Our Results Show That All Mutations Were Inherited From the Father, Advanced Paternal Age Was Found in Sporadic Cases of Noonan Syndrome

Published by the University of Chicago Press

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Title Paternal Germline Origin and Sex-Ratio Distortion in Transmission of PTPN11 Mutations in Noonan Syndrome
Author(s) Marco Tartaglia, Viviana Cordeddu, Hong Chang, Adam Shaw, Kamini Kalidas, Andrew Crosby, Michael A. Patton, Mariella Sorcini, Ineke van der Burgt, Steve Jeffery, and Bruce D. Gelb
Identifiers The American Journal of Human Genetics, volume 75 (2004), pages 492–497
DOI: 10.1086/423493
PubMed ID: 15248152

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Copyright © 2004, The American Society of Human Genetics.
Abstract Germline mutations in PTPN11the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2represent 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. By analyzing intronic portions that flank the exonic PTPN11 lesions in 49 sporadic NS cases, we traced the parental origin of mutations in 14 families. Our results showed that all mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. We also report that advanced paternal age was observed among cohorts of sporadic NS cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic NS caused by PTPN11 mutations, as well as in families inheriting the disorder.

--For those British men whose children had a PTPN11
mutation (n p 15), the mean Z score was 0.93 (P !
.001). For the fathers of children with NS but without
a PTPN11 mutation (n p 43), the mean Z score was
0.62 (P ! .001). 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).
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