X- Linked dominant inheritance Flashcards

1
Q

example of an X-linked dominant disorder that shows greater severity in females and pathogenic mechanism?

A

cranio-frontal syndrome. Females manifest due to cellular interference between the two populations of cells expressing and not expressing ephrin-B1

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2
Q

How many 100 X-linked inherited human disorders or traits have been identified?

A

> 100

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3
Q

Characteristics of X linked dominant inheritance inheritance.

A

dominant trait or condition caused by a mutation in a gene on the X chromosome, expressed in heterozygous females as well as males

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4
Q

X-linked dominant reproductive risk

A

carrier mother 50% of affected child. Carrier father affected daughters and unaffected sons.

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5
Q

Characteristics of male vs female phenotype in an X-linked dominant disorder

A

Affected males tend to have a more severe phenotype than affected females who may show variability

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6
Q

Characteristics of pedigrees displaying X-linked dominant inheritance

A

if descendants of affected males are considered, all sons are healthy while all daughters are affected. An excess of affected female heterozygotes may also be indicative

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7
Q

Characteristics of X-linked dominant inheritance with male lethality in pedigrees

A

observed almost exclusively in females because lethal in males.
Only females (and boys with Klinefelter Syndrome) can live and are affected
history of miscarriages in the family since 50% of males carrying the mutant allele will die before birth itself
• As a result the sex ratio of their live offspring is often skewed

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8
Q

X-linked dominant disorder examples (3)

A
  1. X-linked hypophosphatemia / Vitamin D resistant rickets
  2. X-linked Alport syndrome
  3. Fragile X (although the inheritance of Fragile X is debatable is widely considered X-linked dominant).
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9
Q

X-linked hypophosphatemia / Vitamin D resistant rickets-

gene and background

A

• The kidneys cannot reabsorb phosphate effectively, too much excreted in urine, not enough phosphate available in the blood for normal bone development and maintenance. Highly variable phenotype:
o rickets with bone deformities
o short stature and dental anomalies
o low serum phosphate levels and
o resistance to treatment with ultraviolet radiation or vitamin D ingestion
• Caused by mutations in PHEX gene

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10
Q

X-linked Alport syndrome; gene and background

A
characterized by;
o	kidney disease, blood (hematuria) and high protein in the urine
o	sensorineural hearing loss 
o	eye abnormalities
o	Most develop end stage renal disease
COL4A5 type IV collagen
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11
Q

X- linked dominant with male lethality example

A

Rett syndrome

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12
Q

Rett syndrome; gene and background

A

MECP2 (80%), 8 common missense and nonsense mutations caused by C>T transitions at 8 CpG dinucleotides in exons 3 and 4 (60% mutations)
Also FOXG1 and CDKL5 (All X-linked)
Progressive neurodevelopmental disorder, almost exclusively females. normal development 6-18 months-short period of developmental stagnation-rapid regression in language and motor skills-long-term stability

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13
Q

Males with Rett syndrome born are with

A

severe neonatal encephalopathy =death < two years

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14
Q

Adult males with Rett syndrome exist due to;

A

o 47,XXY karyotype
o post-zygotic MECP2 mutations resulting in somatic mosaicism
o Normal karyotype but mild MECP2 missense change (e.g. p.Ala140Val)-ID in males but very mild in females

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15
Q

~% males with ID and MECP2 muts?

A

1.5%

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16
Q

What can influence severity of symptoms in X- linked dominant disorders where females are usually affected. ?

A

Skewed X inactivation. • E.g. Asymptomatic carriers of Rett syndrome and patients with very mild symptoms have been described, who can show skewed X inactivation that favours the inactivation of the mutated allele

17
Q

Example of an X-linked dominant disorder with males unaffected and mechanism?

A

craniofrontalnasal syndrome.
Cellular interference: casued by mutaitons in ENFB1 encoding ephrin-B1 involved in bi directional cell signalling. X inactivation produces two populations of cells in respect to ephrin-B1 signalling-causes cellular interference between ENFB1 expressing and non-expressing cells. Somatic mosaicism in males could have the same effect.

18
Q

What genes on the X chromosome escape X- inactivation?

A

Genes in PAR 1 and 2