the triad of granulomatous dermatitis, polyarthritis, and uveitis. Blau syndrome exhibits an autosomal dominant inheritance pattern and can be caused by a gain-of-function mutation in nucleotide-binding oligomerization domain 2 (NOD2), a member of the NOD-like receptor family of pattern recognition receptors. Mutations in NOD2 cause upregulation of inflammatory cytokines and resultant autoinflammation. Because of the rarity of this condition and early onset of symptoms, Blau syndrome may be misdiagnosed as juvenile idiopathic arthritis. We present a case of a 37-year-old male patient with a long-documented history of juvenile idiopathic arthritis and uveitis, who developed an asymptomatic eruption of pink papules on the trunk and upper extremities. A biopsy demonstrated noncaseating, well-formed dermal granulomas with relatively sparse lymphocytic inflammation and Langerhans-type giant cells. Genetic testing confirmed a mutation in NOD2. Based on the patient's clinical history, histologic findings, genetic testing, the diagnosis of Blau syndrome was made.

Genetic aortopathies: a case-based approach to multidisciplinary program development.

The incorporation of genetic counseling and testing is essential to evaluation and management of thoracic aortic disease in patients under 60 years of age and those with family histories suspicious for heritable thoracic aortic disease and disorders associated with increased risk for acute type-A aortic dissection. As many as 20% of individuals with thoracic aortic disease under the age of 60 years have autosomal dominant patterns of inheritance. A considerable number of heritability factors remain undefined for these families. Genetic aortopathy programs require a collaborative approach including cardiovascular specialists and surgeons, medical geneticists, genetic counselors, and allied healthcare professionals. Comprehensive evaluation and management of these patients includes collection of detailed phenotypic data to inform the broader community and identify new associated and causative genes of interest, genetic modifiers, and other risk factors. These programs optimize outcomes and reduce the overall burden in the population of acute aortic dissection and related comorbidities.

Post-transplant CFHR5 mutation-related atypical HUS: The need for pre-transplant diagnosis

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) affecting multiple organs and can be sporadic or familial. It is most commonly caused by dysregulation of the alternative complement pathway. aHUS can occur at any age with a high rate of progression to end-stage kidney disease. We describe the case of a 24-year-old man with chronic kidney disease, severe hypertension, and antineutrophilic antibody by IF positive. On biopsy, diffuse global glomerulosclerosis with TMA and IF findings of full house pattern suggestive of lupus nephritis were present. Considering a lupus nephritis case, after 2 years of hemodialysis underwent live-related renal transplant (Father Donor). Immediate post-transplant period developed severe cortical necrosis and TMA. An etiological workup was done to ascertain the cause of post-transplant TMA. After excluding common causes of antibody-mediated rejection (C4d and donor-specific alloantibody neg), calcineurin inhibitor toxicity, and infection, we detected an abnormal complement CFHR5 mutation with an autosomal dominant pattern of inheritance. Pre-transplant diagnosis could have prevented taking the kidney from the father for transplant and further prevented recurrence. Systemic lupus erythematosus and TMA both can have alternate complement pathway dysregulation leading to full house IF pattern and misdiagnosis.

The Role of rs6152 Allele and Non-Genetic Factors in Androgenetic Alopecia: A Pilot Study in the Indonesian Local Population

Background: Androgenetic alopecia (AGA) is a common form of hair loss which inflicts progressive hair loss leading to various patterns. The cause of this disease is believed to be multifactorial, which is majorly attributed to genetic and non-genetic factors. This pilot study aimed to investigate the association of rs6152 allele, a SNP on AR gene, with AGA, as well as explore other contributing factors in the Indonesian local population.
 Methods: In this cross-sectional study, a total of 100 participants, which categorized into alopecia subjects and non-alopecia subjects, were enrolled for rs6152 SNPs detection. Anthropomorphic data such as height and weight, blood pressure and family history were obtained by measurement and questionnaire.
 Results: The study showed low frequency of individuals with rs6152 non-risk alleles (2%) and further analysis showed no significant association between rs6152 allele and AGA. However, familial history analysis revealed a strong association between family history and AGA risks. Additionally, age, gender, hypertension status and BMI were identified as significant factors associated (p-value < 0.05) with AGA.
 Conclusion: rs6152 was not a reliable genetic marker for AGA in the Indonesian local population. While familial history with AGA showed the inheritance pattern of autosomal dominant inheritance with sex limitation, non-genetic factors such as age, gender, hypertension status and BMI were strongly associated with AGA risk. This shows the complexity and multifactorial causes of AGA in the Indonesian local population.

Abstract 6155: Germline variants in cancer susceptibility genes and subsequent neoplasm risks after childhood cancer: A pooled analysis of two large-scale cohorts

Abstract Background: Increasing evidence suggests germline genetic susceptibility influences the risk of developing subsequent neoplasms (SNs)—a major cause of morbidity and mortality—among childhood cancer survivors, but studies have been hampered by sample size and limited gene sets. We pooled two large-scale cohorts of childhood cancer survivors to characterize overall and specific SN risks among individuals carrying germline variants in 88 known cancer susceptibility genes with an autosomal dominant inheritance pattern. Methods: Using whole-genome or whole-exome sequencing data from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort (median [interquartile range] follow-up, 29.7 [13.8] years), we identified rare, potentially protein-damaging germline variants with SnpEff/ClinVar. Conditional logistic regression evaluated overall SN and SN-specific risk, with up to 100 SN-free controls matched to cases by age, sex, primary childhood cancer type, SN type, radiation dose, chemotherapy, study, and follow-up time. Results: Among 11840 individuals (50.6% female) who survived childhood cancer, 2162 (18.3%) developed at least one SN. The risk of developing any SN was elevated among 288 survivors carrying rare, potentially protein-damaging germline variants in an autosomal dominant cancer susceptibility gene (cases=13.3%; controls=9.6%; odds ratio [OR], 1.48; 95% confidence interval [CI], 1.30-1.70; P=5.12x10-5). A similar proportion of carriers was observed among those who developed common SNs such as basal cell carcinoma (N=107/882, 12.1%), meningioma (N=52/373, 13.9%), breast cancer (N=49/353, 13.9%), and thyroid cancer (N=32/243, 13.2%). Higher frequencies of carriers were observed in less common SNs, specifically sarcoma (N=24/151, 15.9%), colorectal cancer (N=15/72, 20.8%), and glioma (N=16/64, 25.0%). The observed associations were generally consistent regardless of treatment type for first primary childhood cancer. Gene-specific analyses revealed that the risk of developing any SN was most pronounced among individuals carrying variants in TP53 (cases=0.6%; controls=0.04%; OR, 9.93; 95% CI, 4.62-21.34; P=0.001) and FANCM (cases=0.9%; controls=0.5%; OR, 2.45; 95% CI, 1.48-4.03; P=0.018). Conclusion: In large-scale cohorts of childhood cancer survivors with long-term follow-up, individuals carrying potentially protein-damaging germline variants in known autosomal dominant cancer susceptibility genes have substantially increased SN risk, emphasizing the importance of genetic testing and consideration of genetic risk in follow-up guidelines. However, these individuals account for a small fraction of all SN cases, warranting future research on underlying risk factors in this population. Citation Format: Shahriar A. Zamani, Danielle M. Karyadi, Stephen W. Hartley, Joshua N. Sampson, Todd Gibson, Peter Kraft, Stephen J. Chanock, Lindsay M. Morton. Germline variants in cancer susceptibility genes and subsequent neoplasm risks after childhood cancer: A pooled analysis of two large-scale cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6155.

Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.

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

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

Síndrome de Lynch. Cáncer de colon familiar no sindrómico

Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome. It accounts for 2% to 4% of all CRC cases globally. It follows an autosomal dominant inheritance pattern and is defined by the presence of a pathogenic germline variant of one of the genes that encodes for DNA repair proteins (MMR), MLH1, MSH2, MSH6, PMS2, or at the 3’ end of the EPCAM gene. This syndrome entails a greater risk of developing CRC and endometrial cancer, in addition to other tumors. Its diagnosis is based on clinical criteria that take into account the family and personal history of cancer, the detection of a deficient MMR phenotype in the tumor tissue, and a genetic study of the germline of individuals at risk of having it. Its early diagnosis allows for establishing screening strategies to try to prevent or detect the presence of tumors in early stages which, in the case of CRC, has been shown to increase survival. Nonsyndromic familial CRC includes cases that have a familial component without a well-established molecular mechanism. They may benefit from more intensive follow-up than what is established for the general population.

A 76-base pair duplication within the enhancer region of the HMX1 gene causes sheep microtia

Sheep congenital microtia is characterized by underdeveloped ears and provides an ideal basis for studying human microtia. This study identified the causal mutation and regulatory mechanisms underlying this disorder. Whole-genome association analysis was conducted using 23 ear tissue samples from sheep with microtia and 28 samples from normal-eared sheep. A significant correlation was found between microtia and a 76-base pair duplication in the enhancer region of the HMX1 gene. Further analysis of offspring phenotypes confirmed an autosomal dominant inheritance pattern. Genotypic analysis showed that individuals that are homozygous for this duplication were earless, heterozygous individuals exhibited shortened ears, and wild-type individuals had normal ears. Moreover, luciferase assays confirmed that this duplication increased HMX1 gene expression, and duplication knock-in mice also exhibited shorter and narrower external ears compared to wild-type mice. Transcriptomic analysis further demonstrated that this duplication enhanced HMX1 gene expression in animal models. This study characterized the causal regulatory mutation underlying sheep microtia.

Role of vosoritide drug on children's with achondroplasia

Achondroplasia is a genetic condition with an autosomal dominant inheritance pattern. It is caused by detrimental heterozygous FGFR3 gene mutations. Gain-of-function mutations in the FGFR3 gene impair chondrocyte differentiation and proliferation, which has a negative impact on the formation of new bone. Vosoritide, also known as voxzogo, is the first pharmacological intervention to receive approval for the treatment of achondroplasia. This therapeutic agent has been sanctioned for administration via at-home injections, which are to be performed under the supervision of a proficient nurse.

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

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

Familial Adenomatous Polyposis within the Pediatric Hereditary Polyposis Registry

Background/Objective: 
 Familial Adenomatous Polyposis (FAP) is a condition characterized by values exceeding hundreds of colorectal adenomatous polyps. FAP has a prevalence of 1 in 8,300 people, demonstrating an autosomal dominant inheritance pattern. This condition follows a pathogenic variation of the Adenomatous Polyposis Coli (APC) gene, located on chromosome 5q21-22. These mutations are heavily correlated with the incidence of colorectal carcinoma, requiring prophylactic colectomy. The management and treatment of FAP requires routine surveillance to reduce gastrointestinal polyp burden. The objective for this study is to characterize the current patient population at Riley with polyposis syndromes and assess clinical surveillance in patients diagnosed with FAP. 
 Methods: 
 Historical data from 2020-2022 GI clinical visits were reviewed using the diagnostic codes Family history of colonic polyps, Benign neoplasm of colon unspecified, and Other phakomatoses not elsewhere classified. These criteria identified 93 patients of which 64 patients were diagnosed with a hereditary polyposis syndrome for inclusion within the registry. Of the 64 patients, 42 had a diagnosis of FAP. Clinical data reviewed included the patient’s age of diagnosis, completion of genetic testing and follow-up, surgical treatment, routine endoscopic surveillance, and modes of imaging. 
 Results: 
 Results indicated a median age of diagnosis of 10 years, lower than previously reported national averages of 13.5-17 years. Evaluation of routine follow-up indicated a rate of endoscopy at 0.822 scopes per year and demonstrated that abdominal CT scans as well as abdominal X-rays were the most common supplemental modes of imaging. 
 Conclusion/ Future Directions: 
 The data from this registry will help direct care of patients with FAP, ensuring they receive treatment in accordance with national guidelines for routine surveillance and prophylactic colectomy. Moving forward, the intention is to expand the registry's date range to incorporate more patients and elaborate further on endoscopic findings for the specific subtypes of FAP.

An Update on the Genetics of Polycystic Ovary Syndrome

PCOS is a common endocrinopathy among women of reproductive age, with a worldwide prevalence of 8 to 13%, depending on the criteria used for diagnosis. It is characterized by a constellation of features, including oligo/anovulation, clinical and/or biochemical hyperandrogenism, and polycystic ovarian morphology. PCOS is one of the common causes of female infertility. It is also associated with metabolic derangements, including obesity, insulin resistance, and compensatory hyperinsulinemia, which increase the likelihood of developing type 2 diabetes mellitus. Despite extensive research, the etiology of PCOS remains largely unknown. It seems likely that the hypothalamic-pituitary-ovarian axis dysfunction, partial folliculogenesis arrest, insulin resistance, and ovarian and adrenal androgen secretion may play a role in the pathogenesis of PCOS. Familial clustering of the cases of PCOS points to a genetic component linked with it. The initial genetic studies suggest an autosomal dominant pattern of inheritance of the disorder in some families; however, most studies support multifactorial origin. Since PCOS is a complex trait, the typical form of inheritance of PCOS follows a non-Mendelian pattern and involves complex genetic mechanisms. Studies involving linkage and association have suggested a connection between genetic variations and the risk of developing PCOS in certain families or populations. Through genome-wide association studies and next-generation sequencing techniques, several candidate genes have been identified that play a role in the etiopathogenesis of the disorder. Pathogenic variants of various genes such as INSR, IRS1, GHRL, LDLR, MC4R, ADIPOQ, UCP1, UCP2, UCP3, FTO, PCSK9, FBN3, NEIL2, FDFT1, PCSK9, CYP11, CYP17, CYP21, HSD17, STAR, POR, AKR1C3, AMH, AMHR2, INHBA, AR, SHBG, LHR, FSHR, FSH β, SRD5A, GATA4, THADA, YAP1, ERBB2, DENND1A, FEM1B, FDFT1, NEIL2, TCF7L2, etc. in some PCOS cases are linked as underlying etiologic associations. This review aims to provide insight into the current genetic knowledge about PCOS. Discovering the genetic factors and pathways involved in the disorder will help us better comprehend the underlying mechanisms of the disorder.

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

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

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

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