Flashcards in 18.03.03 X-linked recessive inheritance Deck (19):
What are the features of X-linked recessive inheritance?
1) Vertical transmission in which carrier females pass the disorder on to affected sons.
2) All daughters of an affected male will inherit the defective gene (daughters are obligate carriers).
3) Women who are carriers have a 50% chance of passing the defective gene to their sons.
4) Similarly, the daughters of heterozygous women will themselves have a 50% chance of being carriers (Inherit defective gene from mother).
5) Affected homozygous females are exceptionally rare.
6) Affected males are usually born to unaffected parents; their mother is usually an asymptomatic carrier and may have affected male relatives.
7) Absence of male-to-male transmission in the pedigree – however, the mating of an affected male with a carrier female may give the appearance of male-to-male transmission
in what circumstances may females be affected with X-linked recessive disorders?
1) Female carriers with skewed X chromosome inactivation, XCI
2) A deletion involving the X chromosome
3) An X-chr rearrgangement or complete absence of an X chromosome (i.e., Turner syndrome)
4) Females with two pathogenic sequence changes (e.g. compound heterozygosity for two DMD pathogenic sequence changes)
Give three examples of X-linked recessive disorders.
X-linked retinitis pigmentosa
X-linked hypohidrotic ectodermal dysplasia (XL-HED)
Red-green colour vision defects (also known as colour blindness)
Which genes are red-green colour vision defects associated with?
OPN1LW (opsin 1 long wave) encoding red pigment and OPN1MW (opsin 1 middle wave) encoding green pigment.
Which X-linked gene is assoicated with X-linked hypohidrotic ectodermal dysplasia (XL-HED). What is the incidence and clinical presentation of this condition?
Xq13.1 EDA, majority
(Autosomal) EDAR and EDARADD
XL-HED is characterised by hypotrichosis (sparseness of scalp and body hair),
hypohidrosis (reduced ability to sweat) and hypodontia (congenital absence of teeth).
Since the phenotype is a property of individual cells, female carriers show patches of normal and abnormal tissue depending on patterns of XCI.
Prevalence of at least 1:5000 newborns.
Which X-linked gene is assoicated with Hunter syndrome. What is the incidence and clinical presentation of this condition?
Xq28: IDS gene which encodes iduronate 2-sulfatase (I2S), an enzyme essential for the breakdown of glycosaminoglycans (GAGs). Without this enzyme, mucopolysaccharides build up in various body tissues, causing damage.
Age of onset, disease severity, and rate of progression vary significantly among affected males. In severe disease, CNS involvement, progressive airway disease and cardiac disease usually result in death in the first or second decade of life. In attenuated disease, CNS is not (or is minimally) involved.
Incidence between 1:100,000 and 1:170,000 male births.
Which X-linked gene is associated with Fabry syndrome. What is the molecular pathology underlying this condition?
Encodes the α-galactosidase A (α-Gal A) enzyme, active in lysosomes. Alpha-galactosidase A normally breaks down a fatty substance called globotriaosylceramide (GL-3).
Mutations in the GLA gene alter the structure and function of the enzyme, preventing it from breaking down this substance effectively. Globotriaosylceramide builds up in cells throughout the body, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. The progressive accumulation of this substance damages cells, leading to the varied signs and symptoms of Fabry disease.
What is the clinical presentation and incidence of Fabry disease?
Characteristic features of Fabry disease include episodes of pain, particularly in the hands and feet (acroparesthesias);
clusters of small, dark red spots on the skin called angiokeratomas;
a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the eye (corneal opacity);
problems with the gastrointestinal system; ringing in the ears (tinnitus) and hearing loss.
Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Some affected individuals have milder forms of the disorder that appear later in life and affect only the heart or kidneys.
Prevalence 1-5/10,000 (varied estimates). Childhood/adolescence onset usually.
Give a brief summary of X-linked retinitis pigmentosa.
Xp11.4: RPGR >70%
XP11.3 RP2 15-20%
XLRP is characterised by night blindness and a decrease in peripheral vision in the third/fourth decade of life.
Genetically heterogeneous (Changes in at least six genes are thought to cause the X-linked form of the disorder).
Give a brief summary of X-linked cone dystrophy.
X-linked cone dystrophy is a type of hereditary retinal degeneration manifesting as progressive dysfunction of day vision with preservation of night vision.
Genetically heterogeneous (at least two genes involved); caused by mutation in an alternative terminal exon 15 (ORF15) of RPGR (Xp11.4)
What are the clinical features of Haemophilia?
The deficiency in clotting activity results in prolonged oozing after injuries / tooth extractions / surgery and delayed or recurrent bleeding prior to complete wound healing.
In severe cases of haemophilia, continuous bleeding occurs even in the absence of injury (spontaneous bleeding).
Serious complications can result from bleeding into the joints, muscles, brain, or other internal organs. The age of diagnosis and frequency of bleeding episodes are related to the level of factor VIII or IX clotting activity.
What is the clinical manifestation in females who carry a haemophilia mutation?
Female carriers can be biochemically abnormal but clinically unaffected.
Approximately 10% of carrier females are at risk for bleeding (even if the family member is mildly affected) and are thus symptomatic carriers, although symptoms are usually mild.
Which gene is associated with Haemophilia A? Describe the mutation spectrum of this gene.
F8 (Xq28): very large gene composed of 26 exons.
Inversions are most common in severe haemophilia A
45% intron 22 inversion
5% intron 1 inversion
Other changes in F8 range in diversity from single base pathogenic substitutions to large insertions and deletions, and from small insertions and deletions to gene rearrangements and whole gene deletions. F8 screening identifies pathogenic variants in as many as 98% of individuals with haemophilia A.
How is Haemophilia managed?
1) Referral to specialist haemophilia centre for assessment, education, and and to facilitate management.
2) For those with severe disease, regular prophylactic intravenous infusions of factor VIII, factor IX concentrate or recombinant factor VIII, factor IX to maintain factor VIII, IX clotting activity higher than 1% nearly eliminates spontaneous bleeding and prevents chronic joint disease. Gene therapy using intravenous infusion of adeno-associated viral vectors expressing factor IX and VIII have shown promising results recently (Rangarajan et al, 2017).
3) For those with mild disease (A or B), including most symptomatic carriers, immediate treatment of bleeding or prophylaxis with intravenous factor VIII or IX concentrate or nasal desmopressin (DDAVP [1-deamino-8-D-arginine vasopressin]) for mild Haemophilia A.
Which gene is associated with Haemophilia B? Describe the mutation spectrum of this gene.
F9 (Xq27.1): smaller gene composed of 8 exons.
90% SNVs throughout the gene.
Molecular genetic testing of F9 identifies pathogenic variants in as many as 90% of individuals with haemophilia B.
What is the worldwide prevalence of Haemophilia A and B?
Haemophilia A is ~ 1 in 6,000 live male births worldwide.
Haemophilia B is ~ 1 in 30,000 live male births worldwide.
Which gene is associated with Androgen Insensitivity Syndrome? What is the function of the protein this gene encodes?
Androgen receptors allow cells to respond to androgens that direct male sexual development.
Androgens and androgen receptors also have other important functions in both males and females, such as regulating hair growth and sex drive.
Pathogenic sequence variants (mostly missense) makes cells less responsive to androgens or prevents cells from using these hormones at all.
What is the presentation of AIS?
Characterised by feminisation (undermasculinisation) of external genitalia at birth (patients are genetically male), abnormal secondary sexual development at puberty and infertility in individuals with a 46,XY karyotype.
Testosterone and luteinizing hormone levels are normal or increased.
Almost always associated with infertility.