scholarly journals A 2020 View on the Genetics of Developmental and Epileptic Encephalopathies

2020 ◽  
Vol 20 (2) ◽  
pp. 90-96 ◽  
Author(s):  
Hannah C. Happ ◽  
Gemma L. Carvill
Keyword(s):  
Molecular Diagnosis ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Autosomal Recessive Inheritance ◽  
Small Subset ◽  
Recessive Inheritance ◽  
Epileptic Encephalopathies ◽  
Pathogenic Variants ◽  
Genetic Mosaicism ◽  
Genetic Landscape

Developmental and epileptic encephalopathies (DEEs) can be primarily attributed to genetic causes. The genetic landscape of DEEs has been largely shaped by the rise of high-throughput sequencing, which led to the discovery of new DEE-associated genes and helped identify de novo pathogenic variants. We discuss briefly the contribution of de novo variants to DEE and also focus on alternative inheritance models that contribute to DEE. First, autosomal recessive inheritance in outbred populations may have a larger contribution than previously appreciated, accounting for up to 13% of DEEs. A small subset of genes that typically harbor de novo variants have been associated with recessive inheritance, and often these individuals have more severe clinical presentations. Additionally, pathogenic variants in X-linked genes have been identified in both affected males and females, possibly due to a lack of X-chromosome inactivation skewing. Collectively, exome sequencing has resulted in a molecular diagnosis for many individuals with DEE, but this still leaves many cases unsolved. Multiple factors contribute to the missing etiology, including nonexonic variants, mosaicism, epigenetics, and oligogenic inheritance. Here, we focus on the first 2 factors. We discuss the promises and challenges of genome sequencing, which allows for a more comprehensive analysis of the genome, including interpretation of structural and noncoding variants and also yields a high number of de novo variants for interpretation. We also consider the contribution of genetic mosaicism, both what it means for a molecular diagnosis in mosaic individuals and the important implications for genetic counseling.

scholarly journals Maternal mosaicism for a missense variant in the SMS gene that causes Snyder-Robinson syndrome

2021 ◽  
pp. mcs.a006122
Author(s):  
Mohammad Marhabaie ◽  
Scott E Hickey ◽  
Katherine E Miller ◽  
Olivia Grischow ◽  
Kathleen M Schieffer ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
De Novo ◽  
Genetic Disorders ◽  
Missense Variant ◽  
Hyperinsulinemic Hypoglycemia ◽  
Spermine Synthase ◽  
Genetic Mosaicism ◽  
The Family ◽  
Bilateral Sensorineural Hearing Loss

There is increasing recognition for the contribution of genetic mosaicism to human disease, particularly as high-throughput sequencing has enabled detection of sequence variants at very low allele frequencies. Here, we describe an infant male who presented at 9 months of age with hypotonia, dysmorphic features, congenital heart disease, hyperinsulinemic hypoglycemia, hypothyroidism, and bilateral sensorineural hearing loss. Whole-genome sequencing of the proband and the parents uncovered an apparent de novo mutation in the X-linked SMS gene. SMS encodes spermine synthase, which catalyzes the production of spermine from spermidine. Inactivation of the SMS gene disrupts the spermidine/spermine ratio, resulting in Snyder-Robinson syndrome. The variant in our patient is absent from the gnomAD and ExAC databases and causes a missense change (p.Arg130Cys) predicted to be damaging by most in silico tools. While Sanger sequencing confirmed the de novo status in our proband, PCR and deep targeted resequencing to ~84,000-175,000x depth revealed that the variant is present in blood from the unaffected mother at ~3% variant allele frequency. Our findings thus provided a long-sought diagnosis for the family while highlighting the role of parental mosaicism in severe genetic disorders.

scholarly journals SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia

2020 ◽  
Vol 6 (4) ◽  
pp. e478 ◽  
Author(s):  
Tommy Stödberg ◽  
Måns Magnusson ◽  
Nicole Lesko ◽  
Anna Wredenberg ◽  
Daniel Martin Munoz ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Autosomal Recessive Inheritance ◽  
Recessive Inheritance ◽  
Inheritance Pattern ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Gastrointestinal Problems ◽  
Life Threatening

ObjectiveTo describe the phenotype in 2 sisters with a rare constellation of neurologic symptoms and secretory impairments and to identify the etiology by the use of whole-genome sequencing (WGS).MethodsAfter an extensive workup failed to reveal the cause of disease, in a girl with a previously not reported phenotype, WGS of the proband, her diseased older sister, an older healthy brother, and their parents was performed, and potentially pathogenic variants were analyzed.ResultsThe proband and her older sister both presented with neonatal Staphylococcus aureus parotitis, apneas, disappearance of the Moro reflex, and hypotonia. The proband survived. Her brain MRI showed white matter and basal ganglia abnormalities, and CSF damage biomarkers were increased. At age 8 years, she exhibits a constellation of symptoms including severe neurodevelopmental disorder, hearing impairment, gastrointestinal problems, and a striking lack of tear fluid, saliva, and sweat. Her respiratory mucosa is dry with potentially life-threatening mucus plugging. Through WGS, 2 loss-of-function variants in SLC12A2 were identified that follow an autosomal recessive inheritance pattern.ConclusionsTaken together with a single previously reported case and the close resemblance to the phenotypes of corresponding mouse models, our study firmly establishes biallelic variants in SLC12A2 as causing human disease and adds data regarding the neurologic phenotype.

scholarly journals Outcomes of 4 years of molecular genetic diagnosis on a panel of genes involved in premature aging syndromes, including laminopathies and related disorders

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Maude Grelet ◽  
Véronique Blanck ◽  
Sabine Sigaudy ◽  
Nicole Philip ◽  
Fabienne Giuliano ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Natural Aging ◽  
Premature Aging ◽  
Pathogenic Variants ◽  
Progeroid Syndromes ◽  
Premature Aging Syndromes

Abstract Background Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated. Methods Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad. Results Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives. Conclusions High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms (“Medicine France Genomics 2025” Plan), in families without molecular diagnosis.

scholarly journals New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

2021 ◽  
Vol 22 (24) ◽  
pp. 13439
Author(s):  
Lucia Pia Bruno ◽  
Gabriella Doddato ◽  
Floriana Valentino ◽  
Margherita Baldassarri ◽  
Rossella Tita ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnosis ◽  
De Novo ◽  
Genetic Locus ◽  
Autism Spectrum ◽  
Bioinformatic Tools ◽  
Pathogenic Variants ◽  
Whole Exome

Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1–3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent–offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.

Pelizaeus Merzbacher phenotype with epilepsy and autosomal recessive inheritance in two siblings

2006 ◽  
Vol 37 (03) ◽  
Author(s):  
U Gaiser ◽  
J Neuberger ◽  
E Regel ◽  
R Emmert ◽  
M Ries
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Recessive Inheritance

TYPICAL CASES OF ISOLATED GROWTH HORMONE DEFICIENCY WITH AUTOSOMAL RECESSIVE INHERITANCE

1970 ◽  
Vol 63 (4) ◽  
pp. 618-624 ◽  
Author(s):  
Y. Kumahara ◽  
Y. Okada ◽  
K. Miyai ◽  
H. Iwatsubo
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Adult Subject ◽  
Hormone Deficiency ◽  
Recessive Inheritance ◽  
Arginine Infusion ◽  
Isolated Growth Hormone Deficiency ◽  
Male Dwarf

ABSTRACT A 25-year-old male dwarf and his sister, a 31-year-old woman were investigated. Their respective heights were 114 and 97 cm with proportional statures. Their bone ages were that found in the adult subject. Thyroid functions and metyrapone test were normal and the total urinary gonadotrophin was determined in both cases. HGH secretion was not stimulated by insulin-induced hypoglycaemia, arginine infusion or exercise. Their parents and six other siblings were normal in height. The two patients were therefore assumed to be suffering from an isolated growth hormone deficiency with autosomal recessive inheritance.

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.

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