scholarly journals The Role of De Novo Variants in Formation of Human Anorectal Malformations

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1298
Author(s):  
Gabriel C. Dworschak ◽  
Iris A. L. M. van Rooij ◽  
Heiko M. Reutter
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Anorectal Malformations ◽  
Molecular Karyotyping ◽  
Associated Anomalies ◽  
Dominant Inheritance ◽  
Genetic Syndromes ◽  
Family Based ◽  
The Individual

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.

scholarly journals Effective variant filtering and expected candidate variant yield in studies of rare human disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Brent S. Pedersen ◽  
Joe M. Brown ◽  
Harriet Dashnow ◽  
Amelia D. Wallace ◽  
Matt Velinder ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Genome Sequencing ◽  
Autosomal Dominant ◽  
De Novo ◽  
Autosomal Dominant Inheritance ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Dominant Inheritance ◽  
Family Based

AbstractIn studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

scholarly journals Cystatin M/E Variant Causes Autosomal Dominant Keratosis Follicularis Spinulosa Decalvans by Dysregulating Cathepsins L and V

2021 ◽  
Vol 12 ◽  
Author(s):  
Katja M. Eckl ◽  
Robert Gruber ◽  
Louise Brennan ◽  
Andrew Marriott ◽  
Roswitha Plank ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Regulatory Element ◽  
Index Patient ◽  
Hair Shaft ◽  
Epidermal Differentiation ◽  
Cysteine Protease Inhibitor ◽  
Dominant Inheritance ◽  
Keratosis Follicularis ◽  
Cystatin M

Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing X-linked KFSD have been described in MBTPS2, the gene for a membrane-bound zinc metalloprotease that is involved in the cleavage of sterol regulatory element binding proteins important for the control of transcription. Few families have been identified with an autosomal dominant inheritance of KFSD. We present two members of an Austrian family with a phenotype of KFSD, a mother and her son. The disease was not observed in her parents, pointing to a dominant inheritance with a de novo mutation in the index patient. Using whole-exome sequencing, we identified a heterozygous missense variant in CST6 in DNA samples from the index patient and her affected son. In line with family history, the variant was not present in samples from her parents. CST6 codes for cystatin M/E, a cysteine protease inhibitor. Patient keratinocytes showed increased expression of cathepsin genes CTSL and CTSV and reduced expression of transglutaminase genes TGM1 and TGM3. A relative gain of active, cleaved transglutaminases was found in patient keratinocytes compared to control cells. The variant found in CST6 is expected to affect protein targeting and results in marked disruption of the balance between cystatin M/E activity and its target proteases and eventually transglutaminases 1 and 3. This disturbance leads to an impairment of terminal epidermal differentiation and proper hair shaft formation seen in KFSD.

scholarly journals Parental segregation study reveals rare benign and likely benign variants in a Brazilian cohort of rare diseases

2021 ◽  
Author(s):  
Caio Robledo Quaio ◽  
Jose Ricardo Magliocco Ceroni ◽  
Murilo Castro Cervato ◽  
Helena Strelow Thurow ◽  
Caroline Monaco Moreira ◽  
...  
Keyword(s):  
Rare Diseases ◽  
Segregation Analysis ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
De Novo ◽  
Molecular Data ◽  
Autosomal Dominant Inheritance ◽  
Dominant Inheritance ◽  
Pathogenic Variants ◽  
Genomic Studies

Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance. In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases. This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a “de novo” event was expected. Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign (n=51) and 211 as likely benign (n=211). In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.

CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

2013 ◽  
Vol 16 (4) ◽  
pp. 802-807 ◽  
Author(s):  
Friederike Baudisch ◽  
Markus Draaken ◽  
Enrika Bartels ◽  
Eberhard Schmiedeke ◽  
Soyhan Bagci ◽  
...  
Keyword(s):  
De Novo ◽  
Bladder Exstrophy ◽  
Anorectal Malformations ◽  
Monozygotic Twin ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Molecular Karyotyping ◽  
Genetic Changes ◽  
Coding Regions ◽  
Whole Exome

Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.

Ultrasound prenatal diagnosis of a de novo 14q distal duplication associated with foetal anomalies: a case report

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Anna Garofalo ◽  
Mariano Lanna ◽  
Luisa Ronzoni ◽  
Valentina Toto ◽  
Giana Izzo ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
De Novo ◽  
Partial Trisomy ◽  
Chromosome Analysis ◽  
Clinical Findings ◽  
Molecular Techniques ◽  
Molecular Karyotyping ◽  
Genetic Syndromes ◽  
Agenesis Of Corpus Callosum ◽  
Magnetic Resonance Imaging Mri

AbstractObjectivesPartial trisomy 14q is a rare chromosomal abnormality with an extremely variable phenotype ranging from mild to severe forms of malformation. Most of the cases described in literature are postnatal clinical findings although few prenatal cases have been reported.Case presentationA 33-year-old woman at 21+6 weeks’ gestation was referred to our hospital for a detailed foetal ultrasound with suspected partial agenesis of corpus callosum and ureterocele. On examination, we found a short corpus callosum and ureterocele with a duplicated right renal collecting system. Moreover, there was an intrarotation of left foot with a prominent part departing from the ankle, both thighs appeared thicker, a thickening of the nuchal fold, a mild hypertelorism and a thick heterogeneous placenta. The patient underwent magnetic resonance imaging (MRI), which confirmed the foetal anomalies. The couple opted for a termination of pregnancy. Chromosome analysis and molecular karyotyping of amniocytes revealed a de novo rearrangement of chromosome 14 with an interstitial gain 14q31.1–14q32.22 and a terminal deletion 14q32.33.ConclusionsThe majority of partial trisomy 14q reporter are postnatal diagnoses. Improvement in the quality of foetal imaging and molecular techniques have made possible to identify many genetic syndromes prenatally. In our opinion, anomalies of the brain, urinary system and limbs may be the core findings of trisomy 14q. To our knowledge, no such case has ever been described previously.

scholarly journals ExACtly zero or once

2017 ◽  
Vol 3 (4) ◽  
pp. e163 ◽  
Author(s):  
Caitlin A. Bennett ◽  
Slavé Petrovski ◽  
Karen L. Oliver ◽  
Samuel F. Berkovic
Keyword(s):  
General Population ◽  
Autosomal Dominant ◽  
De Novo ◽  
Clinical Role ◽  
Variants Of Unknown Significance ◽  
Neurologic Disorders ◽  
Exome Aggregation Consortium ◽  
Unknown Significance ◽  
Strong Segregation

Objective:To assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population.Methods:We studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or ≥4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 individuals. We subsequently evaluated variants in these epilepsy genes that lacked strong segregation support. To determine whether the findings in epilepsies were representative of other diseases, we also assessed the presence of variants in other dominant neurologic disorders (e.g., CADASIL).Results:Published epilepsy variants with strong segregation support (n = 65) were absent (n = 61) or present once (n = 4) in ExAC. By contrast, of 46 published epilepsy variants without strong segregation support, 8 occurred recurrently (2–186 times). Similarly, none of the 45 disease-associated variants from other neurologic disorders with strong segregation support occurred more than once in ExAC. Reanalysis using the larger ExAC V2 plus gnomAD reference cohort showed consistent results.Conclusions:Variants causing autosomal dominant epilepsies are ultra-rare in the general population. Variants observed more than once in ExAC were only found among reports without strong segregation support, suggesting that they may be benign. Clinicians are increasingly faced with the interpretation of genetic variants of unknown significance. These data illustrate that variants present more than once in ExAC are less likely to be pathogenic, reinforcing the valuable clinical role of ExAC.

scholarly journals Parental Segregation Study Reveals Rare Benign and Likely Benign Variants in a Brazilian Cohort of Rare Diseases

2021 ◽  
Author(s):  
Caio Robledo D' Angioli Costa Quaio ◽  
Jose Ricardo Magliocco Ceroni ◽  
Murilo Castro Cervato ◽  
Helena Strelow Thurow ◽  
Caroline Monaco Moreira ◽  
...  
Keyword(s):  
Segregation Analysis ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
De Novo ◽  
Molecular Data ◽  
Autosomal Dominant Inheritance ◽  
Dominant Inheritance ◽  
Pathogenic Variants ◽  
Genomic Studies ◽  
Pattern Determination

Abstract Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance.In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases.This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a “de novo” event was expected.Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign (n=51) and 211 as likely benign (n=211).In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.

scholarly journals Genetic testing for Emberger syndrome

2018 ◽  
Vol 2 (s1) ◽  
pp. 19-21
Author(s):  
Yeltay Rakhmanov ◽  
Paolo Enrico Maltese ◽  
Stefano Paolacci ◽  
Alice Bruson ◽  
Matteo Bertelli
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Genetic Test ◽  
Genetic Disorder ◽  
Incomplete Penetrance ◽  
Dominant Inheritance ◽  
Test Protocol ◽  
Primary Lymphedema ◽  
Research Findings ◽  
Sporadic Cases

Abstract Emberger Syndrome (ES) is a very rare genetic disorder associated with primary lymphedema, myelodysplasia and immunodeficiency. The syndrome has autosomal dominant inheritance with incomplete penetrance. Sporadic cases caused by de novo germinal mutations in the GATA2 gene have also been described. We developed the test protocol on the basis of the latest research findings and diagnostic protocols on lymphatic malformation in ES. The genetic test is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

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