scholarly journals Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

2020 ◽  
Author(s):  
Anne Slavotinek ◽  
Doriana Misceo ◽  
Stephanie Htun ◽  
Linda Mathisen ◽  
Eirik Frengen ◽  
...  
Keyword(s):  
Short Stature ◽  
Mammalian Cells ◽  
Developmental Delays ◽  
Brain Mri ◽  
Failure To Thrive ◽  
Missense Variant ◽  
Cerebellar Hypoplasia ◽  
Loss Of Function ◽  
Feeding Difficulties ◽  
Rna Exosome

AbstractThe RNA exosome is an essential ribonuclease complex involved in the processing and degradation of both coding and noncoding RNAs. We present three patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The common clinical features of these patients comprise failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His, and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess the functional consequences of pathogenic variants in EXOSC5. Loss of function for the zebrafish ortholog results in shortened and curved tails and bodies, reduced eye and head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants show defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. Overall, these findings expand the number of genes encoding RNA exosome components that have been implicated in human disease, while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

scholarly journals Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

2020 ◽  
Vol 29 (13) ◽  
pp. 2218-2239 ◽  
Author(s):  
Anne Slavotinek ◽  
Doriana Misceo ◽  
Stephanie Htun ◽  
Linda Mathisen ◽  
Eirik Frengen ◽  
...  
Keyword(s):  
Short Stature ◽  
Mammalian Cells ◽  
Developmental Delays ◽  
Brain Mri ◽  
Missense Variant ◽  
Cerebellar Hypoplasia ◽  
Loss Of Function ◽  
Feeding Difficulties ◽  
In Trans ◽  
Rna Exosome

Abstract The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5–6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

scholarly journals MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)

2018 ◽  
Vol 56 (5) ◽  
pp. 332-339 ◽  
Author(s):  
Abolfazl Rad ◽  
Umut Altunoglu ◽  
Rebecca Miller ◽  
Reza Maroofian ◽  
Kiely N James ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Critical Role ◽  
Missense Variant ◽  
Corneal Dystrophy ◽  
Reproductive Organs ◽  
Homozygosity Mapping ◽  
Facial Dysmorphism ◽  
Cerebellar Hypoplasia ◽  
Loss Of Function

BackgroundPutative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.ObjectiveA homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families.ResultsWe identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly.ConclusionThis report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.

scholarly journals Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations

2020 ◽  
Vol 105 (10) ◽  
pp. 3190-3202 ◽  
Author(s):  
Patrick C Hanley ◽  
Harsh S Kanwar ◽  
Corine Martineau ◽  
Michael A Levine
Keyword(s):  
Short Stature ◽  
Mammalian Cells ◽  
Extended Family ◽  
Medical Center ◽  
Academic Medical Center ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Wild Type ◽  
Z Scores

Abstract Background NPR2 encodes atrial natriuretic peptide receptor B (ANPRB), a regulator of skeletal growth. Biallelic loss-of-function mutations in NPR2 result in acromesomelic dysplasia Maroteaux type (AMDM; OMIM 602875), while heterozygous mutations may account for 2% to 6% of idiopathic short stature (ISS). Objective Describe the physical proportions and growth characteristics of an extended family with novel NPR2 mutations including members with AMDM, ISS, or normal stature. Design and Participants We performed whole exome sequencing in 2 healthy parents and 2 children with AMDM. Detailed genotyping and phenotyping were performed on members of a multigenerational family in an academic medical center. We expressed mutant proteins in mammalian cells and characterized expression and function. Results The sisters with AMDM were compound heterozygotes for missense mutations in the NPR2 gene, a novel p.P93S (maternal) and the previously reported p.R989L (paternal). Both mutant ANPRB proteins were normally expressed in HEK293T cells and exhibited dominant negative effects on wild-type ANPRB catalytic activity. Heterozygous relatives had proportionate short stature (height z-scores −2.06 ± 0.97, median ± SD) compared with their wild-type siblings (−1.37 ± 0.59). Height z-scores progressively and significantly decreased as NPR2-heterozygous children matured, while remaining constant in their wild-type siblings. Conclusions Biallelic NPR2 mutations cause severe skeletal dysplasia (AMDM), whereas heterozygous mutations lead to a subtler phenotype characterized by progressive short stature with by increasing loss of height potential with age.

scholarly journals The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation

2019 ◽  
Author(s):  
Robert G. Mealer ◽  
Bruce G. Jenkins ◽  
Chia-Yen Chen ◽  
Mark J. Daly ◽  
Tian Ge ◽  
...  
Keyword(s):  
Brain Mri ◽  
Trace Element Analysis ◽  
Missense Variant ◽  
Common Variant ◽  
Loss Of Function ◽  
Element Analysis ◽  
Glycome Profiling ◽  
Depth Analysis ◽  
Mri Scans ◽  
The Common

AbstractA common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers of disease.SummaryA common variant in the manganese transporter SLC39A8 is associated with numerous phenotypes including schizophrenia. Mealer et. al. presents an in-depth analysis of brain MRI and plasma glycomics in human carriers of the common variant, identifying several manganese-related changes with potential for diagnostic and therapeutic biomarker development.

scholarly journals Pathogenic DNM1 Gene Variant Presenting With Unusually Nonsevere Neurodevelopmental Phenotype: A Case Report

2021 ◽  
Vol 7 (5) ◽  
pp. e618
Author(s):  
Elaine Choi ◽  
Breanne Dale ◽  
Rajesh RamachandranNair ◽  
Resham Ejaz
Keyword(s):  
Developmental Delays ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Intractable Epilepsy ◽  
Missense Variant ◽  
Chromosomal Microarray ◽  
Gtpase Domain ◽  
Pathogenic Variants ◽  
Neurodevelopmental Phenotype

Background and ObjectivesTo date, all reports of pathogenic variants affecting the GTPase domain of the DNM1 gene have a clinically severe neurodevelopmental phenotype, including severe delays or intractable epilepsy. We describe a case with moderate developmental delays and self-resolved epilepsy.MethodsThe patient was followed by our neurology and genetics teams. After clinical examination and EEG to characterize the patient's presentation, we conducted etiologic workup including brain MRI, chromosomal microarray, genetic and metabolic investigations, and nerve conduction studies. Subsequently, we arranged an Intellectual Disability Plus Trio Panel.ResultsOur patient presented with seizures at 2 days old, requiring phenobarbital. She also had hypotonia, mild dysmorphic features, and mild ataxia. Although initial workup returned unremarkable, the trio gene panel identified a de novo heterozygous pathogenic missense variant in the DNM1 GTPase domain. Now 4 years old, she has been seizure-free for 3 years without ongoing treatment and has nonsevere developmental delays (e.g., ambulates independently and speaks 2-word phrases).DiscussionOur case confirms that not all individuals with DNM1 pathogenic variants, even affecting the GTPase domain, will present with intractable epilepsy or severe delays. Expanding the known clinical spectrum of dynamin-related neurodevelopmental disorder is crucial for patient prognostication and counseling.

scholarly journals Highly clustered de novo frameshift variants in the neuronal splicing factor NOVA2 result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features

2019 ◽  
Author(s):  
Francesca Mattioli ◽  
Gaelle Hayot ◽  
Nathalie Drouot ◽  
Bertrand Isidor ◽  
Jérémie Courraud ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Rna Binding ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Severe Form ◽  
Neural Cells ◽  
Loss Of Function ◽  
Ataxic Gait ◽  
Feeding Difficulties

ABSTRACTThe Neuro-Oncological Ventral Antigen 2 NOVA2 protein is a major factor regulating neuron specific alternative splicing, previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in the NOVA2 gene affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait and abnormal brain MRI. The six variants lead to the same reading frame, adding a common 133 aa long proline rich C-terminus part instead of the last KH RNA binding domain. We detected forty-one genes differentially spliced after NOVA2 inactivation in human neural cells. The mutant NOVA2 protein shows decreased ability to bind a target RNA, to regulate specific splicing events and to rescue the phenotype of altered retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss of function, although a specific contribution of the novel C terminal extension cannot be excluded on the basis of the genetic findings.

scholarly journals Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders

Brain ◽  
2020 ◽  
Author(s):  
Fanny Mochel ◽  
Agnès Rastetter ◽  
Berten Ceulemans ◽  
Konrad Platzer ◽  
Sandra Yang ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Movement Disorders ◽  
De Novo ◽  
Brain Mri ◽  
Missense Variant ◽  
Loss Of Function ◽  
Patch Clamp Technique ◽  
Abnormal Gait ◽  
Frameshift Deletion ◽  
Uncertain Significance

Abstract KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

ALG1-CDG: A Patient with a Mild Phenotype and Literature Review

2021 ◽  
pp. 1-6
Author(s):  
Ümmühan Öncül ◽  
Engin Kose ◽  
Fatma Tuba Eminoğlu
Keyword(s):  
Developmental Delay ◽  
Brain Mri ◽  
Failure To Thrive ◽  
Protein S ◽  
Multisystem Disease ◽  
C Protein ◽  
Mild Phenotype ◽  
Feeding Difficulties ◽  
Multisystem Involvement ◽  
Swallowing Difficulty

ALG1-congenital disorder of glycosylation (ALG1-CDG) is an autosomal recessive multisystem disease. We here present a patient with a mild phenotype of ALG1-CDG. A 15-month-old female was referred with hypotonia, failure to thrive, and developmental delay. At 8 months of age, failure to thrive, feeding difficulties and developmental delay became apparent, and an epileptic seizure was observed at 11 months of age. Progressive deterioration and swallowing difficulty were observed. A brain MRI revealed a widening of the cerebrospinal fluid spaces and ventricular system, and decreased protein C, protein S and antithrombin III levels were identified. The isoelectric focusing showed a type 1 pattern. A homozygous c.1076C&#x3e;T (p.Ser359Leu) variant was found in the <i>ALG1</i> gene. CDG should be taken into consideration in patients presenting with unexplained multisystem involvement.

scholarly journals New Cohort of Patients With CEDNIK Syndrome Expands the Phenotypic and Genotypic Spectra

2021 ◽  
Vol 7 (1) ◽  
pp. e553
Author(s):  
Annelise Y. Mah-Som ◽  
Cristina Skrypnyk ◽  
Andrea Guerin ◽  
Raafat Hammad Seroor Jadah ◽  
Vinayak Nivrutti Vardhan ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Failure To Thrive ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Early Puberty ◽  
Related Disorder ◽  
Feeding Difficulties ◽  
Membrane Fusion Protein

ObjectiveTo report 6 new patients with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome.MethodsClinical exome or targeted sequencing were performed to elucidate the molecular genetic cause in patients with neurocognitive abnormalities and brain imaging findings.ResultsCEDNIK syndrome is a rare genetic condition caused by biallelic pathogenic loss-of-function variants in synaptosomal-associated protein 29 (SNAP29), which encodes a vesicular membrane fusion protein. Clinical manifestations include significant developmental delay/intellectual disability (DD/ID), brain abnormalities, failure to thrive, and skin abnormalities. To date, 19 patients from 10 unrelated families with CEDNIK syndrome have been reported. We report 5 additional patients with homozygous predicted loss-of-function variants in SNAP29 and one with compound heterozygous variants: a frameshift SNAP29 variant and a 370 kb deletion on 22q11.2. All patients exhibit DD/ID, ichthyosis and/or palmoplantar keratoderma, and hypotonia. Four of 6 subjects had hypomyelinated white matter on MRI, 2 of 6 had early puberty, and 4 of 6 had strabismus, which were previously rarely reported. Other phenotypes were variably present, including dysmorphic features, feeding difficulties, and recurrent respiratory infections. The cohort includes 2 siblings with a c.2T>C variant who have a relatively milder phenotype, a patient with the most C-terminal variant yet described (c.622G>T), and 3 patients with previously described variants (c.354dupG, c.487dupA).ConclusionsThis cohort of 6 additional patients expands the genotypic and phenotypic spectrum of CEDNIK syndrome, highlighting previously under-recognized features such as hypomyelination, seizures, and early puberty. Owing to reduced penetrance of the skin phenotype, cerebral dysgenesis, and neuropathy, we propose renaming this syndrome SNAP29-related disorder.

scholarly journals Blended Phenotype of Silver-Russell Syndrome and SPG50 Caused by Maternal Isodisomy of Chromosome 7

2020 ◽  
Vol 7 (1) ◽  
pp. e544
Author(s):  
Marvin Ziegler ◽  
Bianca E. Russell ◽  
Kathrin Eberhardt ◽  
Gregory Geisel ◽  
Angelica D'Amore ◽  
...  
Keyword(s):  
Short Stature ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Adaptor Protein ◽  
Chromosome 7 ◽  
Imprinting Disorders ◽  
Feeding Difficulties ◽  
Functional Studies ◽  
Uniparental Isodisomy ◽  
Silver Russell Syndrome

ObjectiveUniparental isodisomy can lead to blended phenotypes of imprinting disorders and autosomal recessive diseases. To determine whether a complex neurodevelopmental disorder was caused by uniparental isodisomy, a detailed clinical and molecular characterization was performed.MethodsA combination of clinical, molecular, and imaging data and functional studies in patient-derived fibroblasts.ResultsWe report a 4-year-old female with a blended, complex phenotype of Silver-Russell syndrome (SRS) and hereditary spastic paraplegia type 50 (SPG50) caused by total maternal isodisomy of chromosome 7 (UPiD(7)mat) and a loss-of-function variant in AP4M1 (NM_00472.3: c.59-1G>C, IVS1-1G>C). Functional studies in patient-derived fibroblasts confirmed the loss of adaptor protein complex 4 function. Distinctive facial features, intrauterine growth restriction, short stature, feeding difficulties, and severe gastroesophageal reflux were consistent with SRS. Features associated with SPG50 included early-onset epilepsy, episodes of stereotypical laughter, and thinning of the corpus callosum and ventriculomegaly on brain MRI. Symptoms shared by both syndromes such as developmental delay, short stature, and axial and appendicular hypotonia were also present. Notably, other common manifestations of SPG50 such as microcephaly or spasticity had not developed yet.ConclusionsThis case highlights that atypical clinical features in patients with well-described imprinting disorders should lead to investigations for recessive conditions caused by variants in genes that localize to the region of homozygosity.

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