X-Linked Disorders Flashcards
what does variant mean?
mutation in old terminology
allele that has a permanent alteration in its DNA sequence
characteristics of an X-linked disorder
- multiple affected mal family members in maternal side
- family history of neonatal infantile or childhood deaths in males in the maternal side
- family history of mildly affected females (sisters, mothers, maternal aunts)
- no known risk factors
x-linked recessive pattern
- phenotypic expression much higher in males than females
- heterozygous fmales usually no phenotypes; rare = depending on X-activation in tissues, females may have phenotypes
- daughtrs of afected father always have allele; but father never transmits to son
- affected males within same family always related through females
- significant proportion due to nw or de novo variants in a gene on the X chromosome
x-linked dominant pattern
- affected males = normal sons and affected daughters
- male and female offspring of an affected female = 50% risk of having genetic disease
- more common phenotypic expression in females than males, but females have milder phenotypic expression of the genetic disease
random x chromosome inactivation in females
- every tissue have 2 kinds of cells = either w maternal X active or with paternal X active
- less susceptible to pathogenic variants in genes on her active X chromosome
x-chromosome inactivation
mammalian somatic cells can determine how many X-chr are present in order to transcriptionally silence all but one X chromosome
- compensates for dosage of X-linked genes in females vs males
- once established, mitotically tansmitted, ach cell contains both one active and on inactive chromosome in females
- both males and females hav one active X chromosome
- random X chromosome inactivation in females
techniques to evaluate X chromosome inactivation
- differential DNA methylation of X alleles
- expressed polymorphisms
- analysis of DNA replication timing
what is differential DNA methylation of X alleles?
- more widespread bc DNA more easily accessible and stable
- promoter regions of X-linked generally hypermethylated to maintain their inactive states
- HUMARA most accepted
>
expressed polymorphisms
RNA-level polymorphisms of X-linked informative genes
MECP2 gene
- located on Xq28
- methyl-CpG binding protein 2 gene
- binds methylated CpGs
- chromatin-associated protein
- can activate and repress transcription
- required for maturation of neurons
- highly expressed in human brain
MECP2 disorders in females
- progressive neurodevelopmental disorder
- normal psychomotor in first 6-18mos of life
- developmental stagnation
- rapid regression in language and motor skills, followed by long-term stability
- epetitive, stereoptupic hand movements replace purposeful hand use
- fits of screaming and inconsolable crying
- autistic features
- panic-like attacks
- bruxism
- episodic apnea/hyperpnea
- gait ataxia and apraxia, tremors
- seizures
- acquired microcephaly
MECP2 disorders in males
- more severe phenotypic neurdevelopmental features
- severe meonatal-onset encephalopathy
- abnormal tone
0 involuntary moements - severe seizures
0 breathing abnormalities
0 death occurs oftn before age 2
DMD gene
- located on Xp21.2-p.21.1
- encodes dystrophin protein, a large muscle protein
- hemizygous or heterozygous pathogenic variants in DMD results in dystrophinopathies
ABCD1 gene
- located on Xq28
- encodes ATp-binding cassette subfamily D member 1
> member of ABC protein transporter family - transporter of FAs into peroxisome
- failure to transport FAs = prevents beta-oxidation and allows continued elongation of fatty acids, resulting in accumulation of very long chain FAs
- result = lipids accumulate abnormally in all tissues but predominantly affect the nervous system, adrenal cortex, and Leydig cells of testes
- hemizygous or heterozygous pathogenic variants in ABCD1 results in X-linked adrenoleukodystrophy
diagnosis of adrenoleukodystrophy
- suggestive clinical findings
- elevated very long chain fatty acids (VLCFA)
- brain MRI abnormal in boys with cerebral disease and often provides the first diagnostic lead
0 diagnosis of X-ALD usually established in female proband with detection of heterozygous ABCD1 pathogenic variant and elevated VLCFA
F8 gene
- Xq28
- encodes coag factor VIII
> large plasma glycoprotein
> involved in the blood coagulation cascade as a cofactor for the factor Ixa-dependent activation factor X
> activated proteolytically by a variety of coagulation enzymes (thrombin)
> tightly associated in blood w vWF = protective carrier protein - hemizygous or heterozygous pathogenic variants in F8 = hem A
FMR1 gene
- Xq27.3
- encodes fragile X messenger ribonucleoprotein 1
- selective RNA binding protein
- forms a messenger ribonucleoprotein complex that associates with polyribosomes, suggesting involved in translation
- plays central role in neuronal development and synaptic plasticity through:
> regulation of alternative mRNA splicing
> mRNA stability
> mRNA dendritic transport
> postsynaptic local protein synthesis of target mRNAs
most common heritable form of intellectual disability
fragile X syndrome
> frequency 1 in 3000/4000 male births
fragile X syndrome in males
- neurodevelopmental disorders
- cranofacial features = more obvious w age
- hypotonia
- gastroesophageal reflux
- strabismus
- seizures
- sleep disorders
- joint laxity
- Pes planus
- scoliosis
- recurrent otitis media
- mitral valve prolapse or aortic root dilatation
pedigree is essential in genetic clinics for at least # generation
3
essential first step in determining inheritance patterns
making a pedigree
pictorial representation of a family medical history
pedigree
an allele in its most common form ina population
wild type
these individuals can ameliorate the effects of pathogenic variants
females
- not homozygous for pathogenic variant; x chr inactivation
some x-linked diseases occur only in females or mosaic males
incontinentia pigmenti
orofacial digital syndrome type 1
techniques to evaluate X chromosome inactivation
differential DNA methylation of X alleles
- more widespread; DNA more accessible and stable
- promoter regions of X-linked genes on inactivated X = hypermethylated = maintain inactive state
expressed polymorphisms
analysis of DNA replication timing
DNA methylation of X alleles
- HUMARA most accepted (human androgen receptor assay)
- methyl-CpG-sensitive resitriction-endonucleas-based PCR assay
- targets polymorphic short tandem repeat of X-linked androgen receptor (AR) gene
- methylation of AR alleles on inactive X chromosome = whole X chromosome inactivation
- patenral and maternal X = 50% pbty of being methylated and inactivated
T or F. For DNA methylation of X alleles, a 1:1 ratio for X chromosome inactivation is expected if a random event
T
any deviation from this theoretical ration = skewed X inactivation
methylation-speicific PCR
- independent of methylation-sensitive enzymes
- 2-step approach
Describe the 2-step approach of methylation-specific PCR
- PCR w primers specific for methylated vs. unmethylated DNA
- chemical modification of DNA with sodium bisulfite
- sod bisulf converts methylation difference into a DNA sequence difference; unmethylated cytosines are converted into uracil
expressed polymorphisms
RNA-level polymorphisms of X-linked informative genes
how are x-linked genetic diseases classified?
phenotypes in M vs F
X-inactivation status
location on X chr
affected organ
MECP2 gene
- Xq28
- methyl-CpG binding protein 2 gene
- binds methylated CpGs
- chromatin-associated protein
- can activate and repress transcription
- required for maturation of neurons
- highly expressed in human brain
MECP2 disorders in females
progressive neurodevelopmental disorder
- normal psychomotor (6-18 mos)
- rapid regression in language, motor skills then long-term stability
- repetitive hand movement to replace purposeful hand use
- screaming and crying fits
- autistic features
- panic-like attacks
- bruxism
- episodic apnea/ hyperpnea
- acquired microcephaly, seizures, etc.
MECP2 in males
severe neonatal onset encephalopathy
- abnormal tone
- inv movements
- severe seizures
- breathing abnormalities
- death before age 2
how to diagnose MECP2 disorder
sequencing and deletion/dup analysis of MECP2 gene
more than 99% = simplex = single occurrence in family
- de novo pathogenic variant
- small possibility of inheritance of pathogenic variant from a parent who has germline mosaicism
DMD gene
Xp21.2-p.21.1
dystrophin protein = large muscle protein
how do dystrophinopathies arise?
hemizygous or heterozygous pathogenic variants in DMD -> dystrophinopathies
Duchene muscular dystrophy
- delayed motor milestones; delays in walking independently, standing up from a supine position in early childhood
- waddling gait and difficulty climbing stairs, running, jumping, etc.
- wheelchair dependent by ag 12
- few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death
Becker muscular dystrp[hy
milder than DMD
- later onset skeletal muscle weakness
- men onset of symptoms after 30 y/o; remain ambulatory till 60
- heart failure from dilated cardiomyopathy is a common cause of morbidity
- mean age of death = mid-40s
most common cause of death of Becker muscular dystrophy (BMD)
heart failure from dilated cardiomyopathy
females with DMD
can have classic DMD
prevalence of cardiomyopathy can vary from 3 to 33%
no correlation of phenotype (DMD vs BMD), age, CK level, or muscle symptoms was noted
diagnosis of DMD/BMD
charactristic clinical findings = progressive muscle deficiency, early onset, delayed muscle development
elevated CK concentration
identification of a hemizygous pathogenic variant in DMD
male X-linked adrenoleukodystrophy
- childhood cerebral form = 4 to 8 y/o
> ADHD? hyperactivity?
> progressive impairment of cognition, behaviour, motor function follow initial symptoms
> most have impaired adrenocortical function - adrenomyeloneuropathy (AMN) manifests in an individual in his twenties to mid-age = progressive stiffness and leg weakness, sphincter disturbances, sexual dysfunction, etc.
- “Addison disease only” = primary adrenocortical insufficiency btween 2y/o and adulthood; most common by age 7.5; no evidence of neurologic abnormality BUT AMN usually develops by mid age
X-linked adrenoleukodystrophy in females
more than 20% of carriers develop mild-to-moderate spastic paraparesis in middle age or later
adrenal function normal usually
mistaken for MS
T or F. affected males transmit the ABCD1 pathogenic variant to all of their duaghters and none of their sons
T!
ABCD1 inheritance
M with pathogenic variant = affected
F with variant = carriers and usually not seriously affected
carrier females = 50% chance of transmitting
The phenotypic expression and prognosis of an affected male in this disorder is unpredictably variable
adrenoleukodystrophy
males FVIII def
- prolonged bleeding
- delayed or recurrent bleeding prior to complete wound healing
- severe hem A, moderate hem A and mild hem A
severe hemophilia A
first two years of life; spontaneous joint bleeds, deep-muscle hematomas, prolonged bleeding or excessive pain + swelling from minor injuries
moderate hemophilia A
diagnosed before age 5-6 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
hemophilia A in females
- ~30% of heterozyghous females have FVIII clotting activity below 40%; at risk for bleeding
- major trauma/invasive procedures = prolonged or excessive bleeding
- 25% heterozygous females with nomal FVIII clotting activity report increased bleeding tendency
