scholarly journals When Familial Hearing Loss Means Genetic Heterogeneity: A Model Case Report

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1636
Author(s):  
Camille Cenni ◽  
Luke Mansard ◽  
Catherine Blanchet ◽  
David Baux ◽  
Christel Vaché ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Case Report ◽  
De Novo ◽  
Panel Analysis ◽  
Adult Onset ◽  
Childhood Onset ◽  
Model Case ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Neonatal Thrombocytopenia

We describe a family with both hearing loss (HL) and thrombocytopenia, caused by pathogenic variants in three genes. The proband was a child with neonatal thrombocytopenia, childhood-onset HL, hyper-laxity and severe myopia. The child’s mother (and some of her relatives) presented with moderate thrombocytopenia and adulthood-onset HL. The child’s father (and some of his relatives) presented with adult-onset HL. An HL panel analysis, completed by whole exome sequencing, was performed in this complex family. We identified three pathogenic variants in three different genes: MYH9, MYO7A and ACTG1. The thrombocytopenia in the child and her mother is explained by the MYH9 variant. The post-lingual HL in the paternal branch is explained by the MYO7A variant, absent in the proband, while the congenital HL of the child is explained by a de novo ACTG1 variant. This family, in which HL segregates, illustrates that multiple genetic conditions coexist in individuals and make patient care more complex than expected.

scholarly journals Case report: adult onset diabetes with partial pancreatic agenesis and congenital heart disease due to a de novo GATA6 mutation

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Begona Sanchez-Lechuga ◽  
Muhammad Saqlain ◽  
Nicholas Ng ◽  
Kevin Colclough ◽  
Conor Woods ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Case Report ◽  
Congenital Heart ◽  
De Novo ◽  
Adult Onset ◽  
Onset Diabetes ◽  
Adult Onset Diabetes ◽  
Pancreatic Agenesis

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.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

2021 ◽  
Author(s):  
J Fonseca ◽  
C Melo ◽  
C Ferreira ◽  
M Sampaio ◽  
R Sousa ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epileptic Encephalopathy ◽  
Btb Domain ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

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.

Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia

2019 ◽  
Vol 35 (2) ◽  
pp. 106-110 ◽  
Author(s):  
Andrea Accogli ◽  
Judith St-Onge ◽  
Nassima Addour-Boudrahem ◽  
Joël Lafond-Lapalme ◽  
Alexandre Dionne Laporte ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cerebellar Ataxia ◽  
De Novo ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Adult Onset ◽  
Spinocerebellar Ataxias ◽  
Spectrin Repeat ◽  
Missense Variants ◽  
Pathogenic Variants

The term spinocerebellar ataxia encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including SPTBN2 which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel de novo heterozygous pathogenic missense variant (c.1310G>A) in SPTBN2 in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.

scholarly journals New genes involved in Angelman syndrome-like: expanding the genetic spectrum

2020 ◽  
Author(s):  
Cinthia Aguilera ◽  
Elisabeth Gabau ◽  
Ariadna Ramirez-Mallafré ◽  
Carme Brun-Gasca ◽  
Jana Dominguez-Carral ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Genetic Heterogeneity ◽  
Angelman Syndrome ◽  
De Novo ◽  
System Development ◽  
Neuron System ◽  
Pathogenic Variants ◽  
New Genes ◽  
Whole Exome ◽  
Eeg Abnormalities

AbstractAngelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis. New AS-like genes do not interact directly with UBE3A gene product but are involved in synapsis and neuron system development.

scholarly journals A Comprehensive Review on Inherited Sensorineural Hearing Loss and Their Syndromes

2020 ◽  
Author(s):  
Muhammad Noman ◽  
Shazia Anwer Bukhari ◽  
Muhammad Tahir ◽  
Shehbaz Ali
Keyword(s):  
Hearing Loss ◽  
Hearing Impairment ◽  
Autosomal Dominant ◽  
Genetic Disorders ◽  
World Population ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Whole Exome ◽  
Specific Locus ◽  
Population Effects

Hearing impairment is an immensely diagnosed genetic cause, 5% of the total world population effects with different kind of congenital hearing loss (HL). In third-world countries or countries where consanguineous marriages are more common the frequency rate of genetic disorders are at its zenith. Approximately, the incidence of hearing afflictions is ostensibly 7-8:1000 individuals whereas it is estimated that about 466 million peoples suffer with significant HL, and of theses deaf cases 34 million are children’s up to March, 2020. Several genes and colossal numbers of pathogenic variants cause hearing impairment, which aided in next-generation with recessive, dominant or X-linked inheritance traits. This review highlights on syndromic and non-syndromic HL (SHL and NSHL), and categorized as conductive, sensorineural and mixed HL, which having autosomal dominant and recessive, and X-linked or mitochondrial mode of inheritance. Many hundred genes involved in HL are reported, and their mutation spectrum becomes very wide. Mapping of pathogenic genes in consanguinity family is facilitated to understand the disease history. Review presents the bases of HL and also focused on various genetic factors that cause deafness like the basics of genetic inheritance, and classic and well-characterized inherited factors of it. It also overviews the application of linkage analysis, SNPs genotyping and whole exome sequencing methods, in mapping and identification of new locus, causative genes and their variants in families inherited with HL. Conclusively, this review supports researchers in understanding the location of chromosome, the causative genes and specific locus which causing deafness in humans.

scholarly journals Recessive LOXHD1 Variants Cause a Milder Prelingual Hearing Loss: Genotype-Phenotype Correlation and Three Additional Patients With Novel Variants

2020 ◽  
Author(s):  
Sha Yu ◽  
Wen-xia Chen ◽  
Yun-Fei Zhang ◽  
Chao Chen ◽  
Yihua Ni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Protein Domain ◽  
Low Frequencies ◽  
Genotype Combination ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Splicing Variants ◽  
Novel Variants ◽  
Children With Hearing Loss

Abstract BackgroundBiallelic mutations in LOXHD1 have been identified as the cause of DFNB77 (deafness, autosomal recessive 77). It is a novel, progressive, severe-profound, and late-onset non-syndromic hearing loss, and is genetically and phenotypically highly heterogeneous. This study aimed to provide an additional three cases of DFNB77 to analyze this complex disease.MethodsWe presented three cases of pediatric patients with prelingual milder form of the DFNB77 with residual hearing at low frequencies. Trio whole-exome sequencing (WES) was conducted to identify the pathogenic variants. Additionally, we reviewed the literature to further analyze the relationships between the genotype and audiology phenotype of LOXHD1 worldwide.ResultsSix novel possible pathogenic LOXHD1 variants in three patients were identified by WES, including three missense, one nonsense, and two splicing variants. The literature review showed that 68.5% of DFNB77 patient onset before five years old; Most variants (60%) were associated with a milder phenotype, particularly variants in the protein domain of PLAT 7 and PLAT 9. We found that compared with homozygous LOXHD1 variants, individuals with heterozygous compound variants had a significantly milder phenotype, especially individuals carrying one missense and one splicing or bi-allelic missense variants (P <0.05). Audiometric analysis at different ages showed that the hearing loss degree was aggravated at all frequencies in adulthood and more severe in elderhood.ConclusionsWe report three children with hearing loss carrying six novel LOXHD1 variants identified by WES. Furthermore, our work indicates that DFNB77 may be milder than previously reported, and recommends considering the genotype combination and mutation location of LOXHD1 and race-specificity in DFNB77 molecular diagnoses and management.

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