X- Linked dominant inheritance Flashcards
example of an X-linked dominant disorder that shows greater severity in females and pathogenic mechanism?
cranio-frontal syndrome. Females manifest due to cellular interference between the two populations of cells expressing and not expressing ephrin-B1
How many 100 X-linked inherited human disorders or traits have been identified?
> 100
Characteristics of X linked dominant inheritance inheritance.
dominant trait or condition caused by a mutation in a gene on the X chromosome, expressed in heterozygous females as well as males
X-linked dominant reproductive risk
carrier mother 50% of affected child. Carrier father affected daughters and unaffected sons.
Characteristics of male vs female phenotype in an X-linked dominant disorder
Affected males tend to have a more severe phenotype than affected females who may show variability
Characteristics of pedigrees displaying X-linked dominant inheritance
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
Characteristics of X-linked dominant inheritance with male lethality in pedigrees
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
X-linked dominant disorder examples (3)
- X-linked hypophosphatemia / Vitamin D resistant rickets
- X-linked Alport syndrome
- Fragile X (although the inheritance of Fragile X is debatable is widely considered X-linked dominant).
X-linked hypophosphatemia / Vitamin D resistant rickets-
gene and background
• 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
X-linked Alport syndrome; gene and background
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
X- linked dominant with male lethality example
Rett syndrome
Rett syndrome; gene and background
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
Males with Rett syndrome born are with
severe neonatal encephalopathy =death < two years
Adult males with Rett syndrome exist due to;
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
~% males with ID and MECP2 muts?
1.5%