-
Frontiers in Bioscience (Landmark... Mar 2019Congenital and genetic disorders cause many diseases in Arab countries due to large family sizes and high levels of inbreeding. Saudi Arabia (SA) has the highest... (Review)
Review
Congenital and genetic disorders cause many diseases in Arab countries due to large family sizes and high levels of inbreeding. Saudi Arabia (SA) has the highest consanguinity rates among Middle Eastern countries (~60% of all marriages) and is burdened by the highest number of genetic diseases. Genetic diseases can be life-threatening, often manifesting early in life. Approximately 8% of births in SA are affected, and more common genetic diseases, such as metabolic disease and cancer, manifest later in life in up to 20% of the population. This represents a massive healthcare burden to SA hospitals. The number of genetic disorders in the human population ranges from 7000 to 8000, over 3000 of which are caused by unknown mutations. In 2013, SA initiated the Saudi Human Genome Program (SHGP), which aims to sequence over 100,000 human genomes, with the goal of identifying strategies to discover, prevent, diagnose and treat genetic disorders through precision therapy. High-technology genomics and informatic-based centers that exploit next-generation sequencing (NGS) have now identified mutations underlying many unexplained diseases.
Topics: Autoimmune Diseases; Central Nervous System Diseases; Congenital Abnormalities; Consanguinity; Female; Genome, Human; Genomics; Humans; Intellectual Disability; Kidney Diseases; Limb Deformities, Congenital; Male; Mutation; Neoplastic Syndromes, Hereditary; Precision Medicine; Saudi Arabia; Sequence Analysis, DNA
PubMed: 30844719
DOI: 10.2741/4757 -
International Journal of Molecular... Jun 2021Defects in transcriptional and cell cycle regulation have emerged as novel pathophysiological mechanisms in congenital neuromuscular disease with the recent... (Review)
Review
Defects in transcriptional and cell cycle regulation have emerged as novel pathophysiological mechanisms in congenital neuromuscular disease with the recent identification of mutations in the and genes, encoding, respectively, ASC-1 and ASCC1, two subunits of the ASC-1 (Activating Signal Cointegrator-1) complex. This complex is a poorly known transcriptional coregulator involved in transcriptional, post-transcriptional or translational activities. Inherited defects in components of the ASC-1 complex have been associated with several autosomal recessive phenotypes, including severe and mild forms of striated muscle disease (congenital myopathy with or without myocardial involvement), but also cases diagnosed of motor neuron disease (spinal muscular atrophy). Additionally, antenatal bone fractures were present in the reported patients with mutations. Functional studies revealed that the ASC-1 subunit is a novel regulator of cell cycle, proliferation and growth in muscle and non-muscular cells. In this review, we summarize and discuss the available data on the clinical and histopathological phenotypes associated with inherited defects of the ASC-1 complex proteins, the known genotype-phenotype correlations, the ASC-1 pathophysiological role, the puzzling question of motoneuron versus primary muscle involvement and potential future research avenues, illustrating the study of rare monogenic disorders as an interesting model paradigm to understand major physiological processes.
Topics: Carrier Proteins; Congenital Abnormalities; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Multiprotein Complexes; Mutation; Neuromuscular Diseases; Transcription Factors
PubMed: 34204919
DOI: 10.3390/ijms22116039 -
Current Topics in Developmental Biology 2021Congenital birth defects result from an abnormal development of an embryo and have detrimental effects on children's health. Specifically, congenital heart malformations... (Review)
Review
Congenital birth defects result from an abnormal development of an embryo and have detrimental effects on children's health. Specifically, congenital heart malformations are a leading cause of death among pediatric patients and often require surgical interventions within the first year of life. Increased efforts to navigate the human genome provide an opportunity to discover multiple candidate genes in patients suffering from birth defects. These efforts, however, fail to provide an explanation regarding the mechanisms of disease pathogenesis and emphasize the need for an efficient platform to screen candidate genes. Xenopus is a rapid, cost effective, high-throughput vertebrate organism to model the mechanisms behind human disease. This review provides numerous examples describing the successful use of Xenopus to investigate the contribution of patient mutations to complex phenotypes including congenital heart disease and heterotaxy. Moreover, we describe a variety of unique methods that allow us to rapidly recapitulate patients' phenotypes in frogs: gene knockout and knockdown strategies, the use of fate maps for targeted manipulations, and novel imaging modalities. The combination of patient genomics data and the functional studies in Xenopus will provide necessary answers to the patients suffering from birth defects. Furthermore, it will allow for the development of better diagnostic methods to ensure early detection and intervention. Finally, with better understanding of disease pathogenesis, new treatment methods can be tailored specifically to address patient's phenotype and genotype.
Topics: Animals; Congenital Abnormalities; Genes; Genomics; Heart Defects, Congenital; Humans; Mutation; Phenotype; Xenopus laevis
PubMed: 34074532
DOI: 10.1016/bs.ctdb.2021.03.005 -
Archives of Disease in Childhood Feb 2015To review the clinical and molecular genetic characteristics of 16 patients presenting a suspected diagnosis of Kabuki syndrome (KS) in the first year of life, to... (Review)
Review
OBJECTIVE
To review the clinical and molecular genetic characteristics of 16 patients presenting a suspected diagnosis of Kabuki syndrome (KS) in the first year of life, to evaluate the clinical handles leading to a prompt diagnosis of KS in newborns. Clinical diagnosis of KS can be challenging during the first year of life, as many diagnostic features become evident only in subsequent years.
METHODS
All patients were clinically investigated by trained clinical geneticists. A literature review was performed using the Pubmed online database and diagnostic criteria suggested by DYSCERNE-Kabuki Syndrome Guidelines (2010) were used (a European Network of Centres of Expertise for Dysmorphology, funded by the European Commission Executive Agency for Health and Consumers (DG Sanco), Project 2006122). Molecular analysis of the known causative genes of KS, KMT2D/MLL2 and KDM6A, was performed through MiSeq-targeted sequencing platform. All mutations identified were validated by Sanger sequencing protocols.
RESULTS
Mutations in KMT2D gene were identified in 10/16 (62%) of the patients, whereas none of the patients had KDM6A mutations. Facial dysmorphisms (94%), feeding difficulties (100%) and hypotonia (100%) suggested the clinical diagnosis of KS. No significative differences in terms of facial features were noticed between mutation positive and negative patients of the cohort. Brachydactyly, joint laxity and nail dysplasia were present in about 80% of the patients. Other congenital anomalies were most commonly present in the mutated group of patients, including left-sided cardiac abnormalities, skeletal, renal and anorectal malformations and hypertricosis.
CONCLUSIONS
We present an overview of patients with KS diagnosed during the first year of life. Early diagnosis is serviceable in terms of clinical management and for targeted genetic counselling.
Topics: Abnormalities, Multiple; DNA-Binding Proteins; Face; Female; Hematologic Diseases; Histone Demethylases; Humans; Infant, Newborn; Male; Molecular Diagnostic Techniques; Mutation; Neoplasm Proteins; Nuclear Proteins; Vestibular Diseases
PubMed: 25281733
DOI: 10.1136/archdischild-2013-305858 -
Advances in Experimental Medicine and... 2019Spermatogenesis is a highly complex biological process during which germ cells undergo recurrent rounds of DNA replication and cell division that may predispose to... (Review)
Review
Spermatogenesis is a highly complex biological process during which germ cells undergo recurrent rounds of DNA replication and cell division that may predispose to random mutational events. Hence, germ cells are vulnerable to the introduction of a range of de novo mutations, in particular chromosomal aberrations, point mutations and small indels. The main mechanisms through which mutations may occur during spermatogenesis are (i) errors in DNA replication, (ii) inefficient repair of non-replicative DNA damage between cell divisions and (iii) exposure to mutagens during lifetime. Any genetic alteration in the spermatozoa, if not repaired/eliminated, can be passed on to the offspring, potentially leading to malformations, chromosomal anomalies and monogenic diseases. Spontaneous de novo mutations tend to arise and accumulate with a higher frequency during testicular aging. In fact, there is an increased incidence of some chromosomal aberrations and a greater risk of congenital disorders, collectively termed paternal age effect (PAE), in children conceived by fathers with advanced age. PAE disorders are related to well-characterized de novo point mutations leading to a selective advantage on the mutant spermatogonial stem cells that cause a progressive enrichment over time of mutant spermatozoa in the testis.The purpose of this chapter is to provide a summary on the spontaneous genetic alterations that occur during spermatogenesis, focusing on their underlying mechanisms and their consequences in the offspring.
Topics: Adult Germline Stem Cells; Congenital Abnormalities; Humans; Male; Mutation; Paternal Age; Spermatogenesis; Spermatozoa; Testis
PubMed: 31301044
DOI: 10.1007/978-3-030-21664-1_2 -
Facial Plastic Surgery : FPS Dec 2015Half of the malformations in the ear, nose, and throat region affect the ear. Malformations of the external ear (pinna or auricle with external auditory canal [EAC]) are... (Review)
Review
Half of the malformations in the ear, nose, and throat region affect the ear. Malformations of the external ear (pinna or auricle with external auditory canal [EAC]) are collectively termed microtia. Microtia is a congenital anomaly that ranges in severity from mild structural abnormalities to complete absence of the external ear (anotia). Microtia occurs more frequently in males (∼2 or 3:1), is predominantly unilateral (∼70-90%), and more often involves the right ear (∼60%). The reported prevalence varies geographically from 0.83 to 17.4 per 10,000 births. Microtia may be genetic (with family history, spontaneous mutations) or acquired. Malformations of the external ear can also involve the middle ear and/or inner ear. Microtia may be an isolated birth defect, but associated anomalies or syndromes are described in 20 to 60% of cases, depending on study design. These generally fit within the oculo-auriculo-vertebral spectrum; defects are located most frequently in the facial skeleton, facial soft tissues, heart, and vertebral column, or comprise a syndrome (e.g., Treacher Collins syndrome). Diagnostic investigation of microtia includes clinical examination, audiologic testing, genetic analysis and, especially in higher grade malformations with EAC deformities, computed tomography (CT) or cone-beam CT for the planning of surgery and rehabilitation procedures, including implantation of hearing aids.
Topics: Congenital Abnormalities; Ear; Humans
PubMed: 26667631
DOI: 10.1055/s-0035-1568139 -
Journal of Perinatal Medicine Nov 2018
Topics: Aneuploidy; Congenital Abnormalities; Female; Humans; Pregnancy; Prenatal Diagnosis
PubMed: 30422803
DOI: 10.1515/jpm-2018-0333 -
[Rinsho Ketsueki] the Japanese Journal... 2019Down syndrome (DS) is related to constitutional trisomy 21 and is characterized by typical dysmorphic features and various congenital abnormalities. DS is also...
Down syndrome (DS) is related to constitutional trisomy 21 and is characterized by typical dysmorphic features and various congenital abnormalities. DS is also associated with a broad spectrum of hematological findings, such as transient thrombocytopenia in the neonatal period and acute leukemia. Of those hematological abnormalities, transient abnormal myelopoiesis (TAM) and acute myeloid leukemia (AML) have common genetic abnormalities, i.e., trisomy 21 and GATA1 mutation, and form a continuous spectrum, referred to as myeloid proliferations related to DS. Recent studies have demonstrated interactions between trisomy 21 and GATA1 mutations. Trisomy 21 promotes the expansion of early hematopoietic progenitors and upregulates short form GATA1, resulting in the accelerated production of aberrantly differentiated cells and development of TAM. Following spontaneous remission of TAM, subsequent AML can evolve from a preexisting residual TAM clone through the acquisition of additional mutations involving multiple cohesion components and epigenetic regulators.
Topics: Cell Proliferation; Down Syndrome; GATA1 Transcription Factor; Humans; Leukemia, Myeloid, Acute; Leukemoid Reaction; Mutation; Myeloid Cells
PubMed: 31597856
DOI: 10.11406/rinketsu.60.1299 -
Nature Reviews. Cancer Jul 2020Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death.... (Review)
Review
Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.
Topics: Animals; Cell Transformation, Neoplastic; Congenital Abnormalities; Disease Models, Animal; Gene-Environment Interaction; Genetic Diseases, Inborn; Humans; Mice; Mutation; Neoplasms; Proto-Oncogene Proteins; Signal Transduction
PubMed: 32341551
DOI: 10.1038/s41568-020-0256-z -
The Journal of Investigative Dermatology Jan 2019KLHL24 mutations have recently been associated with epidermolysis bullosa simplex. Initial studies focused on skin fragility. However, the picture of KLHL24 mutations...
KLHL24 mutations have recently been associated with epidermolysis bullosa simplex. Initial studies focused on skin fragility. However, the picture of KLHL24 mutations causing extracutaneous human disease is emerging, with dilated cardiomyopathy as a strong association. In addition, neurological disease is suspected as well. Careful clinical follow-up and functional studies of (mutated) KLHL24 in these tissues are needed.
Topics: Cardiomyopathy, Dilated; Epidermolysis Bullosa Simplex; Humans; Mutation; Skin Abnormalities
PubMed: 30579426
DOI: 10.1016/j.jid.2018.08.010