Genetic Screening
SMN1 - Spinal muscular atrophy
Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease. Most carriers of Spinal Muscular Atrophy related to SMN1 gene have a heterozygous deletion of exon 7 of the SMN1 gene. Single nucleotide variants only account for a minority of carriers. Some people have two copies of SMN1 exon 7 on a single chromosome and a deletion on the other chromosome, these are named "silent carriers" Therapies targeted to the underlying disease mechanism include nusinersen (Spinraza®; an antisense oligonucleotide) for the treatment of all types of SMA and onasemnogene abeparvovec-xioi (Zolgensma®; gene replacement therapy) for the treatment of type I SMA. These targeted treatments may prevent the development or slow the progression of some features of SMA; efficacy is improved when treatment is initiated before symptom onset
CFTR - Cystic fibrosis
Variants in the CFTR gene cause a number of clinically diverse conditions among which the most common and well-known is Cystic Fibrosis. This is a genetic disease characterized, in its classic form, by recurrent bronchopulmonary infections resulting in respiratory disease and recurrent pancreatitis and/or pancreatic insufficiency resulting in growth retardation due to intestinal malabsorption; most men with the condition also have infertility related to an obstructive-derived azoospermia resulting from agenesis of the vas deferens. Other conditions related to CFTR gene variants are characterized by a broad spectrum of clinical manifestations that may include paucisymptomatic forms, particularly characterized by the inconstant presence and variable severity of symptoms characteristic of Cystic Fibrosis. The extreme variability in clinical presentation finds a partial explanation in the different impact that different gene variants can have on the functioning of the CFTR gene. Indeed, it can be considered that there are severe variants that result in the classic picture of cystic fibrosis and mild variants that may result in atypical pictures with much milder expression of symptoms, particularly with reduced or absent pancreatic involvement or simply azoospermia. Clinical variability, however, is not completely explained by the different characteristics of the CFTR gene variants, indicating that other factors, genetic and otherwise, could alter the expression of these variants and, consequently, the clinical picture actually present.
GJB2/6 - Deafness, type 1B, digenic
GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) is the most common genetic cause of congenital (present at birth) severe-to-profound non-progressive sensorineural hearing loss in many world populations.Newborn hearing screening (NBHS) typically identifies severe-to-profound hearing loss. Children with severe-to-profound hearing loss are candidates for cochlear implantation. The treatment should be performed as soon as possible as these children can attain levels of social functioning and education indistinguishable from those of normal-hearing peers. Children with mild-to-moderate hearing loss can be treated with hearing aids customized to the child's age and severity of hearing loss.
HBA1/HBA2 - Alpha-thalssemia
Hemoglobinopathies are a group of conditions caused by the alteration of one or more of the subunits that form the hemoglobin. The different forms have often overlapping clinical manifestations, but can be distinguished on the basis of some specific hematochemical and clinical data. The main hemoglobinopathy related to alterations in the HBA1/2 genes, encoding for the alpha chain of hemoglobin, is Alpha thalassemia. Alpha thalassemia is a general term for a group of inherited blood disorders characterized by reduced or absent production of alpha-globin subunits, resulting in low levels of hemoglobin that is otherwise fully functional. There are two main forms of alpha thalassemia that are associated with significant health problems - hemoglobin (Hb) Bart's hydrops fetalis and hemoglobin H (HbH) disease. Hb Bart's hydrops fetalis is a severe syndrome that is usually fatal to the developing embryo during gestation or shortly after birth. HbH disease is highly variable, and the specific symptoms and severity can vary greatly from one person to another. Some individuals will have only minor symptoms, while others will develop potentially serious complications. The characteristic finding of all forms of alpha thalassemia is anemia, with red blood cells that are small (microcytic), contain low levels of functional hemoglobin (hypochromic), and may break down in prematurely in both the bone marrow (ineffective erythropoiesis) and in the peripheral circulation (hemolysis). Individuals with severe forms of HbH disease are usually treated with regular blood transfusions, which can result in the accumulation of excess iron in the body (iron overload). Although iron overload can damage numerous organs in the body, it can be effectively treated using several highly effective medications
HBB - Beta-thalassemia, Sickle cell anemia and other HBB related hemoglobinopathies
Hemoglobinopathies are a group of conditions caused by the alteration of one or more of the subunits that form the hemoglobin. The different forms have often overlapping clinical manifestations, but can be distinguished on the basis of some specific hematochemical and clinical data. The main hemoglobinopathies related to alterations in the HBB gene, encoding for the beta chain of hemoglobin, are beta thalassemia and sickle cell anemia. Beta Thalassemia in its Major form (Cooley's anemia) manifests with the classic clinical picture (microcytic and hypochromic anemia, from dyserythropoiesis and hemolysis, splenomegaly, growth retardation and progressive pallor, jaundice, muscle weakness, mass formation from extramedullary hematopoiesis, and skeletal changes). In some circumstances, beta Thalassemia may present in an Intermediate form with variable anemia, generally less severe and diagnosed later than the major form. Sickle Cell Anemia is caused by a specific alteration in the HBB gene (c.20A>T (p.Glu7Val)) that gives rise to the HbS form of hemoglobin. HbS is insoluble and tends to form aggregates when the oxygen concentration falls below a certain concentration, such as at the level of capillaries away from the lungs. Typical symptoms are, in addition to anemia, the onset of acute painful episodes as well as susceptibility to infection. Treatment of hemoglobinopathies is complex and may require bone marrow transplantation or recurrent transfusions
HEXA - Tay Sachs disease
Tay-Sachs disease is a rare neurodegenerative disease. There are 3 forms of Tay-Sachs disease, distinguished by the general age of onset: Infantile - the most common severe form, with symptoms appearing in the first few months of life. Symptoms include a loss of skills learned (regression), seizures, and loss of muscle and mental functions. Children with this form do not survive past early childhood. Juvenile - a form with a range of severity, with symptoms appearing any time during childhood (but usually between ages 2 and 5). Symptoms include behavior problems, gradual loss of skills, frequent respiratory infections, and seizures. People with this form typically do not survive past their teenage years. Late onset/adult - the least severe form, with symptoms appearing in late childhood to adulthood. Symptoms may include clumsiness, muscle weakness, psychiatric disorders, and gradual loss of skills, often leading to the need for mobility assistance. Intellect and behavior become impaired in some cases. The lifespan varies from shortened to unaffected.Currently there is no cure for Tay-Sachs disease, and there are no therapies that slow the progression of the disease. Treatment aims to relieve symptoms and increase quality of life.