Page 34 - PCC08

Some spontaneous DNMs occur 1000x more frequently than background
Human genomic mutation rate
Craniosynostosis & limb malformations
• Autosomal dominant
• >98% cases occur as de novo mutation
• Birth prevalence: 1 in 65,000
• Spontaneous mutation rate: ~1:100,000 ~500-1000x higher than background
Mutational hotspots?
• Paternal age-effect (~2.5 - 8.2 yrs)** • Exclusive paternal origin (115/115)
Features shared by other disorders: ‘Paternal age effect’ (PAE) disorders
(~1.2 x 10-8)
i.e. Transversions @ non-CpG
i.e. Transitions @CpG
Apert achondroplasia FGFR2 FGFR3
c.755C>G c.1138G>A xx
~10-40x
10-10 10-9
10-8 10-7
10-6 10-5
Apert syndrome is caused by 2 specific transversions Mutation rate/generation
66% FGFR2 755C>G (Ser252Trp)
33% FGFR2 758C>G (Pro253Arg) Specific GOF mutations in:
Wilkie et al Nat Genet 1995
FGFR2 (Apert, Pfeiffer, Crouzon syndromes)
FGFR3 (achondroplasia, Muenke syndrome, thanatophoric dysplasia) HRAS (Costello syndrome)
PTPN11/SHP2 (Noonan syndrome)
RET (Men2a,2b)
Collectively: Achondropla>s1i/a2,000 births
FGFR3 c.1138G>A p.Gly380Arg
High mutation rate + localised mutation  study de novo mutations directly in sperm
Direct quantification of the FGFR2 c.755C>G Apert mutation in sperm
1000
100
10
r = 0.39
4
3
2
1
4
0
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Apert 755 levels in sperm DNA
O/E 755 Apert fathers (n=52) 3
21 9
5 9
35-40 40-45
1
45-50 >50 Age (years)
<25 25-30 30-35
1
20 40 60
80 Age
0.1
Sperm (n=99)
Blood (n=11)
Paternal age-effect and high birth rate are explained by the levels of Apert mutation in sperm of normal men
Goriely et al Science (2003)
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755C>G mutation level (per million)
Number of Genomic locations (log10)
Relative rate of mutation