Paternal Age 4 years older than general population in Paternal Germline Origin of PTPN11 Mutations in Noonan Syndrome

Paternal Germline Origin and Sex-Ratio Distortion in Transmission of
PTPN11 Mutations in Noonan Syndrome
Marco Tartaglia,1,2 Viviana Cordeddu,1 Hong Chang,4 Adam Shaw,5 Kamini Kalidas,5
Andrew Crosby,5 Michael A. Patton,5 Mariella Sorcini,1 Ineke van der Burgt,6 Steve Jeffery,5
and Bruce D. Gelb2,3
1Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanita`, Rome; Departments of 2Pediatrics and 3Human Genetics,
Mount Sinai School of Medicine, New York; 4Health Institute, Division of Clinical Care Research, Tufts–New England Medical Center, Boston;
5Division of Medical Genetics, St. George’s Hospital Medical School, London; and 6Department of Medical Genetics, University Hospital
Maastricht, Maastricht, The Netherlands
Germline mutations in PTPN11—the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2—represent
a major cause of Noonan syndrome (NS), a developmental disorder characterized by short stature and facial
dysmorphism, as well as skeletal, hematologic, and congenital heart defects. Like many autosomal dominant disorders,
a significant percentage of NS cases appear to arise from de novo mutations. Here, we investigated the
parental origin of de novo PTPN11 lesions and explored the effect of paternal age in NS............


For comparison with other studies of
advanced paternal age, we noted that the average paternal
age of the PTPN11-related cohort was 35.6 years,
which was 6.1 years older than the population average
for the children’s average year of birth (1980). For the
PTPN11-negative cohort, the average paternal age was
33.4 years, which was 4.0 years older than the population
average for the children’s average year of birth
(1981)........

The data presented here provide the first evidence for
a paternal origin of de novo PTPN11 mutations in NS
and for their association with advanced paternal age.
This finding confirms previous studies supporting a predominance
of paternal origin of point mutations in the
majority of autosomal dominant diseases. It is clear that
this predominance does not reflect some genetic quirk
isolated to the FGFR genes, nor does it necessitate a
restricted molecular diversity of mutations, as observed
in some disorders (e.g., achondroplasia). The higher level
of DNA methylation in spermatagonia—compared with
that in oogonia—which would predict increased substitutions
at CpG dinucleotides, has been suggested as an
important contributing factor. .....