Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

BackgroundDevelopmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1.MethodsWe performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families.ResultsWe excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE.ConclusionOur finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance.

Download Full-text

Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

Frontiers in Genetics ◽

10.3389/fgene.2021.649556 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pan Gong ◽

Xianru Jiao ◽

Dan Yu ◽

Zhixian Yang

Keyword(s):

De Novo ◽

Gene Mutations ◽

Epileptic Encephalopathy ◽

Infantile Spasms ◽

Loss Of Function ◽

Gain Of Function ◽

Dysmorphic Features ◽

Pathogenic Variants ◽

Ohtahara Syndrome ◽

Whole Exome

Objective:KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications.Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a ‘change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients.Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.

Download Full-text

Insights from spatial measures of intolerance to identify pathogenic variants in developmental and epileptic encephalopathies

10.1101/2021.07.28.454182 ◽

2021 ◽

Author(s):

Michael Silk ◽

Alex De Sá ◽

Moshe Olshansky ◽

David Benjamin Ascher

Keyword(s):

Early Onset ◽

In Silico ◽

Epileptic Encephalopathy ◽

Disease Heterogeneity ◽

Epileptic Encephalopathies ◽

Pathogenic Variants ◽

Whole Exome ◽

Spatial Measures ◽

Number Of Genes

Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that sometimes lead to death. While a number of genes have been successfully implicated, it remains challenging to identify causative mutations within these genes from the background variation present in all individuals due to disease heterogeneity. Our ability to detect likely pathogenic variants has continued to improve as in silico predictors of deleteriousness have advanced. We investigate their use in prioritising likely pathogenic variants in epileptic encephalopathy patient whole exome sequences and show that the inclusion of structure-based predictors of intolerance improve upon previous attempts to demonstrate enrichment within epilepsy genes.

Download Full-text

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms22062824 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2824

Author(s):

Jan H. Döring ◽

Julian Schröter ◽

Jerome Jüngling ◽

Saskia Biskup ◽

Kerstin A. Klotz ◽

...

Keyword(s):

Neurological Disorders ◽

Transmembrane Domain ◽

Potassium Conductance ◽

Epileptic Encephalopathy ◽

Clinical Spectrum ◽

The Novel ◽

Developmental Abnormalities ◽

Pathogenic Variants ◽

Infantile Seizures ◽

Early Developmental

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

Download Full-text

Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

BMC Musculoskeletal Disorders ◽

10.1186/s12891-020-03890-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Samina Yasin ◽

Outi Makitie ◽

Sadaf Naz

Keyword(s):

Short Stature ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Loss Of Function ◽

Case Presentation ◽

Pathogenic Variants ◽

Skeletal Malformations ◽

Tarsal Bones ◽

The Family ◽

Heterozygous Carriers

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

Download Full-text

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

Journal of Pediatric Genetics ◽

10.1055/s-0040-1722288 ◽

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.

Download Full-text

A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

10.21203/rs.3.rs-317232/v1 ◽

2021 ◽

Author(s):

Ying Zhang ◽

Yanyan Nie ◽

Yu Mu ◽

Jie Zheng ◽

Xiaowei Xu ◽

...

Keyword(s):

Intellectual Disability ◽

Mental Disorders ◽

De Novo ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Loss Of Function ◽

Bioinformatics Analyses ◽

Whole Exome ◽

De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

Download Full-text

A Novel Heterozygous Missense Variant in YWHAG Gene Cause Early-Onset Epilepsy in a Chinese Family

10.21203/rs.3.rs-136482/v1 ◽

2020 ◽

Author(s):

Zhi Yi ◽

Zhenfeng Song ◽

Jiao Xue ◽

Chengqing Yang ◽

Fei Li ◽

...

Keyword(s):

Early Onset ◽

Seizure Control ◽

De Novo ◽

Missense Variant ◽

Epileptic Encephalopathy ◽

Chinese Family ◽

Gene Variants ◽

Case Presentation ◽

Epileptic Encephalopathies ◽

Refractory Seizures

Abstract Background: Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of severe disorders which are characterized by early-onset, refractory seizures and developmental slowing or regression. Genetic variations are significant causes for them. De novo variants in an increasing number of candidate genes have been found to be causal. YWHAG gene variants have been reported to cause developmental and epileptic encephalopathy 56 (DEE56). Case presentation: Here, we report a novel heterozygous missense variant c.170G>A (p.R57H) in YWHAG gene cause early-onset epilepsy in a Chinese family. Both the proband and his mother exhibit early onset seizures, intellectual disability, developmental delay. While the proband achieve seizure control with sodium valproate, his mother's seizures were not well controlled. Conclusions: Our report further confirming the haploinsufficiency of YWHAG results in developmental and epileptic encephalopathies.

Download Full-text

Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.745407 ◽

2021 ◽

Vol 13 ◽

Author(s):

Lin Sun ◽

Jianye Zhang ◽

Ning Su ◽

Shaowei Zhang ◽

Feng Yan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Symptoms ◽

Pathogenic Variants ◽

Dementia Patients ◽

Whole Exome ◽

Uncertain Significance ◽

Genetic Features ◽

Standards And Guidelines ◽

Degenerative Dementia

Background: Sporadic dementias generally occur in older age and are highly polygenic, which indicates some patients transmitted in a poly-genes hereditary fashion.Objective: Our study aimed to analyze the correlations of genetic features with clinical symptoms in patients with degenerative dementia.Methods: We recruited a group of 84 dementia patients and conducted the whole exome sequencing (WES). The data were analyzed focusing on 153 dementia-related causing and susceptible genes.Results: According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, we identified four reported pathogenic variants, namely, PSEN1 c.A344G, APP c.G2149A, MAPT c.G1165A, and MAPT c.G742A, one reported likely pathogenic variant, namely, PSEN2 c.G100A, one novel pathogenic variants, SQSTM1 c.C671A, and three novel likely pathogenic variants, namely, ABCA7 c.C4690T, ATP13A2 c.3135delC, and NOS3 c.2897-2A > G. 21 variants with uncertain significance in PSEN2, C9orf72, NOTCH3, ABCA7, ERBB4, GRN, MPO, SETX, SORL1, NEFH, ADCM10, and SORL1, etc., were also detected in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD).Conclusion: The new variants in dementia-related genes indicated heterogeneity in pathogenesis and phenotype of degenerative dementia. WES could serve as an efficient diagnostic tool for detecting intractable dementia.

Download Full-text

Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia

Human Genome Variation ◽

10.1038/s41439-020-00131-9 ◽

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.

Download Full-text

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

International Journal of Molecular Sciences ◽

10.3390/ijms21020516 ◽

2020 ◽

Vol 21 (2) ◽

pp. 516 ◽

Cited By ~ 5

Author(s):

Lisa Gianesello ◽

Monica Ceol ◽

Loris Bertoldi ◽

Liliana Terrin ◽

Giovanna Priante ◽

...

Keyword(s):

Dent Disease ◽

Low Molecular Weight ◽

Disease Genes ◽

Loss Of Function ◽

Clcn5 Gene ◽

Pathogenic Variants ◽

Whole Exome ◽

Low Molecular Weight Proteins ◽

Clcn5 Mutations

Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.

Download Full-text