Lecture 15 - X-linked Disorders Flashcards
1
Q
What is a pedigree
A
a pictorial representation of a family medical history to visualize whether a disease is tracking through a family and to identify inheritance patterns
2
Q
What are requirements for a pedigree
A
- All family members, including both maternal and
paternal lineages - A minimum of three generations
- Illnesses of each family member
- Current age, age at diagnosis of an illness, and age at
death - Miscarriages or stillbirths
- Adoptions
- Ethnicity
- Birth defects
- Neurodevelopmental disorders
- Known genetic condition
3
Q
What is a genotype
A
an individuals actual DNA sequence at a specific locus
4
Q
What is a phenotype
A
observable ways in which that DNA sequence manifests in the individual
5
Q
What is an allele
A
an alternate form of a gene
6
Q
What is wild-type
A
an allele in its most common form in a population
7
Q
What does variant mean
A
an allele that has a permanent alteration in its DNA sequence
8
Q
What is homozygous
A
two identical alleles
9
Q
What is heterozygous
A
two different alleles
10
Q
What is hemizygous
A
a single allele in a male on their X-chromosome
11
Q
What are indicators of an x-linked genetic disorder
A
- Family history of multiple affected male family members in the maternal side
- Family history of neonatal, infantile or childhood deaths in males in the
maternal side - Family history of mildly affected females (e.g. sisters, mothers, maternal aunts
- No known risk factors
12
Q
What are characteristics of x-linked recessive inheritance
A
- Phenotypic expression much higher in males
than females - Heterozygous females usually do not have
phenotypes, however - X-linked disorders inherited from fathers to all of their daughters
- X-linked disorders never transmitted from father to their sons
- Affected males within the same family always
related through females - Significant proportion is due to new or de novo
variants in a gene on the X-chromosome
13
Q
What are characteristics of x-linked dominant inheritance
A
- affected males have normal sons and effected daughters
- male and female offspring of an affected females have 50% risk of having the genetic disease
- more common phenotypic expression in females than males but females have milder phenotypic expression
14
Q
What is X-inactive specific transcript
A
- Non-coding untranslated RNA
- Major effector of the X-inactivation process
- Component of the X-chromosome
inactivation centre located on the inactive X-chromosome - Causes chromatin condensation and
inactivation, called Barr body - Epigenetics change, involving a change to
gene but does not involve a base change
15
Q
How can females ameliorate the effects of pathogenic variants
A
if they aren’t homozygous for the pathogenic variant, the X with the variant will always be silent as a protection mechanism
16
Q
If a disorder has a lethal variant
A
- most males die in utero
- females or mosaic males survive
- some x-linked diseases occur only in females or mosaic males
17
Q
How to evaluate x chromosome inactivation
A
differential DNA methylation of x alleles, expressed polymorphisms, analysis of DNA replication timing
18
Q
What is the most accepted method of testing DNA methylation of X alleles
A
Human androgen receptor (HUMARA)
19
Q
How does HUMARA work
A
- Methyl-CpG-sensitive restriction-endonuclease-based
PCR assay - Targets the polymorphic short tandem repeat of the Xqlinked androgen receptor (AR) gene
- Methylation status of the AR alleles on inactive X
chromosome correlates with the whole X chromosome
inactivation - Paternal X and maternal X have 50% probability of being
methylated and inactivated - A 1:1 ratio for X chromosome inactivation is
expected if a random event - Any deviations from this theoretical ratio skewed X
inactivation
20
Q
What is methylation-specific PCR
A
- Independent of the use of
methylation-sensitive enzymes - Two-step approach:
- PCR with primers specific for
methylated versus
unmethylated DNA - Chemical modification of DNA
with sodium bisulfite - Sodium bisulfite
treatment converts the
methylation difference
into a DNA sequence
difference - Unmethylated
cytosines are
converted into uracil
21
Q
What is MECP2
A
- located on Xq28
- methyl-CpG binding protein 2
- a chromatin associated protein
- activates and represses transcription
- highly expressed in human brain
22
Q
How does MECP2 present in symptomatic females
A
Progressive neurodevelopmental disorder
* Normal development first 6-18 months of life
* Developmental stagnation
* Rapid regression
* Repetitive, stereotypic hand movements replace
purposeful hand use
* Fits of screaming and inconsolable crying
* Autistic features
* Panic-like attacks
* Bruxism
* Episodic apnea and/or hyperpnea
* Gait ataxia and apraxia, tremors
* Seizures
* Acquired microcephaly
23
Q
How does MECP2 present in males
A
- Severe neonatal-onset encephalopathy
- Abnormal tone
- Involuntary movements
- Severe seizures
- Breathing abnormalities
- Death often occurs before age two years
24
Q
What is the diagnosis of MECP2
A
- Sequencing and deletion/duplication
analysis of MECP2 - More than 99% are simplex cases
(i.e., a single occurrence in a family)
25
What is DMD
- located on Xp21.22
- encodes dystrophin protein (large muscle protein)
- hemizygous or heterozygous pathogenic variants result in dystrophinopathies
26
What is duchene muscular dystrophy
* Delayed motor milestones including delays in
walking independently and standing up from a
supine position in early childhood
* Waddling gait and difficulty climbing stairs,
running, jumping, and standing up from a squatting
position
* Wheelchair dependent by age 12 years
* Cardiomyopathy occurs in almost all individuals
with DMD after age 18 years
* Few survive beyond the third decade, with
respiratory complications and progressive
cardiomyopathy being common causes of death
27
What is becker muscular dystrophy
- later-onset skeletal muscle weakness
- mild end includes men with onset symptoms after age 30
- heart failure from dilated cardiomyopathy is a common cause of morbidity
- mean age of death is in the mid-40s
28
Females with DMD
- sometimes females can have classic DMD
- the prevalence of cardiomyopathy can vary from 3%-33%
- no correleation of phenotype, age, CK level or muscle systems
29
Phenotypes of females with DMD
- Penetrance in heterozygous females
varies, and may depend in part on
patterns of X-chromosome
inactivation (XCI)
- Some studies have shown no clear
correlation between the active-toinactive X-chromosome ratio
observed in XCI studies in leukocytes
and serum CK concentration, clinical
signs, or the proportion of dystrophin-negative fibers observed
on muscle biopsy
- In another study of seven
symptomatic heterozygous females,
the XCI pattern was skewed toward
non-random in the four with deletions or duplications but was
random in the three with
pathogenic nonsense variants
- In another study more than 90% of heterozygous females with skewed XCI (defined as ≥75% of nuclei
harboring the DMD pathogenic variant on the active X-chromosome)
- Direct correlation with a skewed XCI
pattern was also observed recently in
cohorts of symptomatic and asymptomatic DMD/BMD carriers
30
What is the ABCD1 gene
-located on Xq28
- encodes ATP-binding cassette subfamily D member 1
- results in X-linked adrenoleukodystrophy
31
How does X-linked adrenoleukodystrophy present in males
* Childhood cerebral form manifests most commonly between ages four and eight years.
* Initially resembles attention-deficit disorder or hyperactivity
* Progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial
symptoms and often lead to total disability within six months to two years
* Most individuals have impaired adrenocortical function
* Adrenomyeloneuropathy (AMN): progressive stiffness and weakness of the legs, sphincter disturbances, sexual
dysfunction, and often, impaired adrenocortical function in early adulthood, progressive over decades.
* Primary adrenocortical insufficiency from 2 years of age
32
How does X-linked adrenoleukodystrophy present in females
* More than 20% of female carriers develop mild-to-moderate spastic paraparesis in middle age or later
* Adrenal function is usually normal
33
How is X-linked adrenoleukodystrophy diagnosed
- suggestive clinical findings
- elevated very long chain fatty acids
- MRI
34
What is hemophilia A
- located on Xq28
- encodes coagulation factor VIII
35
How does hemophilia A present in males
* Prolonged bleeding after injuries, tooth extractions, or surgery
* Delayed or recurrent bleeding prior to complete wound healing.
* Severe hemophilia A: During the first two years of life
* Spontaneous joint bleeds or deep-muscle hematomas
* Prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth
extractions
* Moderate hemophilia A: Diagnosed before age five to six years
* Prolonged or delayed bleeding after relatively minor trauma
* Mild hemophilia A: Diagnosed later in life
* Pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions
36
How does hemophilia A present in females
* Approximately 30%
of heterozygous females have
factor VIII clotting activity
below 40% and are at risk for
bleeding
* After major trauma or
invasive procedures,
prolonged or excessive
bleeding usually occurs
* 25% of heterozygous females
with normal factor VIII
clotting activity report an
increased bleeding tendency
37
What is the FMR1 gene
- located on Xq27.3
- encodes fragile X messenger ribonucleoprotein 1
- a selective RNA binding protien
- plays a central role in neuronal development and synaptic plasticity
38
What is fragile X syndrome
- most common heritable form of intellectual disability
- penetrance in females in the 50-60% range
- a trinucleotide repeat disorder
39
How does fragile X present in males
- affected males may have characteristic craniofacial features
- neurodevelopmental disorders
- seizures
- sleep disorders
- scoliosis
- mitral valve prolapse or aortic root dilation
40
What is the SLC6A8 gene
- located on Xq28
- encodes solute carrier family 6 member 8
- contains 13 exons, spans about 8.5kb of genomic dna
- sodium-chloride-dependent transporter protein
41
How to diagnose a creatine transporter deficiency
- heterozygous novel missense variant
- 50% of normal creatine uptake in fibroblasts
- chromosome analysis
- no skewed x-inactivation in peripheral blood
