Diseases, syndromes, and other disorders caused by mutations or chromosomal abnormalities of one or more genes are known as genetic conditions. Congenital disorders are not caused by genetic defects or chromosomal variations. Rather, problems that arise during embryonic or fetal development or during the delivery process trigger them. One example of a non-genetic congenital disorder is fetal alcohol syndrome. This is a group of birth defects affected by maternal alcohol consumption when the child is still in the womb, including facial anomalies and intellectual disability.
The majority DNA of gene variations do not contribute to a disease; they are referred to as polymorphisms. A difference in a gene’s DNA leading to an irregular protein that performs incorrectly or not at all is considered a mutation. The same mutation in a gene in afflicted people does not usually yield the same physical results. The differentiation is called gene expression. At a particular position on a chromosome, alleles are alternate variants of a gene. For each locus, a single allele is inherited from each parent. For autosomal loci the genotype of a person at a locus consists of both of the alleles occupying that locus on the two homologous chromosomes.
Phenotype is the manifestation of genotype as a morphological, clinical, molecular, or biochemical phenotype that can be seen clinically or identified either by blood or tissue examination. The phenotype may be specific or quantifiable, such as the prevalence or absence of a disorder or the index of body mass or blood glucose levels. Of course, in a given person, a phenotype may be normal or abnormal, but the focus here is on disease phenotypes, or genetic abnormalities.
The following are some of the most common genetic diseases and their symptoms:
| Disease | Gene/Defect | Inheritance | Phenotypic Features |
| ABACAVIR-INDUCED STEVENS-JOHNSON SYNDROME/ TOXIC EPIDERMAL NECROLYSIS (Genetically Determined Immunological Adverse Drug Reaction) | Approximately 50% of patients carrying an HLA-B*5701 allele develop SJS. | Autosomal Dominant | Widespread red/purple patches on the skin and mucosal membranes (eye, mouth, genitalia) 10 to 14 days after beginning antiretroviral treatment with abacavir. |
| ACHONDROPLASIA | Specific mutations in FGFR3; two mutations, 1138G>A (≈98%) and 1138G>C (1% to 2%), | Autosomal Dominant | Age at onset: Prenatal Rhizomelic short stature Megalencephaly Spinal cord compression |
| AGE-RELATED MACULAR DEGENERATION (Complement Factor H variants) | Approximately 50% of the population-attributable genetic risk is due to a polymorphic variant, Tyr402His, in the complement factor H gene (CFH). | Multifactorial | Age at onset: >50 years Gradual loss of central vision Drusen in the macula Changes in the retinal pigment -epithelium Neovascularization |
| ALZHEIMER DISEASE (Cerebral Neuronal Dysfunction and Death) | Autosomal dominant AD have been identified in the β-amyloid precursor protein gene (APP), the presenilin 1 gene (PSEN1), and the presenilin 2 gene (PSEN2) | Multifactorial or Autosomal Dominant | Age at onset: Middle to late adulthood Dementia Β-Amyloid plagues Neurofibrillary tangles Amyloid angiopathy |
| AUTISM/16p11.2 DELETION SYNDROME (Susceptibility to Autism Spectrum Disorders) | Contiguous gene deletion on chromosome 16p11.2 (microdeletion contains 25 annotated genes) | Autosomal Dominant or De Novo | Age at onset: Birth or first 6 months of life Intellectual disability to normal intelligence Impaired social and communication skills or frank autism spectrum disorder Minor dysmorphic features |
| BECKWITH-WIEDEMANN SYNDROME (uniparental Disomy and Imprinting Defect) | Imbalance in the expression of imprinted genes in the p15 region of chromosome 11. These genes include KCNQOT1 and H19, noncoding RNAs, and CDKN1C and IGF2, which do encode proteins. | Chromosomal with imprinting defect | Age at onset: Prenatal Prenatal and postnatal overgrowth Macroglossia Omphalocele Visceromegaly Embryonal tumor in childhood Hemihyperplasia Renal abnormalities Adrenocortical cytomegaly Neonatal hypoglycemia |
| HEREDITARY BREAST AND OVARIAN CANCER | Loss of BRCA1 or BRCA2 function probably permits the accumulation of other mutations that are directly responsible for neoplasia. | Autosomal Dominant | Age at onset: Adulthood Breast cancer Ovarian cancer Prostate cancer Multiple primary cancers |
| CHARCOT-MARIE-TOOTH DISEASE TYPE 1A (PMP22 Mutation or Duplication) | Dominant negative mutations within PMP22 or increased dosage of PMP22 can each cause peripheral polyneuropathy. | Autosomal Dominant | Age at onset: Childhood to adulthood Progressive distal weakness Distal muscle wasting Hyporeflexia |
| CHARGE SYNDROME (CHD7 Mutation) | Multiple congenital malformations caused by mutations in the CHD7 gene | Autosomal Dominant | Coloboma of the iris, retina, optic disc, or optic nerve Heart defects Atresia of the choanae Retardation of growth and development Genital abnormalities Ear anomalies Facial palsy Cleft lip Tracheoesophageal fistula |
| CHRONIC MYELOGENOUS LEUKEMIA (BCR-ABL1 Oncogene) | The Abelson proto-oncogene (ABL1), which encodes a nonreceptor tyrosine kinase, resides on 9q34, and the breakpoint cluster region gene (BCR), which encodes a phosphoprotein, resides on 22q11 | Somatic Mutation | Age at onset: Middle to late adulthood Leukocytosis Splenomegaly Fatigue and malaise |
| CROHN DISEASE (Increased Risk from NOD2 Mutations) | Coding exons of the NOD2 gene follows either amino acid substitutions (Gly908Arg and Arg702Trp) or premature termination of the protein (3020insC) | Multifactorial Inheritance | Episodic abdominal pain, cramping and diarrhea Occasional Hematochezia Transmural ulceration and granulomas of the gastrointestinal tract Fistulas Patchy involvement usually of the terminal ileum and ascending colon Extraintestinal manifestations including inflammation of the joints, eyes and skin |
| CYSTIC FIBROSIS (CFTR Mutation) | Disorder of epithelial ion transport caused by mutations in the CF transmembrane conductance regulator gene (CFTR) | Autosomal Recessive | Age at onset: Neonatal to adulthood Progressive pulmonary disease Exocrine pancreatic insufficiency Obstructive azoospermia Elevated sweat chloride concentration Growth failure Meconium ileus |
| DEAFNESS (NONSYNDROMIC) (GJB2 Mutation) | The GJB2 gene encodes connexin 26, one of a family of proteins that form gap junctions. | Autosomal Dominant and Recessive | Congenital deafness in the recessive form Progressive childhood deafness in the dominant form |
| DUCHENNE MUSCULAR DYSTROPHY (Dystrophin [DMD] Mutation) | DMD encodes dystrophin, an intracellular protein that is expressed predominantly in smooth, skeletal, and cardiac muscle as well as in some brain neurons | X-Linked | Age at Onset: Childhood Muscle weakness Calf pseudohypertrophy Mild intellectual compromise Elevated serum creatine kinase level |
| FAMILIAL ADENOMATOUS POLYPOSIS (APC Mutation) | Loss of functional APC usually results in high levels of free cytosolic β-catenin; free β-catenin migrates to the nucleus, binds to T-cell factor 4, and inappropriately activates gene expression. | Autosomal Dominant | Age at onset: Adolescence through mild-adulthood Colorectal adenomatous polyps Colorectal cancer Multiple primary cancers |
| FAMILIAL HYPERCHOLESTEROLEMIA (Low-Density Lipoprotein Receptor [LDLR] Mutation) | Disorder of cholesterol and lipid metabolism caused by mutations in LDLR | Autosomal Dominant | Age at onset: Heterozygote –early to middle adulthood homozygote-childhood Hypercholesterolemia Atherosclerosis Xanthomas Arcus corneae |
| FRAGILE X SYNDROME (FMR1 Mutation) | In normal alleles of FMR1, the number of CGG repeats ranges from 6 to approximately 50. In diseasecausing alleles or full mutations, the number of repeats is more than 200. | X-Linked | Age at onset: Childhood Intellectual disability Dysmorphic facies Male postpubertal macroorchidism |
| TYPE I (NON-NEURONOPATHIC) GAUCHER DISEASE (GBA1 Mutation) | The most common disease allele of GBA1 worldwide is the Leu444Pro mutation. | Autosomal Recessive | Age at onset: Childhood or early adulthood Hepatosplenomegaly Anemia Thrombocytopenia Bone pain Short stature |
| GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD Mutation) | Mutations in the X-linked G6PD gene decrease the catalytic activity or the stability of G6PD, or both. | X-linked | Age at onset: Neonatal Hemolytic anemia Neonatal jaundice |
| HEREDITARY HEMOCHROMATOSIS (HFE Mutation) | Mutant HFE interferes with hepcidin signaling, which results in the stimulation of enterocytes and macrophages to release iron. The body therefore continues to absorb and recycle iron, despite an iron-overloaded condition. | Autosomal Recessive | Age at onset: 40 to 60 years in males; after menopause in females Fatigue, impotence, hyperpigmentation, diabetes, cirrhosis, cardiomyopathy Elevated serum transferrin iron saturation Elevated serum ferritin level |
| HEMOPHILIA (F8 or F9 Mutation) | X-linked disorders of coagulation caused by mutations in the F8 and F9 genes. | X-Linked | Age at onset: Infancy to adulthood Bleeding diathesis Hemarthroses Hematomas |
| HIRSCHSPRUNG DISEASE (Neurocristopathy) | The genes implicated in HSCR include RET, EDNRB, EDN3, GDNF, and NRTN. | Autosomal Dominant, Autosomal Recessive, or Multigenic | Age at onset: Neonatal to adulthood Constipation Abdominal distention Enterocolitis |
| HOLOPROSENCEPHALY (NONSYNDROMIC FORM) (Sonic Hedgehog (SHH) Mutation) | Loss-of-function mutations. Some of the cytogenetic abnormalities affecting SHH expression are translocations that occur 15 to 256 kb 5′ to the coding region of SHH. | Autosomal Dominant | Age at onset: Prenatal Ventral forebrain maldevelopment Facial dysmorphism Developmental delay |
| HUNTINGTON DISEASE (HD Mutation) | Mutations in HD usually result from an expansion of a polyglutamine-encoding CAG repeat sequence in exon 1 | Autosomal Dominant | Age at onset: Late childhood to late adulthood Movement abnormalities Cognitive abnormalities Psychiatric abnormalities |
| HYPERTROPHIC CARDIOMYOPATHY (Cardiac Sarcomere Gene Mutations) | Mutations in approximately 20 genes encoding proteins of the cardiac sarcomere. | Autosomal Dominant | Age at onset: Adolescence and early adulthood Left ventricular hypertrophy Myocardial crypts or scarring Elongated mitral leaflets Diastolic dysfunction Heart failure Sudden death |
| INSULIN-DEPENDENT (TYPE 1) DIABETES MELLITUS (Autoimmune Destruction of Islet β Cells) | Caused by autoimmune destruction of islet β cells in the pancreas | Multifactorial | Age at onset: Childhood through adulthood Polyuria, polydipsia, polyphagia Hyperglycemia Ketosis Wasting |
| INTRAUTERINE GROWTH RESTRICTION (Abnormal Fetal Karyotype) | The deletion breakpoints on the short arm of chromosome 4 in 46,XX,del(4)(p15.1p15.32) flank a 14.5-Mb segment of DNA. Haploinsufficiency for one or more of these genes is the likely cause of the phenotype of this fetus. | Spontaneous Chromosomal Deletion | Age at onset: Prenatal Intrauterine growth restriction Increased nuchal fold Dysmorphic facies |
| LONG QT SYNDROME (Cardiac Ion Channel Gene Mutations) | Mutations in at least five known cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) that encode subunits or regulatory proteins for potassium channels. | Autosomal Dominant or Recessive | QTc prolongation (>4700 msec in males, >480 msec in females) Tachyarrhythmias Syncopal episodes Sudden death |
| LYNCH SYNDROME (DNA Mismatch Repair Gene Mutations) | Mutations in DNA mismatch repair genes. (Microsatellite instability) | Autosomal Dominant | Age at onset: Mid adulthood Colorectal cancer Multiple primary cancer |
| MARFAN SYNDROME (FBN1 Mutation) | Mutations of FBN1 affect fibrillin 1 synthesis, processing, secretion, polymerization, or stability. | Autosomal Dominant | Age at onset: Early childhood Disproportionately tall stature Skeletal anomalies Ectopia lentis Mitral valve prolapse Aortic dilatation and rupture Spontaneous pneumothorax Lumbosacral dural ectasia |
| MEDIUM-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY (ACADM Mutation) | The point mutation c.985A>G, which causes an amino acid change from lysine to glutamate at residue 304 (Lys304Glu) of the mature MCAD protein, is found in approximately 70% of mutant alleles. | Autosomal Recessive | Age at onset: Between 3 and 24 months Hypoketotic hypoglycemia Vomting Lethargy Hepatic encephalopathy |
| MILLER-DIEKER SYNDROME (17p13.3 Heterozygous Deletion) | Contiguous gene deletion syndrome caused by heterozygous deletion of 17p13.3 | Chromosomal Deletion | Age at onset: Prenatal Lissencephaly type 1 or type 2 Facial dysmorphism Severe global intellectual disability Seizures Early death |
| MYOCLONIC EPILEPSY WITH RAGGED-RED FIBERS (Mitochondrial tRNAlys Mutation) | Rare panethnic disorder caused by mutations within the mtDNA in the tRNAlys gene. | Matrilineal, Mitochondrial | Age at onset: Childhood through adulthood Myopathy Dementia Myoclonic seizures Ataxia Deafness |
| NEUROFIBROMATOSIS 1 (NF1 Mutation) | Neurofibromatosis results from mutations in the neurofibromin gene (NF1). | Autosomal Dominant | Age at onset: Prenatal to late childhood Café au lait spots Axillary and inguinal freckling Cutaneous neurofibromas Lisch nodules Plexiform neurofibromas Optic glioma Specific osseous lesions |
| NON–INSULIN-DEPENDENT (TYPE 2) DIABETES MELLITUS (Insulin Deficiency and Resistance) | T2D results from a derangement of insulin secretion and resistance to insulin action. | Multifactorial | Age at onset: Childhood through adulthood Hyperglycemia Relative insulin deficiency Insulin resistance Obesity Acathosis nigricans |
| ORNITHINE TRANSCARBAMYLASE DEFICIENCY (OTC Mutation) | Disorder of urea cycle metabolism caused by mutations of the gene encoding ornithine transcarbamylase (OTC). | X-Linked | Age at onset: Hemizygous male with null mutation neonatal; heterozygous female – with severe intercurrent illness, postpartum, or never Hyperammoenemia Coma |
| POLYCYSTIC KIDNEY DISEASE (PKD1 and PKD2 Mutations) | PKD1 encodes polycystin 1, a transmembrane receptor–like protein of unknown function. PKD2 encodes polycystin 2, an integral membrane protein with homology to the voltageactivated sodium and calcium α1 channels. | Autosomal Dominant | Age at onset: Childhood through adulthood Progressive renal failure Renal and hepatic cysts Intracranial saccular aneurysms Mitral valve prolapse Colonic diverticula |
| PRADER-WILLI SYNDROME (Absence of Paternally Derived 15q11-q13) | Loss of expression of genes on paternally derived chromosome 15q11-q13 | Chromosomal Deletion Uniparental Disomy | Age at onset: Infancy Infantile feeding difficulties Childhood hyperphagia and obesity Hypotonia Cognitive impairment Short stature Dysmorphism |
| RETINOBLASTOMA (RB1 Mutation) | Retinoblastoma-associated RB1 mutations occur throughout the coding region and promoter of the gene. | Autosomal Dominant | Age at onset: Childhood Leukocoria Strabismus Visual deterioration Conjuctivitis |
| RETT SYNDROME (Mepc2 Mutations) | It is caused by loss-of-function mutations of the MECP2 gene | X-Linked Dominant | Age at onset: Neonatal to early childhood Acquired microcephaly Neurodevelopmental regression Repetitive stereotypic hand movements |
| SEX DEVELOPMENT DISORDER (46,XX MALE) (SRY Translocation) | In patients with complete gonadal dysgenesis, point mutations, deletions, or translocations of SRY are among the most common causes of such disorders. | Y-Linked or Chromosomal | Age at onset: Prenatal Sterility Reduced secondary sexual features Unambiguous genitalia mismatched to chromosomal sex |
| SICKLE CELL DISEASE (β-Globin Glu6val Mutation) | The Glu6val mutation in β-globin decreases the solubility of deoxygenated hemoglobin and causes it to form a gelatinous network of stiff fibrous polymers that distort the red blood cell, giving it a sickle shape | Autosomal Recessive | Age at onset: Childhood Anemia Infarction Asplenia |
| TAY-SACHS DISEASE (HEXA Mutation) | Mutations of the α subunit or the activator protein cause the accumulation of GM2 in the lysosome and thereby Tay-Sachs disease of the infantile, juvenile, or adult type. (Mutation of the β subunit causes Sandhoff disease). | Autosomal Recessive | Age at onset: Infancy through adulthood Neurodegeneration Retinal cherry-red spot Psychosis |
| THALASSEMIA (α- or β-Globin Deficiency) | Deletion of α-globin genes accounts for 80% to 85% of α-thalassemia, and approximately 15 mutations account for more than 90% of β-thalassemia. | Autosomal Recessive | Age at onset: Childhood Hypochromic microcytic anemia Hepatosplenomegaly Extramedullary hematopoiesis |
| THIOPURINE S-METHYLTRANSFERASE DEFICIENCY (TPMT Polymorphisms) | Thiopurine methyltransferase (TPMT) is the enzyme responsible for phase II metabolism of 6-mercaptopurine (6-MP) and 6-thioguanine by catalyzing S-methylation and thus inactivating these compounds. | Autosomal Semidominant | Age at onset: Deficiency is present at birth, manifestation requires drug exposure Myelosuppression Increased risk for brain tumor in thiopurine methyltransferase-deficient patients with acute lymphoblastic leukemia receiving brain irradiation |
| THROMBOPHILIA (FV and PROC Mutations) | The factor v Leiden mutation removes the preferred site for protein C proteolysis of activated factor v, thereby slowing inactivation of activated factor v and predisposing patients to thrombophilia. | Autosomal Dominant | Age at onset: Adulthood Deep Venous thrombosis |
| TURNER SYNDROME (Female Monosomy X) | Monosomy for the X chromosome can arise either by the failure to transmit a sex chromosome to one of the gametes or by loss of a sex chromosome from the zygote or early embryo. | Chromosomal | Age at onset: Prenatal Short stature Ovarian dysgenesis Sexual immaturity |
| XERODERMA PIGMENTOSUM (Defect of Nucleotide Excision Repair) | Disorder of DNA repair that causes marked sensitivity to UV irradiation | Autosomal Recessive | Age at onset: Childhood UV sensitivity Skin cancer Neurological dysfunction |