Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors

Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], ≥ 35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], ≥ 35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations.     

Paternal age and Down's syndrome data from prenatal diagnoses (DFG)

Summary From prenatal diagnosis data obtained on mothers aged 35 years and above in the Federal Republic of Germany (DFG data), older fathers are demonstrated to have an increased risk of having trisomy 21 offspring. For paternal ages of 41 years upward, the age effect is quite strong. The risk for a fetus to have any de novo chromosomal aberration increases more with advancing paternal age for older mothers than for younger ones. Thus the ages of both parents have to be taken into account as an indication for prenatal diagnosis. Risk figures for trisomy 21 and for any de novo chromosomal aberration are given, together with preliminary recommendations for prenatal diagnosis for different combinations of parental ages.     

Translocation Down syndrome in Ohio 1970-1981: epidemiologic and cytogenetic factors and mutation rate estimates.

Sixteen hundred eighty-eight Down syndrome live births, including 65 (5.2%) translocations, were ascertained in Ohio between 1970 and 1981. Translocations of known origin were 24.4% maternal, 2.2% paternal, and 73.3% de novo. Translocation subtypes were 14/21 (45.7%), 15/21 (2.9%), 21/21 (40.0%), 21/22 (2.9%), and other (8.5%). Among 14/21 translocations, 33.3% were maternal in origin and 66.7% were de novo, while 100% of 21/21 translocations were de novo. No differences were found when the maternal- and paternal-age distributions of all translocations or various translocation subsets were compared with the live-birth control distributions. However, mean maternal and paternal ages of de novo translocations were significantly lower than that of the live-birth controls. Ohio data showed the average maternal age of de novo D/21 cases to be significantly lower than the control. Ages of both parents of de novo G/21 cases and paternal age of D/21 cases were not different from the control. De novo translocation mutation rate estimates were 0.8 X 10(-5) for 14/21, 1.2 X 10(-5) for 21/21, and 2.2 X 10(-5) overall. Ohio estimates (3.2 X 10(-5) for 1970-1972 and 1.4 X 10(-5) for 1973-1975) did not reflect the increase in mutation rate previously found in New York during 1973-1977.     

Parental origin of de novo cytogenetically balanced reciprocal non-Robertsonian translocations

De novo cytogenetically balanced reciprocal non-Robertsonian translocations are rare findings in clinical cytogenetics and might be associated with an abnormal phenotype. Knowledge of the parental origin and mechanisms of formation is still limited. By microdissection of the derivative chromosomes and their normal homologs from metaphases followed by microsatellite-mediated marker analysis we identified 7 cases of paternal and 3 cases of maternal origin in a cohort of 10 patients with de novo cytogenetically balanced reciprocal non-Robertsonian translocations. Neither in the maternal nor in the paternal group of our study parental age seems to be increased. Together with the data from the literature our results confirm that the majority of de novo cytogenetically balanced reciprocal translocations are of paternal origin, but the preponderance does not appear to be as distinct as previously thought and the paternal age does not seem to be necessarily a major contributing factor.     

Increased paternal age and the influence on burden of genomic copy number variation in the general population

Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n = 6,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased father’s age may be independent disease risk factors.     

Extra structurally abnormal chromosomes (ESAC) detected at amniocentesis: frequency in approximately 75,000 prenatal cytogenetic diagnoses and associations with maternal and paternal age.

We analyzed rates of extra structurally abnormal chromosomes (ESAC) detected in prenatal cytogenetic diagnoses of amniotic fluid reported to the New York Chromosome Registry. These karyotypes include both extra unidentified structurally abnormal chromosomes (EUSAC)--often denoted as "markers"--and extra identified structurally abnormal chromosomes (EISAC). The rate of all EUSAC was 0.64/1,000 (0.32-0.40/1,000 mutant and 0.23-0.32 inherited), and that of all EISAC was 0.11/1,000 (0.07/1,000 mutant and 0.04/1,000 inherited). The rate of all ESAC was approximately 0.8/1,000-0.4-0.5/1,000 mutant and 0.3-0.4/1,000 inherited. Mean +/- SD maternal age of mutant cases was 37.5 +/- 2.9, significantly greater than the value of 35.8 years in controls. A regression analysis indicated a rate of change of the log of the rate of about +0.20 with each year of maternal age between 30 and 45 years. When paternal age was introduced, the maternal age coefficient increased to about +0.25--close to that seen for 47, +21--but the paternal age coefficient was -0.06. After being matched for maternal age and year of diagnosis, the case-control difference in paternal age for 24 mutant cases was -2.4 with a 95% confidence interval of -4.6 to -0.1 years. In a regression analysis of the effects of both parental ages on the (log) rate, the maternal age coefficient was +0.25 and the paternal age coefficient was -0.06. These results are consistent with a (weak) negative paternal age effect in the face of a strong maternal age effect. Since ESAC include a heterogeneous group of abnormalities, the maternal age and paternal age trends, if not the result of statistical fluctuation or undetected biases, may involve different types of events. Data in the literature suggest that chromosomes with de novo duplicated inversions of 15p have a strong maternal age effect (but little paternal age effect). Such chromosomes, however, do not account for the active maternal age trends seen in the data analyzed here. Inherited ESAC exhibited no such trends.     

Implications of Advancing Paternal Age: Does It Affect Offspring School Performance?

Average paternal age is increasing in many high income countries, but the implications of this demographic shift for child health and welfare are poorly understood. There is equivocal evidence that children of older fathers are at increased risk of neurodevelopmental disorders and reduced IQ. We therefore report here on the relationship between paternal age and a composite indicator of scholastic achievement during adolescence, i.e. compulsory school leaving grades, among recent birth cohorts in Stockholm County where delayed paternity is notably common. We performed a record-linkage study comprising all individuals in Stockholm County who finished 9 years of compulsory school from 2000 through 2007 (n = 155,875). Data on school leaving grades and parental characteristics were retrieved from administrative and health service registers and analyzed using multiple linear regression. Advancing paternal age at birth was not associated with a decrease in school leaving grades in adolescent offspring. After adjustment for year of graduation, maternal age and parental education, country of birth and parental mental health service use, offspring of fathers aged 50 years or older had on average 0.3 (95% CI −3.8, 4.4) points higher grades than those of fathers aged 30–34 years. In conclusion, advancing paternal age is not associated with poorer school performance in adolescence. Adverse effects of delayed paternity on offspring cognitive function, if any, may be counterbalanced by other potential advantages for children born to older fathers.     

Parental origin of germ-line and somatic mutations in the retinoblastoma gene

Segregation analysis of polymorphic sites within the retinoblastoma (RB) gene and on chromosome 13, as well as the parental origin of the lost allele in the tumor, were analyzed in 24 families with RB patients. Four mutant alleles transmitted through the germ-line and seven de novo germ-line mutant alleles were identified in 11 patients with hereditary RB. Segregation analysis within the RB gene and on chromosome 13 was useful for DNA diagnosis of susceptibility to RB in relatives of hereditary patients, even if mutations were not identified. All seven de novo germ-line mutant alleles were paternally derived. The bias toward the paternal allele for de novo germ-line mutations of the RB gene was statistically significant. Seven paternal alleles and six maternal alleles were lost in 13 non-hereditary RB tumors with no bias in the parental origin of the somatic allele loss. These results suggest that the physical environment or a deficiency in DNA repair during spermatogenesis may be associated with significant risk factors for de novo germ-line mutations.     

Parental and chromosomal origin of unbalanced de novo structural chromosome abnormalities in man

We report the parental origin, and where possible the chromosomal origin of 115 de novo unbalanced structural chromosome abnormalities detectable by light microscopy. These consisted of 39 terminal deletions, 35 interstitial deletions, 8 rings, 12 duplications and 21 unbalanced translocations. In all categories the majority of abnormalities were of paternal origin, although the proportions varied from a high of 84% in the interstitial deletions and rings to a low of 58% in the duplications. Among the interstitial deletions and duplications, there were approximately equal numbers of intra- and interchromosomal abnormalities, while the majority of unbalanced translocations were isodisomic for the duplicated chromosome. The examination of the parental ages in the four main classes of abnormality showed terminal deletions of maternal origin to be associated with a significantly reduced maternal age. Thus, there is a clear propensity for structural chromosome abnormalities to occur in male germ cells, although the chromosomal origin seems similar irrespective of the parental origin.     

Age and chromosome nondisjunction]

The parental age in 77 families of Down syndrome (DS) children with the known origin of extra chromosome 21 and in 12 families of DS children resulting from de novo translocation (more probable than not in 2 meiotic division) was studied. It was shown that when nondisjunction occurred in the 1st meiotic division, both in oogenesis (n = 30) and spermatogenesis (n = 12), mean parental ages and age distributions were different from that of control (400 couples with normal children). The mean age and age distribution were found to differ from control when nondisjunction occurred in the 2nd meiotic division of oogenesis (n = 19). On the basis of our information and the previously published data, lack of the effect of parental age on chromosome segregation in the Ist meiosis may be inferred. It is chromatid disjunction in the 2nd meiosis which is more probably age-dependent. The reasons preventing elucidation of real associations are under debate.     

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.     

Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis

Muenke syndrome, also known as FGFR3-associated coronal synostosis, is defined molecularly by the presence of a heterozygous nucleotide transversion, c.749C>G, encoding the amino acid substitution Pro250Arg, in the fibroblast growth factor receptor type 3 gene (FGFR3). This frequently occurs as a new mutation, manifesting one of the highest documented rates for any transversion in the human genome. To understand the biology of this mutation, we have investigated its parental origin, and the ages of the parents, in 19 families with de novo c.749C>G mutations. All ten informative cases originated from the paternal allele (95% confidence interval 74–100% paternal); the average paternal age at birth overall was 34.7 years. An exclusive paternal origin of mutations, and increased paternal age, were previously described for a different mutation (c.1138G>A) of the FGFR3 gene causing achondroplasia, as well as for mutations of the related FGFR2 gene causing Apert, Crouzon and Pfeiffer syndromes. We conclude that similar biological processes are likely to shape the occurrence of this c.749C>G mutation as for other mutations of FGFR3 as well as FGFR2.S.V. Rannan-Eliya and I.B. Taylor contributed equally to this work.     

Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy

Severe Myoclonic Epilepsy in Infancy (SMEI) is an intractable epileptic syndrome with onset in the first year of life and is commonly caused by de novo mutations in the SCN1A gene, encoding the α1-subunit of the neuronal voltage-gated sodium channel. We report two unrelated families in which probands were affected by SMEI and their parents showed a single febrile seizure during early childhood or no neurological symptoms. Semiquantitative analysis of SCN1A mutations allowed the detection of a somatic and germline mosaicism in one of the parents. The study provides the first example of parental mosaicisms in SMEI and opens a new insight into the phenotypic variability and complex inheritance of this condition. The identification of germline mosaicisms has important consequences in genetic counseling of SMEI when SCN1A mutations appear to occur de novo with standard screening methods.     

Reference Growth Curves for Cypriot Children 6 to 17 Years of Age

Objective: The purpose of the study was to present smoothed percentiles for body weight and height, waist circumference, and body mass index (BMI) in Cypriot children and to compare their BMI 85th and 95th percentiles with those of children in other countries. Research Methods and Procedures: The study was a cross‐sectional study, including a representative sample of 2472 healthy children (49.1% boys) in Cyprus ages 6 to 17 years, who were evaluated during the 1999–2000 school year. Body weight and height and waist circumference were measured using standard procedures. BMI was calculated as weight in kilograms per height in square meters. Smoothed, sex‐specific percentiles for these variables were calculated using polynomial regression models. Crude weight, height, waist, and BMI percentile values are presented in sex‐specific tables and smoothed percentile curves are presented in charts. The 85th and 95th percentiles for BMI were compared with measurements from other countries, because of the concern of the upper limits of BMI in respect to the evaluation of obesity. Results: The 85th and 95th BMI percentile values are higher in Cypriot boys than in Swedish and Iranian boys through all ages and in girls ages 6 to 15 years, whereas after the age of 15 years, both Swedish and Iranian girls’ percentiles are equalized with their Cypriot peers. Discussion: Weight, height, waist circumference, and BMI values and charts are presented for the first time for Cypriot children and adolescents. Much concern should be addressed to the observation that for the majority of the Cypriot sample, the upper BMI limits are higher than the peers of developing and developed countries.     

Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome

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.     

Age variation in the upper limit of hearing.

The upper limit of hearing was measured in 6105 otologically normal ears of subjects ranging in age from 5 to 89 years. The results are as follows: in each age group from 5 to 59 years in both sexes, the upper limit of hearing showed an approximately normal distribution if a logarithmic scale was used for the upper limit of hearing axis. The mode of the distribution shifted to a lower frequency with increasing age. Over age 60 years, the distribution became much wider. Standard upper limit age curves were established by calculating 10th, 25th, 50th, 75th and 90th percentiles for each age group. From early childhood where no age variation was recognized in conventional audiometry, deterioration of the upper limit of hearing was already in progress. This deterioration was slight between ages 25 and 39 but at ages over 40 it was accelerated and led to so-called presbycousis. The upper limit of hearing was found to be one of the best parameters for showing the quantitative age-related changes in hearing.     

Long-term changes in body weight, BMI, and adiposity rebound among children and adolescents in the Czech republic

The Czech Republic has undergone rapid political, social, and economic transformation since the late 1980s. While obesity rates among children and adolescents in the Czech Republic have been previously relatively low, this has changed in recent years. Across the past 50 years, body weight, body mass index (BMI)-for-age, and adiposity rebound (AR) (the time when a child reaches the lowest BMI before their BMI gradually begins to increase until adulthood) occurs earlier. The most dramatic changes have been observed among school-aged children, where BMI values have increased at the 50th, 90th, and 97th percentiles. In contrast, adolescent girls appear to be thinner than in the past. The analyses of weight-for-height percentiles indicated that the 50th percentile of the body weight among boys and girls remained similar in nearly all age categories across the past 50 years. Although the growth pattern of children at the 50th percentile has not changed, the 10th and 90th percentiles have expanded. Our findings suggest that the secular trend of increased height, accelerated growth, and earlier maturation is responsible for Czech children experiencing adiposity rebound at earlier ages compared to the past.     

MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparently is lethal in male embryos. RTT almost exclusively affects female offspring and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosomal inheritance from a carrier mother. We analyzed the parental origin of MECP2 mutations in sporadic cases of RTT, by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of paternal origin in 26 of 27 cases (P<.001). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. We conclude that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is most probably the cause for the high female:male ratio observed in patients with RTT. Affected males recently have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. This distinction will allow geneticists to offer more-specific counseling and discriminate between higher (maternal origin) and lower (paternal origin) recurrence risk.     

Grandmaternal ages at birth of parents of children with down syndrome in St. Petersburg

Data on the age of grandparents of 243 children with Down syndrome (DS) born between 1990 and 1999 are considered in this work in comparison with control families of 330 healthy children. In 102 families, where the age of the mother at the birth of a child with DS was younger 30 (or less than 30) years, the median ages of both maternal and paternal grandmothers of probands were actually the same (26 years). Actually, the median age of grandmothers in 226 young families having healthy children were also the same (27 years). No differences in the indicators in question were revealed between 141 families with DS and 104 families with healthy children, where the mothers were older than 29 years. Thus, our results have not confirmed the hypothesis about the influence of the age of DS probands’ grandmothers on the segregation of chromosomes in their daughters’ oogenesis, as well as the hypothesis about a significant contribution of the inherited trisomy of chromosome 21 to the frequency of DS in the general population.     

Mutations in EZH2 cause Weaver syndrome

We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected proband identified a third de novo mutation in this gene. These data show that mutations in EZH2 cause Weaver syndrome.