Common Genetic Disorders

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:

DiseaseGene/DefectInheritancePhenotypic 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 DominantWidespread red/purple patches on the skin and mucosal membranes (eye, mouth, genitalia) 10 to 14 days after beginning antiretroviral treatment with abacavir.
ACHONDROPLASIASpecific mutations in FGFR3; two mutations, 1138G>A (≈98%) and 1138G>C (1% to 2%),Autosomal DominantAge 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).MultifactorialAge at onset: >50 years
Gradual loss of central vision Drusen in the macula
Changes in the retinal pigment -epithelium
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 DominantAge at onset: Middle to late adulthood
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 NovoAge 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 defectAge at onset: Prenatal Prenatal and postnatal overgrowth
Embryonal tumor in childhood Hemihyperplasia
Renal abnormalities
Adrenocortical cytomegaly Neonatal hypoglycemia
HEREDITARY BREAST AND OVARIAN CANCERLoss of BRCA1 or BRCA2 function probably permits the accumulation of other mutations that are directly responsible for neoplasia.Autosomal DominantAge 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 DominantAge at onset: Childhood to adulthood
Progressive distal weakness
Distal muscle wasting
CHARGE SYNDROME (CHD7 Mutation)Multiple congenital malformations caused by mutations in the CHD7 geneAutosomal DominantColoboma 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 22q11Somatic MutationAge at onset: Middle to late adulthood
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 InheritanceEpisodic abdominal pain, cramping and diarrhea
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 RecessiveAge 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 RecessiveCongenital 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 neuronsX-LinkedAge 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 DominantAge 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 LDLRAutosomal DominantAge at onset: Heterozygote –early to middle adulthood homozygote-childhood Hypercholesterolemia Atherosclerosis  
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-LinkedAge 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 RecessiveAge at onset: Childhood or early adulthood Hepatosplenomegaly
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-linkedAge 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 RecessiveAge 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-LinkedAge at onset: Infancy to adulthood
Bleeding diathesis Hemarthroses
HIRSCHSPRUNG DISEASE (Neurocristopathy)The genes implicated in HSCR include RET, EDNRB, EDN3, GDNF, and NRTN.Autosomal Dominant, Autosomal Recessive, or MultigenicAge at onset: Neonatal to adulthood
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 DominantAge 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 1Autosomal DominantAge 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 DominantAge 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 pancreasMultifactorialAge at onset: Childhood through adulthood
Polyuria, polydipsia, polyphagia Hyperglycemia
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 DeletionAge 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 RecessiveQTc prolongation (>4700 msec in males, >480 msec in females)
Syncopal episodes
Sudden death
LYNCH SYNDROME (DNA Mismatch Repair Gene Mutations)Mutations in DNA mismatch repair genes. (Microsatellite instability)Autosomal DominantAge 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 DominantAge 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 RecessiveAge at onset: Between 3 and 24 months
Hypoketotic hypoglycemia Vomting
Hepatic encephalopathy
MILLER-DIEKER SYNDROME (17p13.3 Heterozygous Deletion)Contiguous gene deletion syndrome caused by heterozygous deletion of 17p13.3Chromosomal DeletionAge at onset: Prenatal Lissencephaly type 1 or type 2 Facial dysmorphism
Severe global intellectual disability
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, MitochondrialAge at onset: Childhood through adulthood
Myoclonic seizures
NEUROFIBROMATOSIS 1 (NF1 Mutation)Neurofibromatosis results from mutations in the neurofibromin gene (NF1).Autosomal DominantAge 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.MultifactorialAge at onset: Childhood through adulthood Hyperglycemia
Relative insulin deficiency Insulin resistance
Acathosis nigricans
ORNITHINE TRANSCARBAMYLASE DEFICIENCY (OTC Mutation)Disorder of urea cycle metabolism caused by mutations of the gene encoding ornithine transcarbamylase (OTC).X-LinkedAge at onset: Hemizygous male with null mutation neonatal; heterozygous female – with severe intercurrent illness, postpartum, or never Hyperammoenemia
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 DominantAge 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-q13Chromosomal Deletion Uniparental DisomyAge at onset: Infancy Infantile feeding difficulties
Childhood hyperphagia and obesity
Cognitive impairment
Short stature
RETINOBLASTOMA (RB1 Mutation)Retinoblastoma-associated RB1 mutations occur throughout the coding region and promoter of the gene.Autosomal DominantAge at onset: Childhood Leukocoria
Visual deterioration Conjuctivitis
RETT SYNDROME (Mepc2 Mutations)It is caused by loss-of-function mutations of the MECP2 geneX-Linked DominantAge 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 ChromosomalAge 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 shapeAutosomal RecessiveAge at onset: Childhood Anemia
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 RecessiveAge at onset: Infancy through adulthood
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 RecessiveAge 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 SemidominantAge 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 DominantAge 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.ChromosomalAge 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 irradiationAutosomal RecessiveAge at onset: Childhood UV sensitivity Skin cancer Neurological dysfunction

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