X-Linked Disorders Flashcards
The HGP sequenced and identified about __ genes in each human
The HGP sequenced and identified about 20,500 genes in each human
Each chromosome comes in __, inherited from each __
Each chromosome comes in pairs, inherited from each parent
What is the essential first step in determining inheritance patterns ?
Investigate pedigree
Define pedigree
- pictorial representation of a family medical history
- tracks inheritance pattern of disease
A pedigree includes
- entire maternal and paternal lineage
- minimum of 3 generations
- illness, defects, conditions of each family member
- age (current, at diagnosis, at death)
- miscarriages/ stillbirths
- adoptions
- ethnicity
Diffentiate genotype vs phenotype
Genotype:
- actual DNA sequence at a specific locus
Phenotype:
- physical manifestations of genotype (hair color, susceptibility to a disease)
Allele vs wild-type vs variant
Allele:
- different forms of a gene
Wild-type:
- most common allele in a population
Variant:
- permanent alteration in a DNA sequence (mutation)
List specific info in family history that may indicate X-linked genetic disorders
- Multiple affected males in the maternal side
- Especially neonatal/ child deaths
- Mildly affected females (sisters mothers, maternal aunts)
- No known risk factors
X-linked recessive inheritance
- higher expression in males > females
- heterozygous females usually do not have phenotype
- X-linked disorders inherited from father to all daughters
- never transmitted from father to sons
- affected males within same family always related through females
- significant proportion due to new/ de novo variants in a gene on X-chromosome
Characteristics of X-linked dominant inheritance
- more commonly expressed in females > males
- BUT females have milder phenotypic expressions of genetic disease
- affected males will have normal sons and affected daughters
- affected female have 50% risk of having children with genetic disease
What is XIST ?
X-inactive specific transcript:
- non-coding untranslated RNA
- major effector of X-inactivation process
- causes chromatin condensation and inactivation = Barr body
- epigenetics change = changes gene but does not involve a base change
Purpose of X-chromosome inactivation in females
- compensates for dosage of X-linked genes in females (XX) vs males (XY) = both males and females only have one active X-chromosome
- X-chromosome with variant is always silenced
- cells that transcribe normal allele compensates enough gene products for deficient variant cells
- deficient cells divide less efficiently, and are eventually overgrown by normal cells
T or F: Random X-chromosome inactivation is a normal, expected process
TRUE; Random X-chromosome inactivation is a normal, expected process
How does DNA methylation of X alleles evaluate X-chromosome Inactivation ?
- Human androgen receptor assay (HUMARA)
- Targets polymorphic short tandem repeat of the Xq-
linked androgen receptor (AR) gene -
Methylation status of the AR on inactive X
chromosome correlates to the whole X chromosome
inactivation
Since Paternal X and maternal X have 50% probability of being
methylated and inactivated
- 1:1 ratio for X chromosome inactivation is expected
- deviations from this theoretical ratio = skewed X inactivation
Describe Methylation-specific PCR
Two-step approach:
- PCR with primers specific for methylated vs unmethylated DNA
- Chemical modification of DNA with sodium bisulfite
- treatment converts unmethylated cytosines into uracil = amplified as Thymine
How does Expressed Polymorphisms of X alleles evaluate X-chromosome Inactivation ?
- not often used
- not clinically useful for blood
Why are males hemizygous ?
Males have a single X chromosome
Phenotype of MECP2 disorder
Progressive neurodevelopmental disorder:
- First year is normal, followed by rapid regression of development
- Repetitive, stereotypic hand movements
- Fits of screaming and inconsolable crying
- Seizures
- Acquired microcephaly
Describe MECP2 gene and describe pathogenesis of disorder
“Methyl-CpG binding protein 2 gene:”
- located on Xq28
- encodes Chromatin-associated protein that activates/ represses transcription
- neurons cannot mature in MECP2 disorders
How are MECP2 disorders diagnosed ?
- Sequencing and deletion/duplication analysis of MECP2
- 99% are de novo (a single occurrence in a family)
Describe DMD gene and inheritance pattern
- Located on Xp21.2 - Xp.21.1
- encodes for Dystrophin protein (large muscle protein)
- X-linked recessive: Hemizygous; MOSTLY IN MEN or heterozygous pathogenic variants (in females) result in dystrophinopathies
Describe DMD phenotype
Duchene Muscular Dystrophy:
- Delayed motor capabilities; waddling gait and difficulty doing active moments
- Wheelchair dependent by 12 years of age
- Few survive beyond 30
- Respiratory complications and progressive cardiomyopathy being common causes of death
Describe Becker Muscular Dystrophy phenotype
- Later-onset skeletal muscle weakness
- Mean age of death = mid-40s
- Heart failure due to cardiomyopathy is the most common cause of death
Diagnosis of DMD
- characteristic clinical findings
- elevated [CK]
- ID of a hemizygous pathogenic variant in DMD gene
Describe ABCD1 gene and pathogenesis of disorder
- Located on Xq28
- Encodes ATP-binding cassette subfamily D member 1
- X-linked recessive: Hemizygous or heterozygous (females) with variant ABCD1 results in X-linked adrenoleukodystrophy
- Failure to transport fatty acids into peroxisome results in accumulation of long-chain fatty acids
- Affects the nervous system, adrenal cortex, and Leydig cells of the testes
Describe purpose of ATP-binding cassette subfamily D member 1 protein ?
- Member of the ATP-binding cassette (ABC) protein transporter family
- Transports certain fatty acids into peroxisome
X-linked adrenoleukodystrophy in females
- Adrenal function usually normal
- More than 20% of female (heterozygous) carriers develop mild-to-moderate spastic paraparesis in middle age or later
Paraparesis: inability to move legs
X-linked adrenoleukodystrophy in males
- Impaired adrenocortical function
- Manifests between 4 to 8 years of age
- Initially resembles attention-deficit disorder/ hyperactivity and progressively leads to cerebral disability
Diagnosis of X-linked adrenoleukodystrophy
- Suggestive clinical findings
- Elevated very long chain fatty acids (VLCFA)
- Abnormal brain MRI in boys
- ID heterozygous ABCD1 pathogenic variant in girls
Describe F8 gene and inheritance pattern of disorder
- Located on Xq28
- Encodes coagulation factor VIII
- X-linked recessive: Hemizygous or heterozygous (female) pathogenic variants in F8 cause hemophilia A
What is FVIII ?
- Large plasma glycoprotein
- Cofactor in blood coagulation cascade; activates FX
- Binds von Willebrand factor during transport in blood
Describe Hemophilia A phenotype in males
- Delayed or recurrent bleeding after injury
Severe hemophilia A:
- During first 2 years of age
- Spontaneous joint bleeds or deep-muscle hematomas
- Prolonged bleeding & excessive pain from minor injuries
Mild hemophilia A:
- Diagnosed later in life
- Prolonged bleeding occurs from surgery or tooth extractions
Hemophilia A in females
~ 30% of heterozygous females have reduced FVIII clotting activity and are at risk for bleeding
- Prolonged bleeding after major injuries
Describe the FMR1 gene and pathogenesis for disorder
- Located on Xq27.3
- Encodes Fragile X messenger ribonucleoprotein 1;
- a selective RNA binding protein for polyribosomes in translation (regulation and mRNA stability)
- central role in neuronal development
- Expanded CCG repeats (>200) = excessive methylation of cytosines in promoter of FMR1 gene = failure to produce protein
Describe Fragile X syndrome phenotype
- Most common heritable form of intellectual disability
- Neurodevelopment disorders
- Seizures
- Sleep disorders
- Scoliosis
Penetrance in females = 50-60% range
NOTE: increases within generations
Describe SLC6A8 gene and inheritance pattern for disorder
- Located on Xq28
- Encodes Solute carrier family 6 member 8
- 13 exons (8.5 kb of genomic DNA)
- X-linked recessive: Hemizygous or heterozygous (female) pathogenic variants in SLC6A8 = creatine transporter deficiency
Describe SLC6A8 phenotype
- creatine transporter deficiency
- Epilepsy
- Developmental delay
- Hyperactivity
SLC6A8 variant diagnosis
- Heterozygous missense variant (c.1067G>T ) = (p.Gly356Val) in SLC6A8
- 50% of normal creatine uptake in fibroblasts
- Chromosome analysis 46, XX
- No skewed X-inactivation in peripheral blood
What is SLC6A8 protein?
Solute carrier family 6 member 8:
- NaCl dependent
- Transports creatine in/ out of cells
- For high energy requiring organs (brain and muscle retina)
