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      Report of a Father With Congenital Bilateral Absence of the Vas Deferens Fathering a Child With Beare–Stevenson Syndrome

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          Abstract

          Background

          Apert, Pfeiffer, and Crouzon syndromes are autosomal dominant diseases characterized by craniosynostosis. They are paternal age effect disorders. The association between paternal age and Beare–Stevenson syndrome (BSS), a very rare and severe craniosynostosis, is uncertain. Gain-of-function mutations in FGFR2 become progressively enriched in testes as men age and were shown to cause these syndromes.

          Case report

          Here, we describe a child affected with BSS, whose father was 36 years old and had congenital bilateral absence of the vas deferens (CBAVD). The child was heterozygous for the pathogenic FGFR2 variant c.1124A > G p.Tyr375Cys. By reviewing the literature, we found that BSS fathers are older than BSS mothers (mean age in years: 39 ± 10 vs 30 ± 6, p = 0.006). Male age greater than 34 years and CBAVD are both factors associated with poor spermogram parameters, which may represent an additional selective pressure to sperm carrying FGFR2 gain-of-function mutations.

          Conclusion

          These findings are consistent with the hypothesis that BSS is a paternal-origin genetic disorder. Further experimental studies would be needed to confirm this hypothesis.

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          Most cited references 48

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          De novo mutations in human genetic disease.

          New mutations have long been known to cause genetic disease, but their true contribution to the disease burden can only now be determined using family-based whole-genome or whole-exome sequencing approaches. In this Review we discuss recent findings suggesting that de novo mutations play a prominent part in rare and common forms of neurodevelopmental diseases, including intellectual disability, autism and schizophrenia. De novo mutations provide a mechanism by which early-onset reproductively lethal diseases remain frequent in the population. These mutations, although individually rare, may capture a significant part of the heritability for complex genetic diseases that is not detectable by genome-wide association studies.
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            New insights into the generation and role of de novo mutations in health and disease

            Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing studies of parent–offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, and other developmental diseases. In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to occur in our population. Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age. Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.
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              Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease.

              Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/503253
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                25 February 2020
                2020
                : 11
                Affiliations
                1 Department of Biochemistry, Federal University of Rio Grande do Norte , Natal, Brazil
                2 Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte , Natal, Brazil
                3 University Hospital Onofre Lopes, Urologic Unit, Federal University of Rio Grande do Norte , Natal, Brazil
                Author notes

                Edited by: Fasil Tekola Ayele, National Institutes of Health (NIH), United States

                Reviewed by: Andrew O. M. Wilkie, University of Oxford, United Kingdom; Muhammad Jawad Hassan, National University of Medical Sciences (NUMS), Pakistan

                *Correspondence: Leonardo C. Ferreira, ferreiralc@ 123456cb.ufrn.br

                This article was submitted to Genetic Disorders, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2020.00104
                7052335
                Copyright © 2020 Ferreira and Dantas Junior

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Counts
                Figures: 1, Tables: 1, Equations: 0, References: 48, Pages: 6, Words: 2957
                Categories
                Genetics
                Case Report

                Genetics

                fgfr2, cbavd, paternal age, craniosynostosis, beare–stevenson

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