Α de novo 3.8-Mb inversion affecting the EDA and XIST genes in a heterozygous female calf with generalized hypohidrotic ectodermal dysplasia

Abstract Background In mammals, hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that is characterized by sparse hair, tooth abnormalities, and defects in cutaneous glands. Only four genes, EDA, EDAR, EDARADD and WNT10A account for more than 90% of HED cases, and EDA, on chromosome X, is involved in 50% of the cases. In this study, we explored an isolated case of a female Holstein calf with symptoms similar to HED. Results Clinical examination confirmed the diagnosis. The affected female showed homogeneous hypotrichosis and oligodontia as previously observed in bovine EDAR homozygous and EDA hemizygous mutants. Under light microscopy, the hair follicles were thinner and located higher in the dermis of the frontal skin in the affected animal than in the control. Moreover, the affected animal showed a five-fold increase in the number of hair follicles and a four-fold decrease in the diameter of the pilary canals. Pedigree analysis revealed that the coefficient of inbreeding of the affected calf (4.58%) was not higher than the average population inbreeding coefficient (4.59%). This animal had ten ancestors in its paternal and maternal lineages. By estimating the number of affected cases that would be expected if any of these common ancestors carried a recessive mutation, we concluded that, if they existed, other cases of HED should have been reported in France, which is not the case. Therefore, we assumed that the causal mutation was dominant and de novo. By analyzing whole-genome sequencing data, we identified a large chromosomal inversion with breakpoints located in the first introns of the EDA and XIST genes. Genotyping by PCR-electrophoresis the case and its parents allowed us to demonstrate the de novo origin of this inversion. Finally, using various sources of information we present a body of evidence that supports the hypothesis that this mutation is responsible for a skewed inactivation of X, and that only the normal X can be inactivated. Conclusions In this article, we report a unique case of X-linked HED affected Holstein female calf with an assumed full inactivation of the normal X-chromosome, thus leading to a severe phenotype similar to that of hemizygous males.

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First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant?

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01078-5 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Mario Tumminello ◽

Antonella Gangemi ◽

Federico Matina ◽

Melania Guardino ◽

Bianca Lea Giuffrè ◽

...

Keyword(s):

Ectodermal Dysplasia ◽

Genetic Disorder ◽

Missense Variant ◽

Pathogenic Variant ◽

Hypohidrotic Ectodermal Dysplasia ◽

Variant Of Uncertain Significance ◽

Uncertain Significance ◽

Clinical Potential ◽

Genomic Variant ◽

Eda Gene

Abstract Background Hypohidrotic Ectodermal Dysplasia (HED) is a genetic disorder which affects structures of ectodermal origin. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of disease. XLHED is characterized by hypotrichosis, hypohydrosis and hypodontia. The cardinal features of classic HED become obvious during childhood. Identification of a hemizygous EDA pathogenic variant in an affected male confirms the diagnosis. Case presentation We report on a male newborn with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. Gene panel sequencing identified a new hemizygous missense variant of uncertain significance (VUS) c.1142G > C (p.Gly381Ala) in the EDA gene, located on the X chromosome and inherited from the healthy mother. Conclusion Despite the potential functional impact of VUS remains uncharacterized, our goal is to evaluate the clinical potential consequences of missense VUS on EDA gene. Even if the proband’s phenotype is characteristic for classic HED, further reports of patients with same clinical phenotype and the same genomic variant are needed to consider this novel VUS as responsible for the development of HED.

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Norgal: extraction and de novo assembly of mitochondrial DNA from whole-genome sequencing data

BMC Bioinformatics ◽

10.1186/s12859-017-1927-y ◽

2017 ◽

Vol 18 (1) ◽

Cited By ~ 21

Author(s):

Kosai Al-Nakeeb ◽

Thomas Nordahl Petersen ◽

Thomas Sicheritz-Pontén

Keyword(s):

Mitochondrial Dna ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

De Novo Assembly ◽

De Novo ◽

Whole Genome Sequencing Data ◽

Whole Genome ◽

Sequencing Data

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X-Linked Hypohidrotic Ectodermal Dysplasia in Crossbred Beef Cattle Due to a Large Deletion in EDA

Animals ◽

10.3390/ani11030657 ◽

2021 ◽

Vol 11 (3) ◽

pp. 657 ◽

Cited By ~ 1

Author(s):

Donal O’Toole ◽

Irene M. Häfliger ◽

Fabienne Leuthard ◽

Brant Schumaker ◽

Lynn Steadman ◽

...

Keyword(s):

Ectodermal Dysplasia ◽

Severe Pneumonia ◽

Large Deletion ◽

Hair Follicles ◽

Enamel Organ ◽

Hypohidrotic Ectodermal Dysplasia ◽

Mandibular Incisor ◽

Base Pair Deletion ◽

Red Angus ◽

Mucosal Glands

X-linked hypohidrotic ectodermal dysplasia-1 (ECTD1) in people results in a spectrum of abnormalities, most importantly hypotrichosis, anodontia/oligodontia, and absent or defective ectodermally derived glands. Five Red Angus-Simmental calves born over a 6-year period demonstrated severe hypotrichosis and were diagnosed as affected with ECTD1-like syndrome. Two died of severe pneumonia within a week of birth. The skin of three affected calves revealed a predominance of histologically unremarkable small-caliber hair follicles. Larger follicles (>50 µm) containing medullated hairs (including guard and tactile hairs) were largely restricted to the muzzle, chin, tail, eyelids, tragus and distal portions of the limbs and tail. The mean histological density of hair follicles in flank skin of two affected calves was slightly greater than that in two unaffected calves. One affected calf was examined postmortem at 10 days of age to better characterize systemic lesions. Nasolabial, intranasal and tracheobronchial mucosal glands were absent, whereas olfactory glands were unaffected. Mandibular incisor teeth were absent. Premolar teeth were unerupted and widely spaced. Other than oligodontia, histological changes in teeth were modest, featuring multifocal disorganization of ameloblasts, new bone formation in dental alveoli, and small aggregates of osteodentin and cementum at the margins of the enamel organ. A 52,780 base pair deletion spanning six out of eight coding exons of EDA and all of AWAT2 was identified. Partial deletion of the EDA gene is the presumed basis for the reported X-chromosomal recessive inherited genodermatosis.

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A de novo frameshift mutation in ZEB2 causes polledness, abnormal skull shape, small body stature and subfertility in Fleckvieh cattle

Scientific Reports ◽

10.1038/s41598-020-73807-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Lilian J. Gehrke ◽

Maulik Upadhyay ◽

Kristin Heidrich ◽

Elisabeth Kunz ◽

Daniela Klaus-Halla ◽

...

Keyword(s):

De Novo ◽

Small Body ◽

Protein Product ◽

Whole Genome Sequencing Data ◽

Chromosome 2 ◽

Sequencing Data ◽

Autosomal Dominant Trait ◽

Intergenic Regions ◽

Body Stature ◽

Growth Of Animals

Abstract Polledness in cattle is an autosomal dominant trait. Previous studies have revealed allelic heterogeneity at the polled locus and four different variants were identified, all in intergenic regions. In this study, we report a case of polled bull (FV-Polled1) born to horned parents, indicating a de novo origin of this polled condition. Using 50K genotyping and whole genome sequencing data, we identified on chromosome 2 an 11-bp deletion (AC_000159.1:g.52364063_52364073del; Del11) in the second exon of ZEB2 gene as the causal mutation for this de novo polled condition. We predicted that the deletion would shorten the protein product of ZEB2 by almost 91%. Moreover, we showed that all animals carrying Del11 mutation displayed symptoms similar to Mowat-Wilson syndrome (MWS) in humans, which is also associated with genetic variations in ZEB2. The symptoms in cattle include delayed maturity, small body stature and abnormal shape of skull. This is the first report of a de novo dominant mutation affecting only ZEB2 and associated with a genetic absence of horns. Therefore our results demonstrate undoubtedly that ZEB2 plays an important role in the process of horn ontogenesis as well as in the regulation of overall development and growth of animals.

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A novel de novo frame-shift mutation of the EDA gene in a Chinese Han family with hypohidrotic ectodermal dysplasia

Journal of Human Genetics ◽

10.1007/s10038-006-0071-8 ◽

2006 ◽

Vol 51 (12) ◽

pp. 1133-1137 ◽

Cited By ~ 20

Author(s):

Changzheng Huang ◽

Qinbo Yang ◽

Tie Ke ◽

Haisheng Wang ◽

Xu Wang ◽

...

Keyword(s):

Ectodermal Dysplasia ◽

De Novo ◽

Hypohidrotic Ectodermal Dysplasia ◽

Chinese Han ◽

Frame Shift ◽

Frame Shift Mutation ◽

Eda Gene

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Severe hypohidrotic ectodermal dysplasia in a girl caused by a de novo 9;X insertion that includesXIST and disrupts theEDA gene

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.31797 ◽

2007 ◽

Vol 143A (13) ◽

pp. 1510-1513 ◽

Cited By ~ 7

Author(s):

Karen Helene Ørstavik ◽

Gun Peggy S. Knudsen ◽

Hilde Nordgarden ◽

Eli Ormerod ◽

Petter Strømme ◽

...

Keyword(s):

Ectodermal Dysplasia ◽

De Novo ◽

Hypohidrotic Ectodermal Dysplasia

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De novo indels within introns contribute to ASD incidence

10.1101/137471 ◽

2017 ◽

Cited By ~ 2

Author(s):

Adriana Munoz ◽

Boris Yamrom ◽

Yoon-ha Lee ◽

Peter Andrews ◽

Steven Marks ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Target Genes ◽

De Novo ◽

Whole Genome Sequencing Data ◽

P Value ◽

Whole Genome ◽

Sequencing Data ◽

Control Sets ◽

The Difference

AbstractCopy number profiling and whole-exome sequencing has allowed us to make remarkable progress in our understanding of the genetics of autism over the past ten years, but there are major aspects of the genetics that are unresolved. Through whole-genome sequencing, additional types of genetic variants can be observed. These variants are abundant and to know which are functional is challenging. We have analyzed whole-genome sequencing data from 510 of the Simons Simplex Collections quad families and focused our attention on intronic variants. Within the introns of 546 high-quality autism target genes, we identified 63 de novo indels in the affected and only 37 in the unaffected siblings. The difference of 26 events is significantly larger than expected (p-val = 0.01) and using reasonable extrapolation shows that de novo intronic indels can contribute to at least 10% of simplex autism. The significance increases if we restrict to the half of the autism targets that are intolerant to damaging variants in the normal human population, which half we expect to be even more enriched for autism genes. For these 273 targets we observe 43 and 20 events in affected and unaffected siblings, respectively (p-value of 0.005). There was no significant signal in the number of de novo intronic indels in any of the control sets of genes analyzed. We see no signal from de novo substitutions in the introns of target genes.

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Increased risk of chronic fatigue and hair loss following COVID-19 in individuals with hypohidrotic ectodermal dysplasia

10.21203/rs.3.rs-529105/v1 ◽

2021 ◽

Author(s):

Verena Hennig ◽

Wolfgang Schuh ◽

Antje Neubert ◽

Dirk Mielenz ◽

Hans-Martin Jäck ◽

...

Keyword(s):

Hair Loss ◽

Ectodermal Dysplasia ◽

Genetic Disorder ◽

Control Group ◽

Hypohidrotic Ectodermal Dysplasia ◽

Control Subjects ◽

Eccrine Glands ◽

Increased Risk ◽

Long Term Consequences

Abstract Background Hypohidrotic ectodermal dysplasia (HED) is a group of genodermatoses in which deficient ectodysplasin A signalling leads to maldevelopment of skin appendages, various eccrine glands, and teeth. Individuals with HED often have disrupted epithelial barriers and, therefore, were suspected to be more susceptible to coronavirus infection. Methods 56 households with at least one member who had coronavirus disease of 2019 (COVID-19) were enrolled in a longitudinal study to compare the course of illness, immune responses, and long-term consequences of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection in HED patients (n = 15, age 9–52 years) and control subjects of the same age group (n = 149). Results In 14 HED patients, mild or moderate typical COVID-19 symptoms were observed that lasted for 4–45 days. Fever during the first days sometimes required external cooling measures. The course of COVID-19 was similar to that in control subjects if patients developed antibodies blocking the SARS-CoV-2 spike protein. Five out of six HED patients with completely abrogated ectodysplasin A signalling (83%) suffered from chronic, in two cases very severe fatigue following COVID-19, while only 25% of HED patients with residual activity of this pathway and 21% of control subjects recovering from COVID-19 experienced postinfectious fatigue. Hair loss after COVID-19 was also more frequent among HED patients (64%) than in the control group (13%). Conclusions HED appears to be associated with an increased risk of long-term consequences of a SARS-CoV-2 infection. Preventive vaccination against COVID-19 should be recommended for individuals affected by this rare genetic disorder.

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Leaf form diversification in an heirloom tomato results from alterations in two different HOMEOBOX genes

10.1101/2020.09.08.287011 ◽

2020 ◽

Author(s):

Hokuto Nakayama ◽

Steven D. Rowland ◽

Zizhang Cheng ◽

Kristina Zumstein ◽

Julie Kang ◽

...

Keyword(s):

Gene Network ◽

Natural Variation ◽

De Novo ◽

Whole Genome Sequencing Data ◽

Phenotypic Traits ◽

Comparative Genome Analysis ◽

Sequencing Data ◽

Single Nucleotide ◽

Leaf Phenotype ◽

Gene Network Analysis

AbstractDomesticated plants and animals display tremendous diversity in various phenotypic traits and often this diversity is seen within the same species. Tomato (Solanum lycopersicum; Solanaceae) cultivars show wide variation in leaf morphology, but the influence of breeding efforts in sculpting this diversity is not known. Here, we demonstrate that a single nucleotide deletion in the homeobox motif of BIPINNATA, which is a BEL-LIKE HOMEODOMAIN gene, led to a highly complex leaf phenotype in an heirloom tomato, Silvery Fir Tree (SiFT). Additionally, a comparative gene network analysis revealed that reduced expression of the ortholog of WUSCHEL RELATED HOMEOBOX 1 is also important for the narrow leaflet phenotype seen in SiFT. Phylogenetic and comparative genome analysis using whole-genome sequencing data suggests that the bip mutation in SiFT is likely a de novo mutation, instead of standing genetic variation. These results provide new insights into natural variation in phenotypic traits introduced into crops during improvement processes after domestication.

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