scholarly journals Prenatal diagnosis of auriculocondylar syndrome with a novel missense variant of GNAI3: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoliang Liu ◽  
Wei Sun ◽  
Jun Wang ◽  
Guoming Chu ◽  
Rong He ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Diagnosis ◽  
Mandibular Condyle ◽  
Missense Variant ◽  
Mandibular Hypoplasia ◽  
Pathogenic Variants ◽  
Binding Function ◽  
Whole Exome ◽  
The Face ◽  
Guanine Nucleotide Binding

Abstract Background Auriculocondylar syndrome (ACS) is a rare disorder characterized by micrognathia, mandibular condyle hypoplasia, and auricular abnormalities. Only 6 pathogenic variants of GNAI3 have been identified associated with ACS so far. Here, we report a case of prenatal genetic diagnosis of ACS carrying a novel GNAI3 variant. Case presentation A woman with 30 weeks of gestation was referred to genetic counseling for polyhydramnios and fetal craniofacial anomaly. Severe micrognathia and mandibular hypoplasia were identified on ultrasonography. The mandibular length was 2.4 cm, which was markedly smaller than the 95th percentile. The ears were low-set with no cleft or notching between the lobe and helix. The face was round with prominent cheeks. Whole-exome sequencing identified a novel de novo missense variant of c.140G > A in the GNAI3 gene. This mutation caused an amino acid substitution of p.Ser47Asn in the highly conserved G1 motif, which was predicted to impair the guanine nucleotide-binding function. All ACS cases with GNAI3 mutations were literature reviewed, revealing female-dominated severe cases and right-side-prone deformities. Conclusion Severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios are prenatal indicators of ACS. We expanded the mutation spectrum of GNAI3 and summarized clinical features to promote awareness of ACS.

scholarly journals Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Yoshitaka Hiromoto ◽  
Yoshiteru Azuma ◽  
Yuichi Suzuki ◽  
Megumi Hoshina ◽  
Yuri Uchiyama ◽  
...  
Keyword(s):  
De Novo ◽  
Missense Variant ◽  
West Syndrome ◽  
Periventricular Nodular Heterotopia ◽  
Psychomotor Delay ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Epileptic Patients ◽  
Nodular Heterotopia ◽  
Refractory Seizures

AbstractPathogenic FLNA variants can be identified in patients with seizures accompanied by periventricular nodular heterotopia (PVNH). It is unusual to find FLNA aberrations in epileptic patients without PVNH on brain imaging. We report a boy with cryptogenic West syndrome followed by refractory seizures and psychomotor delay. We performed whole-exome sequencing and identified a de novo missense variant in FLNA. It is noteworthy that this patient showed no PVNH. As no other pathogenic variants were found in epilepsy-related genes, this FLNA variant likely caused West syndrome but with no PVNH.

scholarly journals Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita

2021 ◽  
pp. jmedgenet-2020-107595
Author(s):  
Annie Laquerriere ◽  
Dana Jaber ◽  
Emanuela Abiusi ◽  
Jérome Maluenda ◽  
Dan Mejlachowicz ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Added Value ◽  
Disease Genes ◽  
Arthrogryposis Multiplex Congenita ◽  
Pathogenic Variants ◽  
New Genes ◽  
Whole Exome ◽  
Disease Loci

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

scholarly journals Identification of a Novel Variant of ARHGAP29 in a Chinese Family with Nonsyndromic Cleft Lip and Palate

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Jian-Xia Tang ◽  
Xiang-Shui Xiao ◽  
Kai Wang ◽  
Jie-Yuan Jin ◽  
Liang-Liang Fan ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variant ◽  
Development Methods

Background. Cleft lip with or without cleft palate (CL/P) is the most common facial birth defect, with a worldwide incidence of 1 in 700-1000 live births. CL/P can be divided into syndromic CL/P (SCL/P) and nonsyndromic CL/P (NSCL/P). Genetic factors are an important component to the etiology of NSCL/P. ARHGAP29, one of the NSCL/P disease-causing genes, mediates the cyclical regulation of small GTP binding proteins such as RhoA and plays an essential role in cellular shape, proliferation, and craniofacial development. Methods. The present study investigated a Chinese family with NSCL/P and explored potential pathogenic variants using whole-exome sequencing (WES). Variants were screened and filtered through bioinformatic analysis and prediction of variant pathogenicity. Cosegregation was subsequently conducted. Results. We identified a novel heterozygous missense variant of ARHGAP29 (c.2615C > T, p.A872V) in a Chinese pedigree with NSCL/P. Conclusion. We detected the disease-causing variant in this NSCL/P family. Our identification expands the genetic spectrum of ARHGAP29 and contributes to novel approaches to the genetic diagnosis and counseling of CL/P families.

scholarly journals Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Do Hyeon Cha ◽  
Heon Yung Gee ◽  
Raul Cachau ◽  
Jong Mun Choi ◽  
Daeui Park ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Kidney Injury ◽  
Genetic Identification ◽  
Diagnostic Screening ◽  
Renal Hypouricemia ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Causal Variants ◽  
Coding Variants ◽  
Independent Cohort

Abstract Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

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

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.

scholarly journals A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Giada Moresco ◽  
Jole Costanza ◽  
Carlo Santaniello ◽  
Ornella Rondinone ◽  
Federico Grilli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Signs ◽  
Missense Variant ◽  
Psychomotor Development ◽  
Helicase Domain ◽  
Protein Activity ◽  
Mrna Metabolism ◽  
Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

scholarly journals A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Chang Bao Xu ◽  
Xu Dong Zhou ◽  
Hong En Xu ◽  
Yong Li Zhao ◽  
Xing Hua Zhao ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Reference Genome ◽  
Genetic Diagnosis ◽  
Primary Hyperoxaluria ◽  
Missense Variant ◽  
Population Heterogeneity ◽  
Chinese Family ◽  
Pathogenic Variants ◽  
Variation Database ◽  
Genetic Level

Abstract Background Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. Case presentation In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband’s mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. Conclusions Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

scholarly journals Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

2020 ◽  
Vol 28 (12) ◽  
pp. 1763-1768
Author(s):  
Thomas Bourinaris ◽  
◽  
Damian Smedley ◽  
Valentina Cipriani ◽  
Isabella Sheikh ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
De Novo ◽  
Age At Onset ◽  
Genetic Diagnosis ◽  
Spastic Paraplegia ◽  
Sequencing Data ◽  
Juvenile Form ◽  
Pathogenic Variants ◽  
Degenerative Disorders ◽  
Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

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

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.

scholarly journals Novel SCN5A and GPD1L Variants Identified in Two Unrelated Han-Chinese Patients With Clinically Suspected Brugada Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Meng Yuan ◽  
Yi Guo ◽  
Hong Xia ◽  
Hongbo Xu ◽  
Hao Deng ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Missense Variant ◽  
Han Chinese ◽  
Chinese Patients ◽  
Splicing Variant ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Gated Channel ◽  
Life Threatening ◽  
Glycerol 3 Phosphate Dehydrogenase

Brugada syndrome (BrS) is a complexly genetically patterned, rare, malignant, life-threatening arrhythmia disorder. It is autosomal dominant in most cases and characterized by identifiable electrocardiographic patterns, recurrent syncope, nocturnal agonal respiration, and other symptoms, including sudden cardiac death. Over the last 2 decades, a great number of variants have been identified in more than 36 pathogenic or susceptibility genes associated with BrS. The present study used the combined method of whole exome sequencing and Sanger sequencing to identify pathogenic variants in two unrelated Han-Chinese patients with clinically suspected BrS. Minigene splicing assay was used to evaluate the effects of the splicing variant. A novel heterozygous splicing variant c.2437-2A&gt;C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A&gt;T [p.(Asp54Val)] in the glycerol-3-phosphate dehydrogenase 1 like gene (GPD1L) were identified in these two patients with BrS-1 and possible BrS-2, respectively. Minigene splicing assay indicated the deletion of 15 and 141 nucleotides in exon 16, resulting in critical amino acid deletions. These findings expand the variant spectrum of SCN5A and GPD1L, which can be beneficial to genetic counseling and prenatal diagnosis.

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