Wiedemann-Steiner syndrome with a novel pathogenic variant in KMT2A: a case report

Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.

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Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden IQSEC2 Pathogenic Variant in a Child with Intellectual Disability

Cytogenetic and Genome Research ◽

10.1159/000515368 ◽

2021 ◽

pp. 1-7

Author(s):

Tuğba Karaman Mercan ◽

Ozden Altiok Clark ◽

Ozgur Erkal ◽

Banu Nur ◽

Ercan Mihci ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Array Cgh ◽

De Novo ◽

Homozygous Deletion ◽

Clinical Findings ◽

Chromosome 4 ◽

Heterozygous Deletion ◽

Whole Exome

Terminal deletions in the long arm of chromosome 4 are an uncommon event, with a worldwide incidence of approximately 0.001%. The majority of these deletions occur de novo. Terminal deletion cases are usually accompanied by clinical findings that include facial and cardiac anomalies, as well as intellectual disability. In this study, we describe the case of a 2-year-old girl, the fourth child born to consanguineous parents. While her karyotype was normal, a homozygous deletion was identified in the chromosome 4q35.2 region by subtelomeric FISH. A heterozygous deletion of the chromosome 4q35.2 region was observed in both parents. According to the literature, this is the first report of a case that has inherited a homozygous deletion of chromosome 4qter from carrier parents. Subsequent array-CGH analyses were performed on both the case and her parents. Whole-exome sequencing was also carried out to determine potential variants. We detected a NM_001111125.3:c.2329G>T (p.Glu777Ter) nonsense variant of the <i>IQSEC2</i> gene in the girl, a variant that is related to X-linked intellectual disability.

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Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype–phenotype correlations in the Chinese population

Bioscience Reports ◽

10.1042/bsr20203356 ◽

2020 ◽

Vol 40 (12) ◽

Author(s):

Yuduo Wu ◽

Hairui Sun ◽

Jianbin Wang ◽

Xin Wang ◽

Ming Gong ◽

...

Keyword(s):

Exome Sequencing ◽

Marfan Syndrome ◽

Whole Exome Sequencing ◽

Chinese Population ◽

De Novo ◽

Low Frequency ◽

Monogenic Disease ◽

De Novo Mutations ◽

Fbn1 Gene ◽

Whole Exome

Abstract Marfan syndrome (MFS) is a dominant monogenic disease caused by mutations in fibrillin 1 (FBN1). Cardiovascular complications are the leading causes of mortality among MFS. In the present study, a whole-exome sequencing of MFS in the Chinese population was conducted to investigate the correlation between FBNI gene mutation and MFS. Forty-four low-frequency harmful loci were identified for the FBN1 gene in HGMD database. In addition, 38 loci were identified in the same database that have not been related to MFS before. A strict filtering and screening protocol revealed two patients of the studied group have double mutations in the FBN1 gene. The two patients harboring the double mutations expressed a prominent, highly pathological phenotype in the affected family. In addition to the FBN1 gene, we also found that 27 patients had mutations in the PKD1 gene, however these patients did not have kidney disease, and 16 of the 27 patients expressed aortic related complications. Genotype-phenotype analysis showed that patients with aortic complications are older in the family, aged between 20 and 40 years.

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Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

Pediatric Research ◽

10.1038/s41390-021-01509-3 ◽

2021 ◽

Author(s):

Adam L. Numis ◽

Gilberto da Gente ◽

Elliott H. Sherr ◽

Hannah C. Glass

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

List Type ◽

Sequencing Analysis ◽

Neonatal Seizures ◽

Pathogenic Variants ◽

Targeted Analysis ◽

Whole Exome ◽

Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

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Analysis workflow to assess de novo genetic variants from human whole-exome sequencing

STAR Protocols ◽

10.1016/j.xpro.2021.100383 ◽

2021 ◽

Vol 2 (1) ◽

pp. 100383

Author(s):

Nicholas S. Diab ◽

Spencer King ◽

Weilai Dong ◽

Garrett Allington ◽

Amar Sheth ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

De Novo ◽

Whole Exome ◽

Analysis Workflow

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Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes

Genes ◽

10.3390/genes12010065 ◽

2021 ◽

Vol 12 (1) ◽

pp. 65

Author(s):

Patricia Haug ◽

Samuel Koller ◽

Jordi Maggi ◽

Elena Lang ◽

Silke Feil ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Screening ◽

De Novo ◽

Efficient Tool ◽

Sequencing Technologies ◽

Whole Exome ◽

Screening And Identification ◽

High Throughput Dna Sequencing ◽

New Mutations

Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M.

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Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab253 ◽

2021 ◽

Author(s):

Bixia Zheng ◽

Steve Seltzsam ◽

Chunyan Wang ◽

Luca Schierbaum ◽

Sophia Schneider ◽

...

Keyword(s):

Urinary Tract ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Congenital Anomalies ◽

De Novo ◽

Horseshoe Kidney ◽

Missense Variant ◽

Whole Exome ◽

Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

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Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2

European Journal of Orthodontics ◽

10.1093/ejo/cjaa023 ◽

2020 ◽

Author(s):

Piranit Nik Kantaputra ◽

Prapai Dejkhamron ◽

Worrachet Intachai ◽

Chumpol Ngamphiw ◽

Katsushige Kawasaki ◽

...

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Upper Limb ◽

Autosomal Recessive ◽

Cleft Lip ◽

Clinical Findings ◽

Protein Model ◽

Whole Exome ◽

Cleft Lip Palate

Summary Background Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. Objective To report for the first time the molecular aetiology of JHS. Patient and methods Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed. Results Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect. Conclusions Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.

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