Paternal-age-related de novo mutations and risk for five disorders

Taylor, Jacob; Debost, Jean-Christophe Philippe Goldtsche; Morton, Sarah U.; Wigdor, Emilie M.; Heyne, Henrike O.; Lal, Dennis; Howrigan, Daniel P.; Bloemendal, Alex; Larsen, Janne Tidselbak; Kosmicki, Jack A.; Weiner, Daniel J.; Homsy, Jason; Seidman, Jonathan G.; Agerbo, Esben; McGrath, John; Mortensen, Preben Bo; Petersen, Liselotte; Daly, Mark J.; Robinson, Elise

doi:10.1101/192740

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…Using spontaneous labor as a reference (no exposure to sOT), cases categorized as “fetal indication” for delivery (Table 1) as a group had significantly higher odds of ASD (OR = 2.00, 95% CI = 1.01–3.94, p = 0.044). To control for the possibility that fetal indications could confound the results in Tables 3 to 6, this variable was included as a covariate in subsequent analysis as was the presence of maternal hypertension (Curran et al, 2018), maternal diabetes (Li et al, 2016; OR = 2.04, p = 0.077), maternal education (as a substitute for the lack of socioeconomic status data), birth weight (Burstyn et al, 2010), maternal smoking (Caramaschi et al, 2018) or alcohol use during pregnancy (Bölte et al, 2019), the child’s race (Baio et al, 2018), and paternal age (Taylor et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

Soltys

Scherbel

Kurian

et al. 2020

Autism

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A case-control study was performed to determine whether an association exists between exposure to synthetic oxytocin and a subsequent autism spectrum disorder diagnosis; 171 children under age 18 meeting Diagnostic and Statistical Manual of Mental Disorders (5th ed.) autism spectrum disorder criteria were compared to 171 children without autism spectrum disorder diagnosis matched by gender, birth year, gestational age, and maternal age at birth. A conditional logistic regression model was used to examine the association of clinical variables and autism spectrum disorder. Significantly elevated odds ratios for autism spectrum disorder were associated with first-time Cesarean section (odds ratio = 2.56), but not a repeat Cesarean section. Odds ratios were also significantly elevated for subjects whose mother’s body mass index was 35 or higher at birth (odds ratio = 2.34) and subjects in which the reason for delivery was categorized as “fetal indication” (odds ratio = 2.00). When controlling for these and other variables, the odds of developing autism spectrum disorder were significantly elevated in males with long duration of exposure (odds ratio = 3.48) and high cumulative dose of synthetic oxytocin (odds ratio = 2.79). No significant associations of synthetic oxytocin dosing and autism spectrum disorder were noted in female subjects. The association of elevated autism spectrum disorder odds found with high duration and high cumulative dose synthetic oxytocin in male subjects suggests the need for further investigation to fully elucidate any cause and effect relationship. Lay abstract Oxytocin is a hormone naturally produced in the human body that can make the womb (uterus) contract during labor. Manufactured oxytocin is frequently given to mothers in labor to strengthen the contractions or in some cases to start labor. This study compared children with a diagnosis of autism and children without autism to see whether children with autism received more oxytocin during labor. The odds of a child having an autism diagnosis were significantly higher if the delivery was a first-time Cesarean section, if the mother had a body mass index of 35 or higher, or if the reason for delivery were a range of fetal problems that made delivery necessary. It was found that boys who were exposed to oxytocin for longer periods of time during labor and received higher total doses of oxytocin had significantly higher odds of developing autism. There were no significant associations of oxytocin dosing and autism noted in female children. As this is the first study to look at any relationship between the dose of oxytocin received during labor and the odds of developing autism, further study needs to be done to determine whether there is any cause and effect relationship. Thus, at this time, there is no recommended change in clinical practice.

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Section: Resultsmentioning

confidence: 99%

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

Soltys

Scherbel

Kurian

et al. 2020

Autism

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“…The fact that aging is a large contributor to germline mutation has several implications for contemporary and historic populations. Children from parents of advanced age are more likely to suffer diseases caused by DNMs, such as intellectual disability, developmental disorders, autism, and epilepsy [4,39,[79][80][81]. In line with this, studies of historic populations indicated that late-born children on average have lower genetic fitness, as they were less likely to survive infancy and to engage in marriage [82][83][84].…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 91%

De Novo Mutations Reflect Development and Aging of the Human Germline

2019

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Human germline de novo mutations (DNMs) are both a driver of evolution and an important cause of genetic diseases. In the past few years, whole-genome sequencing (WGS) of parentoffspring trios has facilitated the large-scale detection and study of human DNMs, which has led to exciting discoveries. The overarching theme of all of these studies is that the DNMs of an individual are a complex mixture of mutations that arise through different biological processes acting at different times during human development and life. De novo mutationsHuman de novo mutations (DNMs, see Glossary) are germline mutations that newly occurred within one generation. While the vast majority of the genome has been inherited from earlier generations, DNMs provide new genetic variation. The consequences of the new genetic mutation can vary widely. While neutral or advantageous mutations might become established in the genome of our species and thereby contribute to human evolution, changes to crucial genetic sequences can also result in misfunctioning of biological systems, resulting in severe disease. One of the earliest known examples of this was Down syndrome, which is caused by a de novo trisomy of chromosome 21 [1][2][3]. In recent years DNMs have been found to be a prominent cause of neurodevelopmental diseases, including intellectual disability, autism, and schizophrenia [4,5]. The unbiased study of de novo point mutations in humans was for many years hampered by the lack of techniques to scan the entire genome in a cost-effective way. The introduction of next-generation sequencing (NGS) technologies has spurred investigations of DNMs in humans [6]. DNMs can refer to a variety of different mutation types, such as single-nucleotide substitutions, insertions, deletions, and copy-number variants (CNVs). In this review we focus on single-nucleotide mutations and review the progress made in this field since the introduction of WGS, exploring their biology and possible underlying mechanisms (Figure 1, Key Figure ), but not the potential pathological consequences.

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“…10,[29][30][31] High paternal age is suggested to increase the risk of de novo variants in general. 32,33 We have not accounted for paternal age in our study, but this could be a topic for further investigations. The fact that the incidence of syndromic craniosynostosis was stable over the three time periods in addition to our calculation being based on very low numbers might indicate that this finding is a coincidence that should not be emphasized.…”

Section: Incidencementioning

confidence: 99%

Epidemiology of craniosynostosis in Norway

Tønne

Due-Tønnessen

Wiig

et al. 2020

Journal of Neurosurgery: Pediatrics

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OBJECTIVEThe authors present population-based epidemiological data for craniosynostosis regarding incidence, age at diagnosis, sex differences, and frequency of syndromic and familial cases.METHODSThe prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve data on all individuals with craniosynostosis treated between 2003 and 2017. The cohort was divided into three 5-year groups based on year of birth: 2003–2007, 2008–2012, and 2013–2017.RESULTSThe authors identified 386 individuals with craniosynostosis. Of these, 328 (85%) consented to be registered with further information. The incidence increased significantly during the study period and was 5.5 per 10,000 live births (1/1800) in the last 5-year period. The increase was seen almost exclusively in the nonsyndromic group. Syndromic craniosynostosis accounted for 27% of the cases, and the incidence remained stable throughout the three 5-year periods. Both syndromic and nonsyndromic craniosynostosis were highly suture specific. There was a male preponderance (male/female ratio 2:1), and males accounted for 75% of the individuals with midline synostosis. Overall, 9.5% were index individuals in families with more than one affected member; of these, 73% were nonsyndromic cases.CONCLUSIONSThe incidence of craniosynostosis increased during the study period, and the observed incidence is among the highest reported. The authors attribute this to increasing awareness among healthcare professionals. The number of syndromic cases was high, likely due to a broader definition compared to the majority of earlier reports. The study revealed a high number of familial cases in both syndromic and nonsyndromic craniosynostosis, thus highlighting the importance of genetics as an underlying cause of craniosynostosis.

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Paternal-age-related de novo mutations and risk for five disorders

Cited by 7 publications

References 43 publications

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

An association of intrapartum synthetic oxytocin dosing and the odds of developing autism

De Novo Mutations Reflect Development and Aging of the Human Germline

Epidemiology of craniosynostosis in Norway

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