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De novo Mutations and the Lack of Heritability in Birth...
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De novo Mutations and the Lack of Heritability in Birth Defects

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (1 August 2021) | Viewed by 14404

Special Issue Editors

Dr. Heiko Reutter

E-Mail Website
Guest Editor
Institute of Human Genetics, University Hospital of Bonn, 53127 Bonn, Germany
Interests: molecular genetics; DNA; PCR; DNA sequencing; gene expression; cloning; animal model; zebrafish; developmental genetics; human genetics
Special Issues, Collections and Topics in MDPI journals
Dr. Alina Hilger

E-Mail Website
Guest Editor
1. Department of Pediatrics, Children’s Hospital, University Hospital Bonn, 53113 Bonn, Germany
2. Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
Interests: genetics; pediatric nephrology; mutation; nephrology; human genetics; molecular genetics; developmental genetics; zebrafish

Special Issue Information

Dear Colleagues,

The prevention and treatment of major birth defects are key concerns for child health. About 25% of all pediatric deaths and about one-third of all pediatric hospital admissions are associated with birth defects. Many birth defects are associated with lifelong physical and psychosocial impairments affecting both the child and their family. For the majority of defects, the underlying cause remains unknown, but is thought to be likely heterogeneous.

The implicated mortality and/or reduced fecundity in many major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. The experience in medical genetics suggests that these mutational de novo events will comprise genomic alterations of different size ranging from small changes affecting single nucleotides to large alterations resulting in losses or gains of several thousand to millions of base pairs.

The availability of large-scale array-based copy number variation analysis and exome sequencing has enabled researchers to systematically investigate large patient cohorts, allowing for the identification of mutational de novo events. However, the interpretation of these de novo events in regards to their clinical significance remains difficult for many reasons.

In this Special Issue, we aim to revisit the genetic advancements over the past decade. We further aim to discuss the use of public databases and in silico prediction tools to characterize (single nucleotid) de novo variants, and the necessity for functional characterization of de novo variants.

Dr. Heiko Reutter
Dr. Alina Hilger
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • birth defects
  • exome sequencing
  • array analysis
  • de novo mutational events
  • in silico prediction tools
  • public databases
  • functional characterization

Published Papers (5 papers)

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Research

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8 pages, 528 KiB  
Article
Genome-Wide Survey for Microdeletions or -Duplications in 155 Patients with Lower Urinary Tract Obstructions (LUTO)
by Luca M. Schierbaum, Sophia Schneider, Stefan Herms, Sugirthan Sivalingam, Julia Fabian, Heiko Reutter, Stefanie Weber, Waltraut M. Merz, Marcin Tkaczyk, Monika Miklaszewska, Przemyslaw Sikora, Agnieszka Szmigielska, Grazyna Krzemien, Katarzyna Zachwieja, Maria Szczepanska, Katarzyna Taranta-Janusz, Pawel Kroll, Marcin Polok, Marcin Zaniew and Alina C. Hilger
Genes 2021, 12(9), 1449; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091449 - 20 Sep 2021
Cited by 4 | Viewed by 2407
Abstract
Lower urinary tract obstruction (LUTO) is, in most cases, caused by anatomical blockage of the bladder outlet. The most common form are posterior urethral valves (PUVs), a male-limited phenotype. Here, we surveyed the genome of 155 LUTO patients to identify disease-causing CNVs. Raw [...] Read more.
Lower urinary tract obstruction (LUTO) is, in most cases, caused by anatomical blockage of the bladder outlet. The most common form are posterior urethral valves (PUVs), a male-limited phenotype. Here, we surveyed the genome of 155 LUTO patients to identify disease-causing CNVs. Raw intensity data were collected for CNVs detected in LUTO patients and 4.392 healthy controls using CNVPartition, QuantiSNP and PennCNV. Overlapping CNVs between patients and controls were discarded. Additional filtering implicated CNV frequency in the database of genomic variants, gene content and final visual inspection detecting 37 ultra-rare CNVs. After, prioritization qPCR analysis confirmed 3 microduplications, all detected in PUV patients. One microduplication (5q23.2) occurred de novo in the two remaining microduplications found on chromosome 1p36.21 and 10q23.31. Parental DNA was not available for segregation analysis. All three duplications comprised 11 coding genes: four human specific lncRNA and one microRNA. Three coding genes (FBLIM1, SLC16A12, SNCAIP) and the microRNA MIR107 have previously been shown to be expressed in the developing urinary tract of mouse embryos. We propose that duplications, rare or de novo, contribute to PUV formation, a male-limited phenotype. Full article
(This article belongs to the Special Issue De novo Mutations and the Lack of Heritability in Birth Defects)
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Review

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18 pages, 1417 KiB  
Review
Heritability and De Novo Mutations in Oesophageal Atresia and Tracheoesophageal Fistula Aetiology
by Erwin Brosens, Rutger W. W. Brouwer, Hannie Douben, Yolande van Bever, Alice S. Brooks, Rene M. H. Wijnen, Wilfred F. J. van IJcken, Dick Tibboel, Robbert J. Rottier and Annelies de Klein
Genes 2021, 12(10), 1595; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101595 - 10 Oct 2021
Cited by 4 | Viewed by 2504
Abstract
Tracheoesophageal Fistula (TOF) is a congenital anomaly for which the cause is unknown in the majority of patients. OA/TOF is a variable feature in many (often mono-) genetic syndromes. Research using animal models targeting genes involved in candidate pathways often result in tracheoesophageal [...] Read more.
Tracheoesophageal Fistula (TOF) is a congenital anomaly for which the cause is unknown in the majority of patients. OA/TOF is a variable feature in many (often mono-) genetic syndromes. Research using animal models targeting genes involved in candidate pathways often result in tracheoesophageal phenotypes. However, there is limited overlap in the genes implicated by animal models and those found in OA/TOF-related syndromic anomalies. Knowledge on affected pathways in animal models is accumulating, but our understanding on these pathways in patients lags behind. If an affected pathway is associated with both animals and patients, the mechanisms linking the genetic mutation, affected cell types or cellular defect, and the phenotype are often not well understood. The locus heterogeneity and the uncertainty of the exact heritability of OA/TOF results in a relative low diagnostic yield. OA/TOF is a sporadic finding with a low familial recurrence rate. As parents are usually unaffected, de novo dominant mutations seems to be a plausible explanation. The survival rates of patients born with OA/TOF have increased substantially and these patients start families; thus, the detection and a proper interpretation of these dominant inherited pathogenic variants are of great importance for these patients and for our understanding of OA/TOF aetiology. Full article
(This article belongs to the Special Issue De novo Mutations and the Lack of Heritability in Birth Defects)
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11 pages, 297 KiB  
Review
The Role of De Novo Variants in Patients with Congenital Diaphragmatic Hernia
by Charlotte Bendixen and Heiko Reutter
Genes 2021, 12(9), 1405; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091405 - 11 Sep 2021
Cited by 5 | Viewed by 2087
Abstract
The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both de novo and inherited, have been described. Due to [...] Read more.
The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both de novo and inherited, have been described. Due to impaired reproductive fitness, especially of syndromic CDH patients, and still significant mortality rates, the contribution of de novo variants to the genetic background of CDH is assumed to be high. This assumption is supported by the relatively low recurrence rate among siblings. Advantages in high-throughput genome-wide genotyping and sequencing methods have recently facilitated the detection of de novo variants in CDH. This review gives an overview of the known de novo disease-causing variants in CDH patients. Full article
(This article belongs to the Special Issue De novo Mutations and the Lack of Heritability in Birth Defects)
8 pages, 553 KiB  
Review
The Role of De Novo Variants in Formation of Human Anorectal Malformations
by Gabriel C. Dworschak, Iris A. L. M. van Rooij and Heiko M. Reutter
Genes 2021, 12(9), 1298; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091298 - 24 Aug 2021
Cited by 1 | Viewed by 2023
Abstract
Anorectal malformations (ARM) represent a rare birth defect of the hindgut that occur in approximately 1 in 3000 live births. Around 60% of ARM occur with associated anomalies including defined genetic syndromes and associations with chromosomal aberrations. The etiology of ARM is heterogeneous, [...] Read more.
Anorectal malformations (ARM) represent a rare birth defect of the hindgut that occur in approximately 1 in 3000 live births. Around 60% of ARM occur with associated anomalies including defined genetic syndromes and associations with chromosomal aberrations. The etiology of ARM is heterogeneous, with the individual environmental or genetic risk factors remaining unknown for the majority of cases. The occurrence of familial ARM and previous epidemiologic analysis suggest autosomal dominant inheritance in a substantial subset of ARM patients. The implicated mortality and reduced fecundity in patients with ARM would lead to allele loss. However, mutational de novo events among the affected individuals could compensate for the evolutionary pressure. With the implementation of exome sequencing, array-based molecular karyotyping and family-based rare variant analyses, the technologies are available to identify the respective factors. This review discusses the identification of disease-causing variants among individuals with ARM. It highlights the role of mutational de novo events. Full article
(This article belongs to the Special Issue De novo Mutations and the Lack of Heritability in Birth Defects)
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12 pages, 503 KiB  
Review
The Genomic Architecture of Bladder Exstrophy Epispadias Complex
by Glenda M. Beaman, Raimondo M. Cervellione, David Keene, Heiko Reutter and William G. Newman
Genes 2021, 12(8), 1149; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081149 - 28 Jul 2021
Cited by 5 | Viewed by 4346
Abstract
The bladder exstrophy–epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this [...] Read more.
The bladder exstrophy–epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this malformation is still unknown. This review presents the current knowledge on this multifactorial disorder, including phenotypic and anatomical characterization, epidemiology, proposed developmental mechanisms, existing animal models, and implicated genetic and environmental components. Full article
(This article belongs to the Special Issue De novo Mutations and the Lack of Heritability in Birth Defects)
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