Sex-Linked Inheritance

Sex-linked inheritance is a form of mendelian inheritance. The term describes traits that are inherited via either the X or the Y chromosome. For X-linked recessive transmission, the allele is recessive and carried on the X chromosome. Males are more likely to express X-linked recessive disorders because they possess only 1 X chromosome. For X-linked dominant transmission, the allele is dominant and carried on the X chromosome. Because of this, only 1 copy of the disease allele is required for phenotypic expression. X-linked dominant disorders are less common than X-linked recessive disorders.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Definition

Sex-linked inheritance occurs when genetic traits are inherited on either the X or the Y chromosome. There are 2 major sex-linked modes of inheritance: X-linked recessive and X-linked dominant.

X-linked recessive inheritance:

  • Females:
    • Both maternal and paternal X chromosomes must be affected to express the trait.
    • Often carriers of X-linked recessive traits 
    • Expression of X-linked recessive traits can occur if:
      • Female inherits an affected allele from both maternal and paternal X chromosomes.
      • Female carrier has a nonrandom inactivation of the healthy X chromosome.
  • Males:
    • More frequently affected than females (only 1 X chromosome)
    • Male-to-male inheritance is impossible (father transmits only Y chromosome to son).

X-linked dominant inheritance:

  • Very rare
  • Males and females have an equal probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability of expressing the trait. 
  • Females: 
    • Inheritance can be from either the maternal or the paternal X chromosome.
    • Usually less severe phenotypical presentation in females because of 2nd X chromosome

X-Linked Recessive Inheritance and Diseases

X-linked recessive inheritance

Children of an unaffected father and a heterozygous (carrier) mother have the following risks:

  • Male offspring: 50% risk of disease
  • Female offspring: 0% risk of disease and 50% risk of being a carrier
Table: Risk of children of an unaffected father and a heterozygous (carrier) mother
Unaffected father
x y
Heterozygous (carrier) mother x xx (unaffected female) xy (unaffected male)
x xx (carrier female) xy (affected male)
x: affected X chromosome; x: unaffected x chromosome; y: unaffected Y chromosome

Children of an affected father and a heterozygous (carrier) mother have the following risks:

  • Male offspring: 50% risk of disease
  • Female offspring: affected chromosome always transmitted → 50% risk of disease and 50% risk of being a carrier
Table: Risk of children of an affected father and a heterozygous (carrier) mother
Hemizygously affected father
x y
Heterozygous (carrier) mother x xx (carrier female) xy (unaffected male)
x xx (affected female) xy (affected male)
x: affected X chromosome; x: unaffected x chromosome; y: unaffected Y chromosome

Children of an affected father and an unaffected mother have the following risks:

  • Male offspring: 0% risk of disease
  • Female offspring: affected chromosome from father always transmitted → 100% risk of being a carrier, but 0% risk of disease
Table: Risk of children of an affected father and an unaffected mother
Hemizygously affected father
x y
Unaffected mother x xx (carrier female) xy (unaffected male)
x xx (carrier female) xy (unaffected male)
x: affected X chromosome; x: unaffected x chromosome; y: unaffected Y chromosome

Children of a hemizygous affected father and a homozygous (affected) mother have the following risks:

  • Male offspring: 100% affected
  • Female offspring: 100% affected
Table: Risk of children of a hemizygous affected father and a homozygous (affected) mother
Hemizygously affected father
x y
Homozygously affected mother x xx (affected female) xy (affected male)
x xx (affected female) xy (affected male)
x: affected X chromosome; x: unaffected x chromosome; y: unaffected Y chromosome

X-linked recessive diseases

  • Red-green color blindness: also known as daltonism. Red-green color blindness is a common trait in humans that results in confusion of green and red. About 56 different genes have been associated with causing color blindness when mutated, not all of which are located on the X chromosome. Red-green color blindness can be present from birth or develop later in life. About 8% of males, but only 0.4% of females, have some form of color blindness.
  • Hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia A: blood clotting disorder caused by mutations in the F8 gene, resulting in factor VIII deficiency. Even heterozygous females can have mild symptoms of hemophilia. Management includes factor VIII replacement therapy and desmopressin.
  • Hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia B: blood clotting disorder caused by mutations in the F9 gene, resulting in factor IX deficiency. Management is mostly by factor IX replacement therapy. 
  • Duchenne muscular dystrophy Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder that is caused by a mutation in the DMD gene. The mutation leads to the production of abnormal dystrophin, resulting in muscle-fiber destruction and replacement with fatty or fibrous tissue. Duchenne Muscular Dystrophy (DMD): caused by mutations in the DMD gene.  Duchenne muscular dystrophy Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder that is caused by a mutation in the DMD gene. The mutation leads to the production of abnormal dystrophin, resulting in muscle-fiber destruction and replacement with fatty or fibrous tissue. Duchenne Muscular Dystrophy is characterized by rapidly progressive muscle weakness and degeneration, starting with proximal muscle groups in early infancy. Management is symptomatic, including physical therapy, steroid injections to improve muscle strength, assistive breathing devices, and heart transplantation.
  • Becker muscular dystrophy Becker muscular dystrophy Becker muscular dystrophy (BMD) is an X-linked recessive genetic disorder that is caused by a mutation in the DMD gene. Abnormal, partially functional muscle dystrophin protein is produced, which leads to progressive muscle weakness and the eventual loss of ambulation. Becker Muscular Dystrophy (BMD): also caused by mutations in the DMD gene. Becker muscular dystrophy Becker muscular dystrophy Becker muscular dystrophy (BMD) is an X-linked recessive genetic disorder that is caused by a mutation in the DMD gene. Abnormal, partially functional muscle dystrophin protein is produced, which leads to progressive muscle weakness and the eventual loss of ambulation. Becker Muscular Dystrophy presents similarly to DMD, but it has a later onset and a milder clinical course.
  • X-linked ichthyosis: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin condition caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations or deletion in the STS gene. This mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations or deletion results in diffuse skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin scaling due to a slow rate of shedding of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin cells developing in the 1st few weeks of life. Management is symptomatic with alpha-hydroxy acids, lubricating bath oils, and emollients.
  • X-linked agammaglobulinemia X-linked agammaglobulinemia X-linked agammaglobulinemia, also known as Bruton's agammaglobulinemia or Bruton's disease, is a rare, recessive genetic disorder characterized by the improper development of B cells, leading to a lack of mature B cells capable of responding to stimulation by cell-mediated immune responses or certain antigen-presenting cells. X-linked Agammaglobulinemia (XLA): type of primary immunodeficiency caused by mutations in the BTK gene. Affected individuals develop recurrent bacterial infections early in life owing to absence of mature B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells. Also, these individuals may have no tonsils or adenoids. 
  • Glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency (G6PD): nonimmune hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia due to mutations in the G6PD gene. Hemolysis tends to occur secondary to infection or exposure to certain medications, chemicals, or foods. The disorder is associated with neonatal jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, Heinz bodies on peripheral smear, and increased susceptibility to infections due to NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway deficiency in phagocytes.

X-Linked Dominant Inheritance and Diseases

X-linked dominant inheritance

Children of a hemizygous (unaffected) father and a heterozygous (affected) mother have the following risks:

  • Male offspring: 50% risk of disease
  • Female offspring: 50% risk of disease
Table: Risk of children of a hemizygous (unaffected) father and a heterozygous (affected) mother
Unaffected father
x y
Heterozygously affected mother x xx (unaffected female) xy (unaffected male)
X Xx (affected female) Xy (affected male)
X: affected X chromosome; x: unaffected x chromosome; y: unaffected Y chromosome

Children of a hemizygous (unaffected) father and a homozygous (affected) mother have the following risks:

  • Male offspring: 100% risk of disease
  • Female offspring: 100% risk of disease
Table: Risk of children of a hemizygous (unaffected) father and a homozygous (affected) mother
Unaffected father
x y
Homozygously affected mother X Xx (affected female) Xy (affected male)
X Xx (affected female) Xy (affected male)
X: affected X chromosome; x: unaffected x chromosome; y: unaffected Y chromosome

Children of a hemizygous (affected) father and a heterozygous (affected) mother have the following risks:

  • Male offspring: 50% risk of disease
  • Female offspring: 100% risk of disease
Table: Risk of children of a hemizygous (affected) father and a heterozygous (affected) mother
Hemizygously affected father
X y
Heterozygously affected mother X XX (affected female) Xy (affected male)
x Xx (affected female) xy (unaffected male)
X: affected X chromosome; x: unaffected x chromosome; y: unaffected Y chromosome

Children of a hemizygous (affected) father and a homozygous (unaffected) mother have the following risks:

  • Male offspring: 0% risk of disease
  • Female offspring: 100% risk of disease
Table: Risk of children of a hemizygous (affected) father and a homozygous (unaffected) mother
Hemizygously affected father
X y
Unaffected mother x Xx (affected female) xy (unaffected male)
x Xx (affected female) xy (unaffected male)
X: affected X chromosome; x: unaffected x chromosome; y: unaffected Y chromosome

X-linked dominant diseases

  • Hypophosphatemic rickets Rickets Rickets and osteomalacia are disorders of decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children. Although most cases of rickets are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Rickets commonly presents with skeletal deformities and growth abnormalities. Osteomalacia and Rickets: condition characterized by reduced phosphate reabsorption, most commonly caused by mutations in the PHEX gene. Symptoms tend to vary significantly among affected individuals. Severe forms may cause bowing of the legs and other bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones deformities, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones and joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and poor bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones growth.
  • Rett syndrome Rett syndrome Rett syndrome is a rare genetic neurological and developmental disorder that affects the development of the brain. There are various stages of Rett syndrome characterized by different symptoms and clinical signs, including increasing problems with the use of muscles that control movement, coordination, and communication. Rett Syndrome: neurodevelopmental disorder caused by mutations in the MECP2 gene and almost exclusively affecting females. The majority of cases of Rett syndrome Rett syndrome Rett syndrome is a rare genetic neurological and developmental disorder that affects the development of the brain. There are various stages of Rett syndrome characterized by different symptoms and clinical signs, including increasing problems with the use of muscles that control movement, coordination, and communication. Rett Syndrome are caused by de novo mutations, and affected males tend to die shortly after birth. Rett syndrome Rett syndrome Rett syndrome is a rare genetic neurological and developmental disorder that affects the development of the brain. There are various stages of Rett syndrome characterized by different symptoms and clinical signs, including increasing problems with the use of muscles that control movement, coordination, and communication. Rett Syndrome is characterized by normal initial development followed by loss of developmental milestones Developmental milestones Developmental milestones are the skills or abilities that most children are able to perform when they reach a certain age. Understanding the appropriate milestones and at what age they are reached helps clinicians identify symptoms of delayed development. Developmental milestones are divided into 5 important domains: gross motor, fine motor, language, social, and cognitive. Developmental Milestones and Normal Growth, stereotypic hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand movements, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and gait abnormalities. Treatment is purely symptomatic and includes physiotherapy and anticonvulsants. 
  • Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. Alport Syndrome: common genetic kidney disorder caused by mutations in COL4A5, COL4A4, and COL4A3. These mutations result in defective type IV collagen leading to glomerular disease, ocular abnormalities, and sensorineural hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss. Management includes strict blood pressure control, hearing aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS, and kidney transplantation.
  • Fragile X syndrome Fragile X syndrome Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a genetic condition with X-linked inheritance. Both boys and girls may be affected, but the severity is much worse in boys. Characteristic features include a long face, prominent forehead and chin, large ears, flat feet, and large testes post-puberty for boys. Fragile X Syndrome: condition caused by mutations in the FMR1 gene leading to mild-to-moderate intellectual disability. Typical physical features include a long, narrow face, large ears, flexible fingers, and large testicles Testicles The testicles, also known as the testes or the male gonads, are a pair of egg-shaped glands suspended within the scrotum. The testicles have multiple layers: an outer tunica vaginalis, an intermediate tunica albuginea, and an innermost tunica vasculosa. The testicles are composed of testicular lobules and seminiferous tubules. Testicles. Other symptoms are problems with social interactions, delayed speech development, hyperactivity, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Management is purely symptomatic.

References

  1. Raby, B. (2021). Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian). UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/inheritance-patterns-of-monogenic-disorders-mendelian-and-non-mendelian
  2. Van Esch, H. (2021). Fragile X syndrome: clinical features and diagnosis in children and adolescents. UpToDate. Retrieved June 26, 2021, from https://www.uptodate.com/contents/fragile-x-syndrome-clinical-features-and-diagnosis-in-children-and-adolescents
  3. Kashtan, C. (2021). Clinical manifestation, diagnosis, and treatment of Alport syndrome (hereditary nephritis). UpToDate. Retrieved June 26, 2021, from https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-alport-syndrome-hereditary-nephritis
  4. Schultz, R., Glaze, D. (2021). Rett syndrome: genetics, clinical features, and diagnosis. UpToDate. Retrieved June 26, 2021, from https://www.uptodate.com/contents/rett-syndrome-genetics-clinical-features-and-diagnosis
  5. Scheinman, S., Carpenter, T., Drezner, M. (2021). Hereditary hypophosphatemic rickets and tumor-induced osteomalacia. UpToDate. Retrieved June 26, 2021, from https://www.uptodate.com/contents/hereditary-hypophosphatemic-rickets-and-tumor-induced-osteomalacia
  6. Darras, B. (2021). Duchenne and Becker muscular dystrophy: clinical features and diagnosis. UpToDate. Retrieved June 26, 2021, from https://www.uptodate.com/contents/duchenne-and-becker-muscular-dystrophy-clinical-features-and-diagnosis
  7. Hand, J. (2021). Recessive X-linked ichthyosis. UpToDate. Retrieved June 26, 2021, from https://www.uptodate.com/contents/recessive-x-linked-ichthyosis
  8. Hernandex-Trujilo, V. (2021). Agammaglobulinemia. UpToDate. Retrieved June 26, 2021, from https://www.uptodate.com/contents/agammaglobulinemia
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  10. NIH, Genetic and Rare Diseases Information Center. (n.a.) Hemophilia A. Retrieved September 5, 2021, from https://rarediseases.info.nih.gov/diseases/6591/hemophilia-a

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