Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation is present on a sex chromosome rather than a non-sex chromosome. In humans, these are termed X-linked recessive, X-linked dominant and Y-linked.

1. “X-chromosome & Sex-linked Diseases”
College of Health Sciences
School of Medicine
Department of Medical Physiology
P.by: Habtemariam Mulugeta
ID No. GSR/2895/14
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2. “X-chromosome & Sex-linked Diseases”
Advanced Reproductive System
2 Habtemariam M.

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Outline
 Objectives
 Introduction
 Types of Sex Linked Inheritance
 X-linked Recessive Inheritance
 Most Common X-linked Recessive Disorders
 Less Common X-linked Recessive Disorders
 X-linked Dominant Inheritance
 X-linked Dominant Disorders
 Y-linked Inheritance
 Y linked Disorders
 Sex chromosome Anomaly
 Summary
 Acknowledgement
 References
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Objectives
 After completing this session, students should be able to:
Describe briefly about Sex-linked Diseases.
Explain about Types Sex-linked Inheritance.
Differentiate Sex-linked Diseases and Sex Chromosome Abnormalities.
Familiarize with the Major Sex-linked Diseases.
Appreciate Patterns of Sex-linked Diseases Inheritance.
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Introduction
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 Sex-linked as related to genetics, refers traits that are influenced by genes
carried on the sex chromosomes.
 Sex-linked disorder: a genetic disorder caused by or linked to gene(s) located in
the sex chromosome.
 In humans, the sex chromosomes are the X chromosome and Y chromosome.
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https://www.ncbi.nlm.nih.gov/books/NBK557383/

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Cont.
 The X chromosome is more commonly linked to genetic mutations and
disorders.
 Usually, the X-linked traits and disorders are expressed more in males than in
females.
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https://www.ncbi.nlm.nih.gov/books/NBK557383/

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Cont.
 Different Ways of Genetic Condition Inheritance:
 Autosomal dominant
 Autosomal recessive
 Codominant inheritance
 Mitochondrial inheritance
 X-linked inheritance
 Y-linked inheritance
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https://medlineplus.gov/genetics/

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Autosomal Dominant
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Figure 1: Autosomal dominant Figure 2: Autosomal dominant – New Mutation

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Autosomal Recessive
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Figure 3: Autosomal recessive

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Codominant Inheritance
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Figure 4: Codominant inheritance Figure 5: barbary ape (macaque)

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Mitochondrial Inheritance
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Figure 6: Mitochondrial inheritance

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Types of Sex Linked Inheritance
1) X-linked Inheritance
2) Y-linked Inheritance
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Figure 7: Illustration of some X-linked heredity outcomes

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X-linked Inheritance
 The X chromosome contains 867 identified genes; most of these genes are
responsible for the development of tissues like bone, neural, blood, hepatic,
renal, retina, ears, ear, cardiac, skin & teeth.
 There are at least 533 disorders due to the involvement of the genes on the
X chromosome.
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Dobyns WB et’al (2004) https://www.ncbi.nlm.nih.gov/books/NBK557383/

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Cont.
 A 'trait' or 'disorder' determined by a gene on the X chromosome
demonstrates X-linked inheritance.
 X linked inheritance are either
 X linked recessive
 X linked dominant
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Dobyns WB et’al (2004)

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X-linked Recessive Inheritance
 It is a mode of inheritance in which a mutation in a gene on the X chromosome
causes the phenotype to be always expressed in males and in females who are
homozygous for the gene mutation.
 Females with one copy of the mutated gene are carriers and do not usually
express the phenotype.
 Differences in X-chromosome inactivation can lead to varying degrees of clinical
expression in carrier females.
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Patterns of X-linked Recessive Inheritance
1) The affected fathers cannot pass X-linked
recessive traits to their sons.
2) X-linked recessive traits are more commonly
expressed in males than females.
3) X-linked recessive traits tend to skip generations.
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Figure 8: Queen Victoria

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Cont.
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Figure 9: X-linked recessive inheritance
https://www.uzbrussel.be/web/genetics/sex-linked-disorders

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Most Common X-linked Recessive Disorders
• Red Green color blindness:
• a very common trait in humans and frequently used to explain X-linked disorders.
• 7 – 10% of men and 0.49 - 1% of women are affected.
• Hemophilia A:
• a blood clotting disorder caused by a mutation of the Factor VIII gene and leading
to a deficiency of Factor VIII.
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Cont.
• Hemophilia B:
• a blood clotting disorder caused by a mutation of the Factor
IX gene and leading to a deficiency of Factor IX.
• Duchenne Muscular Dystrophy:
• It is associated with mutations in the dystrophin gene.
• It is characterized by rapid progression of muscle
degeneration.
• Eventually leading to loss of skeletal muscle control,
respiratory failure & death.
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Figure 10: Histopathology of
Duchenne Muscular Dystrophy
https://www.nature.com/scitable/topicpage/sex
-linked-diseases-the-case-of-duchenne-800/

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Cont.
• Becker's muscular dystrophy:
• a milder form of Duchenne.
• which causes slowly progressive muscle weakness of the legs and pelvis.
• X-linked ichthyosis:
• caused by a hereditary deficiency of the steroid sulfatase (STS) enzyme.
• It is fairly rare, affecting 1 in 2,000 to 1 in 6,000 males.
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Cont.
• X-linked agammaglobulinemia (XLA):
• It affects the body's ability to fight infection & XLA patients do not generate mature B cells.
• Patients with untreated XLA are prone to develop serious and even fatal infections.
• Glucose-6-phosphate dehydrogenase deficiency:
• It causes nonimmune hemolytic anemia in response to a number of causes, most commonly
infection or exposure to certain medications, chemicals, or foods.
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Less Common X-linked Recessive Disorders
 Adrenoleukodystrophy; leads to progressive brain damage, failure of the adrenal
glands and eventually death.
 Alport syndrome; glomerulonephritis, end stage kidney disease, and hearing loss.
 Androgen insensitivity syndrome; variable degrees of under virilization and/or
infertility in XY persons of either sex.
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Cont.
 Barth syndrome; metabolism distortion, delayed motor skills, stamina deficiency, hypotonia, chronic
fatigue, delayed growth, cardiomyopathy, and compromised immune system.
 Blue Cone Monochromacy; low vision acuity, color blindness, photophobia, infantile nystagmus.
 Centronuclear myopathy (CNM); where cell nuclei are abnormally located in skeletal muscle cells.
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Cont.
 Charcot–Marie–Tooth disease (CMTX2-3); disorder of nerves (neuropathy) that is characterized
by loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the
hands and arms in the advanced stages of disease.
 Coffin–Lowry syndrome; severe mental retardation sometimes associated with abnormalities of
growth, cardiac abnormalities, kyphoscoliosis as well as auditory and visual abnormalities.
 Fabry disease; A lysosomal storage disease causing anhidrosis, fatigue, angiokeratomas, burning
extremity pain and ocular involvement.
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Cont.
 Hunter syndrome; potentially causing hearing loss, thickening of the heart valves leading to a
decline in cardiac function, obstructive airway disease, sleep apnea, and enlargement of the liver
and spleen.
 Hypohidrotic ectodermal dysplasia, presenting with hypohidrosis, hypotrichosis, hypodontia.
 Kabuki syndrome (the KDM6A variant); multiple congenital anomalies and mental retardation.
 Spinal and bulbar muscular atrophy; muscle cramps and progressive weakness.
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Cont.
 Lesch–Nyhan syndrome; neurologic dysfunction, cognitive and behavioral disturbances including
self-mutilation, and uric acid overproduction (hyperuricemia)
 Lowe syndrome; hydrophthalmia, cataracts, intellectual disabilities, aminoaciduria, reduced renal
ammonia production and vitamin D-resistant rickets
 Menkes disease; sparse and coarse hair, growth failure, and deterioration of the nervous
system.
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Cont.
 Nasodigitoacoustic syndrome; misshaped nose, brachydactyly of the distal phalanges,
sensorineural deafness.
 Nonsyndromic deafness; hearing loss.
 Norrie disease; cataracts, leukocoria along with other developmental issues in the eye.
 Occipital horn syndrome; deformations in the skeleton.
 Ocular albinism; lack of pigmentation in the eye.
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Cont.
 Ornithine transcarbamylase deficiency; developmental delay and mental retardation. Progressive
liver damage, skin lesions, and brittle hair may also be seen
 Oto-palato-digital syndrome; facial deformities, cleft palate, hearing loss
 Siderius X-linked mental retardation syndrome; cleft lip and palate with mental retardation and
facial dysmorphism, caused by mutations in the histone demethylase PHF8
 Simpson–Golabi–Behmel syndrome; coarse faces with protruding jaw and tongue, widened nasal
bridge, and upturned nasal tip
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Cont.
 Spinal muscular atrophy caused by UBE1 gene mutation; weakness due to loss of the motor neurons
of the spinal cord and brainstem
 Wiskott–Aldrich syndrome; eczema, thrombocytopenia, immune deficiency, and bloody diarrhea
 X-linked severe combined immunodeficiency (SCID); infections, usually causing death in the first
years of life
 X-linked sideroblastic anemia; skin paleness, fatigue, dizziness and enlarged spleen and liver.
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X-linked Dominant Inheritance
 X-linked Dominance: is a mode of genetic inheritance by which a Dominant
Gene is carried on the X chromosome.
 As an Inheritance Pattern, it is less common than the X-linked Recessive Type.
 X-linked dominant traits do not necessarily affect males more than females.
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Patterns of X-linked Dominant Inheritance
 When the mother alone is the carrier of a mutated gene associated
with a disease, her children will inherit the disorder as follows:
 of her Daughters and Sons: 50% will have the disorder, 50%
will be completely unaffected.
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Cont.
 When the father alone is the carrier of a defective gene associated
with a disorder, his children will inherit the disorder as follows:
 Of his Daughters: 100% will have the disorder
 Of his Sons: 0% (none) will have the disorder
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Cont.
 If both parents were carriers of a defective gene associated with a disease, their
children would inherit the disorder as follows:
 Of their Daughters: 100% will have the disorder.
☠ The chance of a Daughter receiving 2 copies of the X chromosome with the
defective gene is 50%.
 Of the Sons: 50% will have the disorder, 50% will be completely unaffected.
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Cont.
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Figure 11: X-linked dominant inheritance
https://www.uzbrussel.be/web/genetics/sex-linked-disorders

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X-linked Dominant Disorders
 Aicardi Syndrome is a rare genetic malformation syndrome characterized by
the partial or complete absence of a key structure in the brain called the corpus
callosum, the presence of retinal abnormalities, and seizures in the form of
infantile spasms.
 X-linked Dominant Porphyria is a group of diseases in which substances
called porphyrins build up, negatively affecting the skin or nervous system.
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Cont.
 X-linked Hypophosphatemia (XLH): affect the bones and teeth, causing
pain, abnormalities, and osteoarthritis.
 Rett syndrome (RTT): affected often have slower growth, difficulty walking,
and a smaller head size.
 Alport syndrome: characterized by kidney disease, hearing loss, and eye
problems.
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Cont.
 Incontinentia pigmenti (IP): affects the skin, hair, teeth, nails and central
nervous system.
 Giuffrè–Tsukahara syndrome: characterized by the association of radioulnar
synostosis with microcephaly, scoliosis, short stature and intellectual deficit.
 Goltz syndrome: associated with shortness of stature and some evidence
suggests that it can cause epilepsy.
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Y linked Inheritance
 It describes traits that are produced by
genes located on the Y chromosome.
 It can be difficult to detect.
 The Y-chromosome, generally does not
undergo genetic recombination.
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Sayres, Wilson (2012)
https://opengenetics.pressbooks.tru.ca/chapter/y-linked-gene/
Figure 12: Structure of the Y-Chromosome in Humans

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Patterns for Y-linked Inheritance
 Curt Stern established these requirements of Y linkage:
1. Trait expression and transmission is only in males.
2. If a male has a trait, so should:
 his father and paternal grandfather
 his sons and their sons.
3. It is absent from daughters of trait carriers.
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Curt, Stern (1957) Lee, Andrew (2004).

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Cont.
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https://migrc.org/
Figure 13: Pedigree tree showing the inheritance of a Y-linked trait

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Cont.
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https://www.invitra.com/en/wp-content/uploads/2014/06/y-linked-inheritance-pattern.png
Figure 14: Y linked Inheritance

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Cont.
 Y linkage is similar to, but different from X linkage;
although, both are forms of sex linkage.
 In general, traits that exist on the Y chromosome are Y-linked.
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Genes known to be contained on the human Y chromosome
 ASMTY (acetylserotonin methyltransferase),
 TSPY (testis-specific protein),
 IL3RAY (interleukin-3 receptor),
 SRY (sex-determining region),
 ZFY (zinc finger protein),
 PRKY (protein kinase, Y-linked),
 AZF2 (azoospermia factor 2),
 ANT3Y (adenine nucleotide translocator-3 on the Y),
 RBM1 (RNA binding motif protein, Y chromosome, family 1, member A1),
 AMGL (amelogenin),
 BPY2 (basic protein on the Y chromosome),
 AZF1 (azoospermia factor 1),
 DAZ (Spermatogenes is deleted in azoospermia),
 RBM2 (RNA binding motif protein 2), and
 UTY (ubiquitously transcribed TPR gene on Y chromosome).
 USP9Y
 AMELY
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Y linked Disorders
 Webbed Toes/Fingers: mainly due to a local arrest of
development, leading to retention of the normal embryonic
webbing.
 formed normally in some marsupials, rodents, and
insectivores.
 occur in varying degrees in some Primates, such as
Hylobates.
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Figure 16: The hand of a person
with Greig cephalopolysyndactyly
with syndactyly of several digits

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Cont.
 Hypertrichosis is an atypical form of hair growth in
excess over the body .
 Localized Vs Generalized
 Congenital Vs Acquired
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Figure 15: Generalized Hypertrichosis
Lee, Andrew (2004)

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Cont.
 Porcupine Man: a group of rare skin disorders
characterized by massive hyperkeratosis with an
appearance like spiny scales.
 This term is also used to refer to a form of
epidermal nevi having extensive bilateral
distribution.
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Figure 18: Person with Porcupine Man

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Sex Chromosome Anomaly
 It is a group of disorders that affects the number or the structure of the
X and Y chromosomes.
 Aneuploidies
 45,X (Turner syndrome);
 47,XXY (Klinefelter syndrome);
 47,XYY;
 47,XXX.
 Sex chromosome mosaicism involving a
normal cell line.
 45,X/46,XX
 45,X/46,XY.
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Cont.
 Structural abnormalities of the X and Y chromosomes
 Deletions,
 Duplications,
 Translocations,
 Isochromosomes,
 Ring chromosomes.
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Summary
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 Sex-linked disorder: a genetic disorder caused by or linked to gene(s) located in the sex chromosome.
 Types of Sex linked Inheritance: X and Y linked
 X linked recessive Inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome
causes the phenotype to be always expressed in males and in females who are homozygous for the gene
mutation.
 X-linked Dominance: is a mode of genetic inheritance by which a Dominant Gene is carried on the X
chromosome.
 Y linked Inheritance describes traits that are produced by genes located on the Y chromosome.
 Sex chromosome Anomaly is a group of disorders that affects the number or the structure of the X and Y
chromosomes.

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Acknowledgement
 Firstly, I would like thanks Our Lord and Savior Jesus Christ Son of the
True Living God, Son of Theotokos.
 Next my deepest gratitude goes to my instructor Dr. Dresbachew who
gave me this chance to prepare and present on “X-chromosome & sex-
linked diseases.”
 Finally, I would like to thank my family and friends for the support of all
my works.
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References
• "History of Bleeding Disorders". National Hemophilia Foundation. 2014-03-04. Retrieved 2020-06-09.
• "Rett Syndrome Fact Sheet". National Institute of Neurological Disorders and Stroke. Archived from the original on 14
October 2017. Retrieved 14 October 2017.
• "Y-linked gene definition - Medical Dictionary: Definitions of Popular Terms Defined on MedTerms"
(http://www.medterms.com/script/main/art.asp?articlekey=15745). Medterms.com. 2012-09-20. Retrieved 2014-06-29.
• Carlo Gelmetti; Caputo, Ruggero (2002). Pediatric Dermatology and Dermatopathology: A Concise Atlas. T&F STM.
p. 160. ISBN 1-84184-120-X.
• Curt, Stern (1957). "The Problem of Complete Y-Linkage in Man"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1931892). American Journal of Human Genetics. 9 (3): 147–166.PMC
1931892 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1931892). PMID 13469791
(https://pubmed.ncbi.nlm.nih.gov/13469791).
• Dalal AB, Sarkar A, Priya TP, Nandineni MR (August 2010). "Giuffrè-Tsukahara syndrome: Evidence for X-linked
dominant inheritance and review". American Journal of Medical Genetics. Part A. 152A (8): 2057–60.
doi:10.1002/ajmg.a.33505. PMID 20635354
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Cont.
 Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Oosterwijk JC, Ober C (August 2004).
"Inheritance of most X-linked traits is not dominant or recessive, just X-linked". American Journal of Medical
Genetics. Part A. 129A (2): 136–43. doi:10.1002/ajmg.a.30123. PMID 15316978
• Genetics home reference (2006), genetic conditions illustrations, National Library of Medicine.
• GP Notebook - X-linked recessive disorders Archived 2011-06-13 at the Wayback Machine Retrieved on 5 Mars,
2009
• Hemophilia B". Archived 2007-12-01 at the Wayback Machine National Hemophilia Foundation.
• https://medlineplus.gov/genetics/
• https://www.ncbi.nlm.nih.gov/books/NBK557383/
 https://www.uzbrussel.be/web/genetics/sex-linked-disorders
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