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Patient & Family Handbook Immune Deficiency Foundation Patient & Family Handbook For Primary Immunodeficiency Diseases Chapter 24 Immune Deficiency Foundation Patient & Family Handbook For Primary Immunodeficiency Diseases 6th Edition The development of this publication was supported by Shire, now Takeda. 110 West Road, Suite 300 Towson, MD 21204 800.296.4433 www.primaryimmune.org [email protected] Chapter 24 Inheritance Joud Hajjar, MD, MS, Texas Children’s Hospital, Houston, Texas, USA Maha Syed, MD, Texas Children’s Hospital, Houston, Texas, USA Primary immunodeficiency diseases (PI) are mostly caused by genetic abnormalities that lead to weaknesses in the immune system. To understand the inheritance in PI, it’s good to understand a few basic concepts in genetics. Inheritance of Primary spelling errors might not lead to a significant change in the word, and those variants do not cause disease, Immunodeficiency Diseases while other spelling errors can cause diseases, such Every cell in the human body contains genetic as PI. If these errors occur in the egg or sperm of material that instructs the job of that cell. This one of the parents, it can cause disease in the child. genetic material is packaged into 23 pairs of Occasionally, the errors occur in the fertilized egg, chromosomes (22 numbered chromosomes, and one and neither of the parents actually carry that variant. pair of sex chromosomes (XX for females and XY for males). Children inherit one chromosome in each pair Figure 24:1 X-Linked Recessive Inheritance - from their mother, and one chromosome of each pair Carrier Mother from their father. Mother Father During fertilization, the egg which consists of 23 chromosomes (haploid) fuses with 23 chromosomes of the sperm and the resulting zygote has 46 XX XY chromosomes (diploid). This way each parent contributes half of their genetic information and Eggs Sperm physical characteristics, such as hair color, eye color, blood type, etc., onto the offspring. The sex of the X X X Y offspring is determined by which chromosome (X or Y) of the sperm (X or Y) fuses with the egg (only X). An X chromosome results in a female offspring and a Y chromosome in a male offspring. (Figure 24:1) The genetic material packaged in these XX XY XX XY chromosomes is made up of DNA, which is composed of individual molecules called nucleotides. Girl Boy Girl Boy Four nucleotides make up the DNA, these are Adenine (A), Thymidine (T), Guanine (G), and Cytosine (C). The DNA is made up of long chains Types of Inheritance of codons comprised of three nucleotides (letters) PI can be inherited in one of three different ways: that are arranged in a specific way, similar to the X-linked recessive, autosomal recessive or autosomal arrangement of alphabetical letters to form words dominant. Family history and laboratory studies can and sentences. Errors in the spelling of the words be helpful in establishing the possible role of genes (because of misplacement of one or more letters) or chromosomes in a particular PI and may be useful lead to genetic mutations, now called variants. Some to identify a particular pattern of inheritance. IDF Patient & Family Handbook 115 X-linked Recessive Inheritance Mothers who are carriers can pass on the disease to their sons if the sons inherit the affected X, and in X-linked recessive is a mode of inheritance where this type of inheritance, a family history may show the gene causing disease is present on the X multiple males affected with the disease. Mothers chromosome, mainly affecting males. Males who are carriers can also pass on the affected X to have only one X chromosome. If the inherited X their daughters, who then become carriers of the chromosome carries the mutated gene in a male, disease themselves. this will lead to disease expression, as there is no additional X chromosome to compensate and the Mutations in X chromosomes may occur Y chromosome does not carry information that spontaneously and may occur in individuals with no duplicates that of the X chromosome. An affected previous family history. male will pass on the defective gene to all his female offspring. All of his daughters will be carriers, and The following are examples of PI with X-linked all of his sons will carry the healthy Y chromosome recessive inheritance: and will therefore not be affected by the disease. • Bruton’s or X-Linked Agammaglobulinemia (XLA) Females have two X chromosomes and must inherit both mutated genes – one from each parent • Wiskott-Aldrich Syndrome to develop the disorder. Therefore, females are carriers if they inherit one faulty X gene, while the • Severe Combined Immunodeficiency second normal X gene continues to carry out its (SCID), caused by mutations in the function and consequently prevents the abnormal common gamma chain gene from expression. Females with one affected X • Hyper IgM Syndrome, due to mutations in and one healthy X appear to be a healthy carriers. CD40 ligand However, at times, female carriers could present with symptoms similar to males with X-linked disease due • X-linked Lymphoproliferative Disease, two forms to a process called X-inactivation. In this process, some cells shut down (inactivate) the X chromosome • Chronic Granulomatous Disease (CGD), the most coming from the mother, and other cells inactivate common form the X chromosome from the father. In the case of • Properdin Deficiency X-linked disease carrier, if the inactivation happened to the X chromosome coming from the mother, • Dyskeratosis Congenita then the only active chromosome will be the X chromosome coming from the father, which carries The chances of a woman who carries the faulty gene the disease-causing variant, leading to symptoms having an affected child is different based on the similar to the affected males. Carriers can pass on the gender of the child. If the father is a non- carrier, mutated gene to their children. there are four possible combinations in every pregnancy (See Figure 24:3). Figure 24:2 X-Linked Recessive Inheritance - Affected Father • 1 chance in 4, (25% chance) that a son will inherit the Y chromosome from his father and X-linked Affected Father Unaffected Mother recessive gene mutation from his mother. He will, therefore, be affected. A o N N X Y XX • 1 chance in 4, (25% chance) that a son will inherit the Y chromosome from his father and Eggs Sperm the working copy of the X-linked gene from his A o N N mother. He will not be affected by the condition. X Y X X • 1 chance in 4, (25% chance) that a daughter will inherit both working copies of the X-linked genes: one copy from her father and one from her mother. In this case, she will not only be A N A N o XN o XN unaffected by the condition, but she will also X X X X Y Y NOT be a carrier of the X linked recessive gene mutation. Carrier Females Carrier Males 116 Chapter 24: Inheritance • 1 chance in 4, (25% chance) that a daughter will children (See Figure 24:4). Chances remain the same inherit from her father the working copy of the for all future pregnancies, and the outcome of each X-linked gene and the faulty X-linked recessive pregnancy is not affected by previous pregnancies. gene mutation from her mother. She will be a genetic carrier of the condition like her mother Figure 24:4 Autosomal Recessive Inheritance - and will usually be unaffected. SCID Example To summarize, if the offspring is a boy, there is 50% Carrier Mother Carrier Father chance he will be affected by the disease. If the offspring is a girl, there is a 50% that she will be S S N S N C C C a genetic carrier of the disease. The outcome of I I I future pregnancies will not be affected by previous D D D pregnancies, meaning that it is possible for all (100%) Eggs Sperm of the boys in a family where the mother is a carrier N S N to be affected with X-linked conditions. C S I C D I Figure 24:3 X-Linked Recessive Inheritance - D Carrier Mother Carrier Mother Unaffected Father S S N N S N N C C C I I I AX XN N O D D D X Y Affected Carrier Carrier Normal Child Child Child Child Eggs Sperm The following are frequently recognized autosomal AX XN NX YO recessive deficiencies: • Various forms of Severe Combined Immunodeficiency (SCID) » Adenosine deaminase (ADA) deficiency AX XN AX Yo NXXN NXYO » Recombinase activating gene (RAG) deficiency Carrier Affected Normal Normal » Jak3 deficiency Female Male Female Male » ARTEMIS SCID Autosomal Recessive Inheritance • MHC class II deficiency Genes present on one of the 22 pairs of • Chronic Granulomatous Disease (CGD), chromosomes/autosomes are known as autosomal. three forms In autosomal recessive disease, two abnormal copies of the gene, typically one from each parent, must • Leucocyte adhesion deficiency (LAD) be inherited to cause symptoms of the condition. Usually, parents of the child affected by an autosomal • Chediak-Higashi syndrome recessive condition carry one copy of an abnormal • Familial forms of hemophagocytic gene and are unaffected because of normal lymphohistiocytosis (HLH). functioning of the other gene. In this scenario, where both parents are carriers of an abnormal autosomal The incidence of autosomal recessive diseases is recessive gene, there is a 25% chance (1 in 4) that rare. Most affected infants do not have any previous any offspring, irrespective of gender will be affected family history. However, consanguineous marriages by the disorder. There is a 50% chance (1 in 2) that and increased frequency of asymptomatic carriers of the offspring will be a carrier (have one abnormal mutations in certain populations (such as ARTEMIS gene), and a 25% (1 in 4) that the baby will not inherit SCID in Navajo populations) increase the incidence the faulty gene, and therefore will not be affected of such diseases.
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