A novel SHANK3 interstitial microdeletion in a family with intellectual disability and brain MRI abnormalities resembling Unidentified Bright Objects

BackgroundJoubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%–75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.MethodsWe reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.ResultsHeterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.ConclusionHeterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.

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Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations

Neurology Genetics ◽

10.1212/nxg.0000000000000206 ◽

2017 ◽

Vol 3 (6) ◽

pp. e206 ◽

Cited By ~ 21

Author(s):

Carla Marini ◽

Michele Romoli ◽

Elena Parrini ◽

Cinzia Costa ◽

Davide Mei ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Focal Epilepsy ◽

Brain Mri ◽

Somatic Mosaicism ◽

Epileptic Encephalopathy ◽

Seizure Onset ◽

Severe Intellectual Disability ◽

The Mean

Objective:To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations.Methods:Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel.Results:The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism.Conclusions:KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.

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A rare familial rearrangement of chromosomes 9 and 15 associated with intellectual disability: a clinical and molecular study

Molecular Cytogenetics ◽

10.1186/s13039-021-00565-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Natalya A. Lemskaya ◽

Svetlana A. Romanenko ◽

Mariia A. Rezakova ◽

Elena A. Filimonova ◽

Dmitry Yu. Prokopov ◽

...

Keyword(s):

Intellectual Disability ◽

Extra Chromosome ◽

Brain Mri ◽

Partial Trisomy ◽

Breakpoint Region ◽

Chromosome Anomaly ◽

Chromosome 15 ◽

Derivative Chromosome ◽

Balanced Translocation ◽

Mri Features

Abstract Background There are many reports on rearrangements occurring separately in the regions of chromosomes 9p and 15q affected in the case under study. 15q duplication syndrome is caused by the presence of at least one extra maternally derived copy of the Prader–Willi/Angelman critical region. Trisomy 9p is the fourth most frequent chromosome anomaly with a clinically recognizable syndrome often accompanied by intellectual disability. Here we report a new case of a patient with maternally derived unique complex sSMC resulting in partial trisomy of both chromosomes 9 and 15 associated with intellectual disability. Case presentation We characterise a supernumerary derivative chromosome 15: 47,XY,+der(15)t(9;15)(p21.2;q13.2), likely resulting from 3:1 malsegregation during maternal gametogenesis. Chromosomal analysis showed that a phenotypically normal mother is a carrier of balanced translocation t(9;15)(p21.1;q13.2). Her 7-year-old son showed signs of intellectual disability and a number of physical abnormalities including bilateral cryptorchidism and congenital megaureter. The child’s magnetic resonance imaging showed changes in brain volume and in structural and functional connectivity revealing phenotypic changes caused by the presence of the extra chromosome material, whereas the mother’s brain MRI was normal. Sequence analyses of the microdissected der(15) chromosome detected two breakpoint regions: HSA9:25,928,021-26,157,441 (9p21.2 band) and HSA15:30,552,104-30,765,905 (15q13.2 band). The breakpoint region on chromosome HSA9 is poor in genetic features with several areas of high homology with the breakpoint region on chromosome 15. The breakpoint region on HSA15 is located in the area of a large segmental duplication. Conclusions We discuss the case of these phenotypic and brain MRI features in light of reported signatures for 9p partial trisomy and 15 duplication syndromes and analyze how the genomic characteristics of the found breakpoint regions have contributed to the origin of the derivative chromosome. We recommend MRI for all patients with a developmental delay, especially in cases with identified rearrangements, to accumulate more information on brain phenotypes related to chromosomal syndromes.

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Is Brain MRI Needed in Diagnostic Evaluation of Mild Intellectual Disability?

Neuropediatrics ◽

10.1055/s-0040-1716902 ◽

2020 ◽

Author(s):

Miro Pekka Jussila ◽

Päivi Olsén ◽

Jaakko Niinimäki ◽

Maria Suo-Palosaari

Keyword(s):

Intellectual Disability ◽

Clinical Symptoms ◽

Brain Mri ◽

Neurological Symptoms ◽

Diagnostic Evaluation ◽

Mild Intellectual Disability ◽

Mri Findings ◽

Patient Reports ◽

Epilepsy Diagnosis ◽

Abnormal Head

Abstract Aim The purpose of our study was to suggest an imaging strategy and guidelines for the selection of the children with mild intellectual disability (ID) for magnetic resonance imaging (MRI), to avoid unnecessary imaging. Methods The brain MRIs and patient reports of 471 children were reviewed for the imaging findings and ID severity. The correlation between the clinical and brain MRI findings was analyzed in the 305 children with mild ID. Results Thirty-eight (12.5%) of the children with mild ID had significant abnormal brain MRI findings. Thirty-five of these had other neurological symptoms or diseases in addition to ID, which were an indication for brain MRI. In the logistic regression analysis, seizures (in patients without an epilepsy diagnosis), epilepsy, movement disorders, dysmorphia, encephalitis, traumatic brain injury, and abnormal head size were statistically significant symptoms or comorbidities associated with abnormal MRI findings. Only three children (1.0%) with mild ID had a significant MRI finding without any other clinical symptoms or disease. Conclusion Routine MRI in children with mild ID without specific neurological symptoms, dysmorphic features, or related diseases is not suggested for revealing an etiology of mild ID. Since children with ID usually need to be sedated for MRI, routine imaging in the diagnostic evaluation of mild ID should be carefully considered. Clinical examination, other symptoms, and related diseases should be carefully assessed to decide the need for MRI.

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INPP5K-Related congenital muscular dystrophy: when juvenile cataracts give clues to a complex diagnosis

10.5327/1516-3180.511 ◽

2021 ◽

Author(s):

Roberta Ismael Lacerda Machado ◽

Bruno de Mattos Lombardi Badia ◽

Wladimir Bocca Vieira de Rezende Pinto ◽

Igor Braga Farias ◽

José Marcos Vieira de Albuquerque Filho ◽

...

Keyword(s):

Cognitive Impairment ◽

Intellectual Disability ◽

Genetic Testing ◽

Motor Development ◽

Brain Mri ◽

Congenital Muscular Dystrophy ◽

The Elderly ◽

Adult Brain ◽

Mild Intellectual Disability ◽

Leg Weakness

Introduction: Congenital muscular dystrophies (CMDs) are a group of rare genetic muscle diseases that present at birth or during infancy with hypotonia and weakness. Multiple forms of CMDs are also associated with cerebral and ocular phenotypes. Recently, INPP5K mutations have been described associated with CMD, cataracts and cognitive impairment. The INPP5K gene, encodes SKIP, one of the enzymes that phosphorylate the 5-phosphate position of phosphoinositides and is highly expressed in developing and adult brain, eye and muscle. Methods: We performed a case report of three Brazilian patients with INPP5KCMD with cataracts and intellectual disability under clinical follow-up at our service. Results: Case 1: 39 years old, female, presenting with progressive leg weakness since childhood, mild intellectual disability and bilateral cataracts at 20 years. Her 35-yearold sister (Case 2) had a similar clinical picture with limb-girdle weakness since childhood, cognitive impairment and early- onset bilateral cataracts. Both with myopathic pattern in EMG, elevated creatine phosphokinase (CK) and dystrophic pattern in muscle biopsy. Brain MRI studies disclosed a large megacistern in the elderly and no abnormalities in the younger sister. Genetic testing: c.653_655del(p.(Ser218del) in homozygosity in INPP5K gene. Case 3: 20 years old, female, normal motor development but learning difficulties since childhood. Presented with progressive pelvic girdle weakness in childhood and bilateral cataracts in late adolescence. Exams disclosed elevated CK, brain MRI was normal and genetic testing with the following mutation in INPP5K gene:c.[881_883del];[1088T>C];p.[Ser294del];[Ile363Thr]. Conclusion: We describe patients with CMD, cataracts and intellectual disability, caused by mutation in the INPP5K gene. In literature few cases are reported.

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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

10.1101/858696 ◽

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.

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Reply to letter: “Brain MRI abnormalities resembling unidentified bright objects in a patient with Phelan- McDermid syndrome”

European Journal of Paediatric Neurology ◽

10.1016/j.ejpn.2018.01.015 ◽

2018 ◽

Vol 22 (3) ◽

pp. 570

Author(s):

Gaetano Terrone ◽

Giuseppina Vitiello ◽

Ennio Del Giudice

Keyword(s):

Brain Mri ◽

Unidentified Bright Objects

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A New Case of de novo Variant c.892C>T (p.Arg298Trp) in NACC1: A First Case Report From China

Frontiers in Pediatrics ◽

10.3389/fped.2021.754261 ◽

2021 ◽

Vol 9 ◽

Author(s):

Baiyu Lyu ◽

Yan Dong ◽

Juan Kang

Keyword(s):

Intellectual Disability ◽

Congenital Cataract ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Brain Mri ◽

Case Presentation ◽

Feeding Difficulties ◽

Severe Intellectual Disability ◽

First Case ◽

Infantile Epilepsy

Background: The nucleus accumbens associated 1 (NACC1) gene is a transcription factor member of the BTB/POZ family. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties.Case Presentation: We report a new case with a neurodevelopmental disorder characterized by severe intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. Brain MRI reveals brain dysplasia. We observe a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 gene in this case. Now, the child regularly goes to the hospital for rehabilitation training (once a month). Sodium Valproate (10 mg/kg/day) and Clobazam (10 mg/kg/day) are used in the treatment of epilepsy. A total of three articles were screened, and two papers were excluded. The search revealed one article related to a syndrome caused by a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1; they screened the main clinical features of eight cases of a syndrome, which were summarized and analyzed.Conclusions: The NACC1 gene is a member of the BTB/POZ family of transcription factors. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. At present, there is no effective cure. In the future, we need more cases to determine the phenotype–genotype correlation of NACC1 variants. Many questions remain to be answered, and many challenges remain to be faced. Future transcriptional studies may further clarify this rare, recurrent variant, and could potentially lead to targeted therapies.

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Clinical, neuroimaging and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability

10.1101/2020.10.10.20202622 ◽

2020 ◽

Author(s):

Sonja Neuser ◽

Barbara Brechmann ◽

Gali Heimer ◽

Ines Brösse ◽

Susanna Schubert ◽

...

Keyword(s):

Intellectual Disability ◽

Neurodegenerative Disorder ◽

Respiratory Infections ◽

Brain Mri ◽

Molecular Data ◽

Global Developmental Delay ◽

Cross Sectional ◽

Human Phenotype ◽

Missense Variants ◽

Mri Scans

ABSTRACTPURPOSEBi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we aim to provide a comprehensive clinical description and variant interpretation framework.METHODSThrough an international collaboration, we identified 13 individuals from 12 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data of this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms.RESULTSA cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 59%. We evaluated 14 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains difficult. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi population.CONCLUSIONBased on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

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