Mutagenic efect of paternal advanced age

Souhrn

Increased frequency of chromosomal aberrations in children of mothers aged 35 years and older is very well known and since 1973 is an indication to investigate the fetal karyotype in cells obtained by investive method ( amniocentesis), because the genetic risk of severe affection in higher than the risk of necessary invasive method for cytogenetic investigation. Mutagenic effect of advanced paternal age is known only among geneticists (1,2,3,4) The reason is not only low absolute risk of new mutation but particularly a high number of involved genes and last but not least the limited spectrum of prenatal detection of autosomal dominant disorders by molecular genetics. Therefore the preventive methods for elimination of this risk are very limited. Only a few of them could be recognized prenatally by noninvasive methods of prenatal diagnostics, such as skeletal dysplasias, acrocephaly, limb defects

We have studied genealogical, anamnestic and clinical data of 83 patients with clinical suspection on neurocardiofaciocutaneous syndrome (NCFCs) (5,6,7). The diagnosis has not been confirmed in 29 patients, no mutation was detected in 10 investigated genes (PTPN11,SOS1, HRAS, BRAF, RAF1, MEK1, MEK 2, KRAS, NRAS, SHOC2 ). In 54 patients with autosomal dominant inherited Noonan syndrome, LEOPARD association, Costello syndrome and cardiofaciocutaneous syndrome the diagnosis was confirmed on DNA level and the biological fitness estimated in this disorder. Paternal age at conception was compared in the group of patients with familial and sporadic occurrence of Noonan and NCFC syndromes.

The clinical prognosis of this disorder is represented by biological fitness of patients. Coeficient of selection is 0,604 in Noonan and LEOPARD syndromes (29 from 48) All 6 patients with Costello and cardiofaciocutaneous syndromes are due to new mutation ( selection 1). Clinical prognosis due to severe congenital deart defects, failure to thrive in infancy, increased risk for malignancy event. another health disturbance was problematic.

We have studied paternal age at birth of child in 54 patients with autosomal dominant Neurocardiofaciocutaneous syndrome ( Noonan, LEOPARD, Costello, CFC ) with high population incidence and decreased biological fitness. High mutation rate is therefore expected. Identification of genes responsible for manifestation of this disorder enables to confirm the diagnosis and to recognize inherited and de novo mutation. Genealogy and DNA analysis of PTPN11, SOS1, HRAS, BRAF, RAF1, MEK1, MEK2, KRAS and NRAS, SHOC2 were obtained in cohort of 54 patients with NCFC syndromes and their parents. There were 48 patients with Noonan and LEOPARD syndromes. In 29 cases occurred due to mutation de novo, 19 patients inherited the mutation from one of parents ( biological fitness 0,395). All 6 patients with Costello syndrome and CFC syndrome were affected due to new mutation. DNA analysis revealed 32 mutation in PTPN11 gene, mutation in SOS1 gene was found in 10 patients, RAF1 mutation was present in 3 patients, mutation in MEK1, KRAS and NRAS genes was present in one patient each. In Costello syndrome and CFC syndrome mutation in HRAS (4 patients) and BRAF ( 2 patients) genes were detected. Genealogic data allow to analyse the parental age in group of patients with new mutation and inherited mutation. Parental age at conception of patients with Noonan syndrome due to new mutation was significantly increased in comparison to the group of fathers of Noonan patients with inherited mutation.- 38,4 years and 29,6 years resp. range 28 to 55 and 25 to 35 years resp. Maternal age was mildly increased too, 30,0 and 27,7 resp. range 24 to 42 years and 21 to 36 years resp. – but not significantly. The results support the mutagenic effect of paternal age,espec. mutation with autosomal dominant character.

Key words:
advanced parental age, mutagenic effect, chromosomal mutations, gene mutations, manifestation of new mutation, coeficient of selection, mutation rate.