TY - JOUR
T1 - Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome
AU - Tartaglia, Marco
AU - Cordeddu, Viviana
AU - Chang, Hong
AU - Shaw, Adam
AU - Kalidas, Kamini
AU - Crosby, Andrew
AU - Patton, Michael A.
AU - Sorcini, Mariella
AU - Van Der Burgt, Ineke
AU - Jeffery, Steve
AU - Gelb, Bruce D.
N1 - Funding Information:
We are indebted to the families who participated in the study and to the physicians who referred the subjects. The study was supported in part by grants from Telethon (GGP04172 to M.T.), Ricerca Finalizzata 1% FSN2002 “Valutazione molecolare e funzionale delle malformazioni e disfunzioni cardiache su base genetica” (M.T.), the National Institutes of Health (HL71207 and HD01294 to B.D.G.), the March of Dimes (FY03-52 to B.D.G.), the Birth Defects Foundation-UK (S.J.), and the British Heart Foundation (S.J.).
PY - 2004/9
Y1 - 2004/9
N2 - 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. 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.
AB - 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. 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.
UR - http://www.scopus.com/inward/record.url?scp=4143100212&partnerID=8YFLogxK
U2 - 10.1086/423493
DO - 10.1086/423493
M3 - Article
C2 - 15248152
AN - SCOPUS:4143100212
SN - 0002-9297
VL - 75
SP - 492
EP - 497
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -