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Frontiers in Genetics 2024Bladder exstrophy epispadias complex (BEEC) is a rare congenital anomaly of unknown etiology, although, genetic and environmental factors have been associated with its...
INTRODUCTION/BACKGROUND
Bladder exstrophy epispadias complex (BEEC) is a rare congenital anomaly of unknown etiology, although, genetic and environmental factors have been associated with its development. Variants in several genes expressed in the urogenital pathway have been reported as causative for bladder exstrophy in human and murine models. The expansion of next-generation sequencing and molecular genomics has improved our ability to identify the underlying genetic causes of similarly complex diseases and could thus assist with the investigation of the molecular basis of BEEC.
OBJECTIVE
The objective was to identify the presence of rare heterozygous variants in genes previously implicated in bladder exstrophy and correlate them with the presence or absence of bladder regeneration in our study population.
PATIENTS AND METHODS
We present a case series of 12 patients with BEEC who had bladder biopsies performed by pediatric urology during bladder neck reconstruction or bladder augmentation. Cases were classified as "sufficient" or "insufficient" (n = 5 and 7, respectively) based on a bladder volume of greater than or less than 40% of expected bladder size. Control bladder tissue specimens were obtained from patients (n = 6) undergoing biopsies for conditions other than bladder exstrophy. Whole exome sequencing was performed on DNA isolated from the bladder specimens. Based on the hypothesis of mutations, as well as the potential implications of autosomal dominant conditions with incomplete penetrance, each case was evaluated for autosomal dominant variants in a set of genes previously implicated in BEEC.
RESULTS
Our review of the literature identified 44 genes that have been implicated in human models of bladder exstrophy. Our whole exome sequencing data analysis identified rare variants in two of these genes among the cases classified as sufficient, and seven variants in five of these genes among the cases classified as insufficient.
CONCLUSION
We identified rare variants in seven previously implicated genes in our BEEC specimens. Additional research is needed to further understand the cellular signaling underlying this potentially genetically heterogeneous embryological condition.
PubMed: 38903756
DOI: 10.3389/fgene.2024.1266210 -
Biochemical and Biophysical Research... Jun 2024Leukemia is a complex disease shaped by the intricate interplay of genetic and environmental factors. Given our preliminary data showing different leukemia incidence in...
Leukemia is a complex disease shaped by the intricate interplay of genetic and environmental factors. Given our preliminary data showing different leukemia incidence in genetically homogenous AKR mice harboring the spontaneous leukemia-inducing mutation Rmcfs, we sought to unravel the role of metabolites and gut microbiota in the leukemia penetrance. Our metabolomic analysis revealed distinct serum metabolite profiles between mice that developed leukemia and those that did not. We discovered that linoleic acid (LA), an essential ω-6 polyunsaturated fatty acid, was significantly decreased in the leukemia group, with the lower levels observed starting from 25 weeks before the onset. A predictive model based on LA levels demonstrated high accuracy in predicting leukemia development (area under curve 0.82). In vitro experiment confirmed LA's cytotoxic effects against leukemia cells, and in vivo study showed that a diet enriched with LA prolonged survival in AKR mice. Furthermore, gut microbiome analysis identified specific Lachnospiraceae species, that affect host lipid metabolism, are exclusively present in the leukemia group, suggesting their potential influence on LA metabolism and leukemia development. These findings shed light on the complex relationship between metabolites, gut microbiota, and leukemia development, providing valuable insights into the role of non-genetic factors in leukemia penetrance and potential strategies for leukemia prevention.
PubMed: 38901226
DOI: 10.1016/j.bbrc.2024.150257 -
Heart Failure Reviews Jun 2024Inherited cardiomyopathies are genetic diseases that can lead to heart failure and sudden cardiac death. These conditions tend to run in families, following an autosomal... (Review)
Review
Inherited cardiomyopathies are genetic diseases that can lead to heart failure and sudden cardiac death. These conditions tend to run in families, following an autosomal dominant pattern where first-degree relatives have a 50% chance of carrying the pathogenic variant. Despite significant advancements and increased accessibility of genetic testing, accurately predicting the phenotypic expression of these conditions remains challenging due to the inherent variability in their clinical manifestations and the incomplete penetrance observed. This poses challenges in providing patient care and effectively communicating the potential risk of future disease to patients and their families. To address these challenges, this review aims to synthesize the available evidence on penetrance, expressivity, and factors influencing disease expression to improve communication and risk assessment for patients with inherited cardiomyopathies and their family members.
PubMed: 38898187
DOI: 10.1007/s10741-024-10405-x -
European Journal of Medical Genetics Jun 2024Retinoblastoma is the most common eye cancer in children. It is caused by pathogenic alterations of both alleles of the tumor suppressor gene RB1. In heritable...
Retinoblastoma is the most common eye cancer in children. It is caused by pathogenic alterations of both alleles of the tumor suppressor gene RB1. In heritable retinoblastoma, a constitutional RB1 variant predisposes the cells to tumor formation, and loss of the other allele is a prerequisite for the development of retinoblastoma. Heritable retinoblastoma is inherited in an autosomal dominant manner; however, the majority of cases are the result of a de novo pathogenic RB1 variant. Penetrance is usually high (>90%), but with marked inter-familial variability. In some families, penetrance is incomplete and family members who develop tumors tend to remain unilaterally affected. Moreover, some families with low penetrance also show a parent-of-origin effect. We describe a patient with unilateral retinoblastoma caused by a previously unreported likely pathogenic RB1 variant (c.1199T>C) that disrupts a highly conserved amino acid residue within the A-box functional domain. Segregation analysis showed that the variant had unusually low penetrance as nine non-affected family members carried the same variant. We emphasize the use of genetic analysis on tumor DNA for classifying the RB1 variant, and underline the challenges in clinical management and counseling of families carrying the specific RB1 variant.
PubMed: 38897371
DOI: 10.1016/j.ejmg.2024.104956 -
Current Opinion in Pulmonary Medicine Jun 2024The identification of extra-pulmonary symptoms plays a crucial role in diagnosing interstitial lung disease (ILD). These symptoms not only indicate autoimmune diseases...
PURPOSE OF REVIEW
The identification of extra-pulmonary symptoms plays a crucial role in diagnosing interstitial lung disease (ILD). These symptoms not only indicate autoimmune diseases but also hint at potential genetic disorders, suggesting a potential overlap between genetic and autoimmune origins.
RECENT FINDINGS
Genetic factors contributing to ILD are predominantly associated with telomere (TRG) and surfactant-related genes. While surfactant-related gene mutations typically manifest with pulmonary involvement alone, TRG mutations were initially linked to syndromic forms of pulmonary fibrosis, known as telomeropathies, which may involve hematological and hepatic manifestations with variable penetrance. Recognizing extra-pulmonary signs indicative of telomeropathy should prompt the analysis of TRG mutations, the most common genetic cause of familial pulmonary fibrosis. Additionally, various genetic diseases causing ILD, such as alveolar proteinosis, alveolar hemorrhage, or unclassifiable pulmonary fibrosis, often present as part of syndromes that include hepatic, hematological, or skin disorders.
SUMMARY
This review explores the main genetic conditions identified over the past two decades.
PubMed: 38896087
DOI: 10.1097/MCP.0000000000001088 -
Iranian Journal of Public Health Feb 2024Holoprosencephaly, a complicated brain abnormality arising from incomplete prosencephalon cleavage, affects both the forebrain and the face. Holoprosencephaly Type 11,...
Holoprosencephaly, a complicated brain abnormality arising from incomplete prosencephalon cleavage, affects both the forebrain and the face. Holoprosencephaly Type 11, with variable expression or partial penetrance, is caused by pathogenic variants associated with the disrupted Sonic Hedgehog ()-pathway. Herein, we aimed to describe a family with genetic nose problems. After counselling and drawing pedigree in Farhud's Genetic Clinic, Tehran, Iran in 2021, DNA extraction of a proband and a few members of his family (patient and control) was conducted. Whole exome sequencing was utilized for detecting the gene and its variant in the proband with a nose deformity. The results were confirmed with Sanger sequencing. This variant was checked in other members by Sanger sequencing. Analysis of the Exome data showed a heterozygous splicing variant in the gene (NM_016952; c.3276+1G>T) in the proband who had a nose deformity and then the results were confirmed with Sanger sequencing. Such a variant was observed in Proband's brother with a nose deformity and was not observed in Proband's cousin with no abnormal phenotype. Recent investigations, in an Iranian family, with a heterozygous splicing mutation as a human candidate gene are discussed for the first time in relation to the likely pathogenesis of facial deformities, particularly nose deformity, in Holoprosencephaly.
PubMed: 38894838
DOI: 10.18502/ijph.v53i2.14933 -
Cancers May 2024Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic,... (Review)
Review
Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed.
PubMed: 38893191
DOI: 10.3390/cancers16112075 -
International Journal of Molecular... May 2024Developmental and epileptic encephalopathy-9 (DEE9) is characterized by seizure onset in infancy, mild to severe intellectual impairment, and psychiatric features and is...
Developmental and epileptic encephalopathy-9 (DEE9) is characterized by seizure onset in infancy, mild to severe intellectual impairment, and psychiatric features and is caused by a mutation in the gene on chromosome Xq22. The rare, unusual X-linked type of disorder affects heterozygous females and mosaic males; transmitting males are unaffected. In our study, 165 patients with epilepsy were tested by Next Generation Sequencing (NGS)-based panel and exome sequencing using Illumina technology. screening identified three point mutations, one indel, and one 29 bp-long deletion in five unrelated female probands. Two novel mutations, c.1152_1180del (p.Gln385Serfs*6) and c.830_831delinsAA (p.Phe277*), were identified and found to be de novo pathogenic. Moreover, among the three inherited mutations, two originated from asymptomatic mothers and one from an affected father. The c.1682C>T and c.1711G>T mutations were present in the DNA samples of asymptomatic mothers. After targeted parental testing, X chromosome inactivation tests and Sanger sequencing were carried out for mosaicism examination on maternal saliva samples in the two asymptomatic mutation carrier subjects. Tissue mosaicism and X-inactivation tests were negative. Our results support the opportunity for reduced penetrance in DEE9 and contribute to expanding the genotype-phenotype spectrum of -related epilepsy.
Topics: Humans; Protocadherins; Female; Cadherins; Epilepsy; High-Throughput Nucleotide Sequencing; Mutation; Pedigree; Male; Child, Preschool; Child; Infant; Age of Onset
PubMed: 38891919
DOI: 10.3390/ijms25115732 -
Journal of Medicinal Chemistry Jun 2024Selective activation of the M muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders....
Selective activation of the M muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M selective positive allosteric modulators (PAMs), ultimately culminating in the identification of PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.
PubMed: 38888621
DOI: 10.1021/acs.jmedchem.4c00293 -
European Journal of Heart Failure Jun 2024The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on...
AIMS
The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement.
METHODS AND RESULTS
We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%.
CONCLUSIONS
Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common.
PubMed: 38887861
DOI: 10.1002/ejhf.3339