WED 202 Lamb-shaffer syndrome: importance of snp array in diagnosing neurodevelopmental syndromes

We describe the seizure phenotype of a 26 year old lady who presented with a probable photic-induced convulsion on a background of mild intellectual disability, facial dysmorphia, fused cervical vertebrae and ventricular septal defect. There was no prior history of seizures.Routine EEG was polyrhythmic with a prominent photoparoxysmal response at 14 Hz and 40 Hz. CT head was normal. A SNP array demonstrated a rare 51 kb deletion at 12 p12.1 which disrupts the SOX5 gene.SOX5 is a developmentally important gene encoding a transcription factor that plays a role in multiple developmental pathways including of the nervous system. Loss of function of this gene is associated with Lamb-Shaffer syndrome, first characterised in 2012 with global developmental delay, intellectual disability, mild dysmorphic facies, language impairment and variable skeletal abnormalities.3 of the original cohort of 16 patients described experienced seizures and the nature of their epilepsy was not further defined. Only a further 7 cases have been reported to date, none of whom experienced seizures. Our case helps to broaden the phenotype of Lamb-Shaffer syndrome, highlights the importance of looking for copy number variation and poses questions regarding the neurobiology of photo-sensitivity.

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Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

European Journal of Human Genetics ◽

10.1038/s41431-020-00769-7 ◽

2021 ◽

Author(s):

Meena Balasubramanian ◽

Alexander J. M. Dingemans ◽

Shadi Albaba ◽

Ruth Richardson ◽

Thabo M. Yates ◽

...

Keyword(s):

Intellectual Disability ◽

Protein Function ◽

Autism Spectrum ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Related Disorder ◽

Feeding Difficulties ◽

Facial Phenotype ◽

Novel Variants ◽

Common Behaviour

AbstractWitteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.

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Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay

Genetics in Medicine ◽

10.1038/s41436-020-01047-z ◽

2021 ◽

Author(s):

Uirá Souto Melo ◽

Devon Bonner ◽

Kevin C. Kent Lloyd ◽

Ala Moshiri ◽

Brandon Willis ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Global Developmental Delay ◽

Loss Of Function

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EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay

Clinical Genetics ◽

10.1111/cge.13842 ◽

2020 ◽

Vol 98 (6) ◽

pp. 555-561

Author(s):

Muhammad Umair ◽

Mariam Ballow ◽

Abdulaziz Asiri ◽

Yusra Alyafee ◽

Abeer Tuwaijri ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Global Developmental Delay ◽

Speech Delay ◽

Mild Intellectual Disability ◽

Homozygous Variant

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ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

Nature Communications ◽

10.1038/s41467-019-12428-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Marie F. Smeland ◽

Conor McClenaghan ◽

Helen I. Roessler ◽

Sanne Savelberg ◽

Geir Åsmund Myge Hansen ◽

...

Keyword(s):

Intellectual Disability ◽

Cardiac Dysfunction ◽

Systolic Dysfunction ◽

Splice Site Mutation ◽

Cerebral White Matter ◽

Sulfonylurea Receptor ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Site Mutation ◽

Gain Of Function

Abstract Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Genetics in Medicine ◽

10.1038/s41436-021-01246-2 ◽

2021 ◽

Author(s):

Marjolein J. A. Weerts ◽

Kristina Lanko ◽

Francisco J. Guzmán-Vega ◽

Adam Jackson ◽

Reshmi Ramakrishnan ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Neurodevelopmental Disorder ◽

Epileptic Activity ◽

Language Delay ◽

Global Developmental Delay ◽

Sequence Variants ◽

Loss Of Function ◽

Phenotypic Spectrum

Abstract Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability

10.21203/rs.3.rs-376611/v1 ◽

2021 ◽

Author(s):

Diana Miclea ◽

Sergiu Osan ◽

Simona Bucerzan ◽

Delia Stefan ◽

Radu Popp ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Copy Number ◽

Clinical Phenotype ◽

Snp Array ◽

Uniparental Disomy ◽

Global Developmental Delay ◽

Chromosome 15 ◽

Metabolic Evaluation ◽

Pathogenic Cnvs

Abstract Developmental delay and intellectual disability represent a common pathology in general population, involving about 3% of the pediatric age population and more and more often the genetic etiology is proven. The aim of this study was to determine the clinically relevant copy number variants in patients diagnosed with global developmental delay/intellectual disability in our population, using the technology SNP array. Material and methods. We analyzed 189 patients diagnosed with GDD//ID, presented in Clinical Emergency Hospital for Children Cluj-Napoca. The patients were completely clinically investigated, including dysmorphic evaluation, internal malformation evaluation, psychiatric and neuropsychological examinations, metabolic evaluation, standard karyotyping. Genomic analysis was done using SNP array technique. Results. 50/189 patients (26.45%) presented pathogenic CNVs and uniparental disomy (32/189 patients, 16.93%) or VOUS (variants of unknown significance) (18/189 patients, 9.52%). Two patients presented uniparental disomy of chromosome 15, one with clinical phenotype of Prader-Willi syndrome and the other with clinical phenotype with Angelman syndrome. The recurrent pathogenic CNVs were seen in 18/32 patients (56%) with pathogenic findings (CNVs or uniparental disomy). Conclusions. These data encouraged to continue using a microarray genetic testing as useful test for the diagnostic performance together with other new tools as exome or genome sequencing for a global genome view in diseases which have not a specific phenotype, such as intellectual disability.

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Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenotype Correlation

Genes ◽

10.3390/genes12091360 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1360

Author(s):

Carolina Sanchez-Jimeno ◽

Fiona Blanco-Kelly ◽

Fermina López-Grondona ◽

Rebeca Losada-Del Pozo ◽

Beatriz Moreno ◽

...

Keyword(s):

Intellectual Disability ◽

Attention Deficit ◽

Autism Spectrum ◽

Global Developmental Delay ◽

Sequence Variants ◽

Loss Of Function ◽

Phenotype Correlation ◽

Feeding Difficulties ◽

Pathogenic Variants ◽

Genotype Phenotype Correlation

Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of patients harboring AUTS2 sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3′ end of the gene, confirming the genotype-phenotype correlation initially described.

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Successful treatment of choreo-athetotic movements in a patient with an EEF1A2 gene variant

SAGE Open Medical Case Reports ◽

10.1177/2050313x18807622 ◽

2018 ◽

Vol 6 ◽

pp. 2050313X1880762 ◽

Cited By ~ 1

Author(s):

Eboni I Lance ◽

Martin Kronenbuerger ◽

Julie S Cohen ◽

Orion Furmanski ◽

Harvey S Singer ◽

...

Keyword(s):

Intellectual Disability ◽

Movement Disorder ◽

Successful Treatment ◽

Elongation Factor ◽

Abrupt Onset ◽

Epileptic Encephalopathy ◽

Prior History ◽

Gene Encoding ◽

Eukaryotic Translation ◽

Pathogenic Variants

Pathogenic variants in EEF1A2, a gene encoding a eukaryotic translation elongation factor, have been previously reported in pediatric cases of epileptic encephalopathy and intellectual disability. We report a case of a 17-year-old male with a prior history of epilepsy, autism, intellectual disability, and the abrupt onset of choreo-athetotic movements. The patient was diagnosed with an EEF1A2 variant by whole exome sequencing. His movement disorder responded dramatically to treatment with tetrabenazine. To the best of our knowledge, this is the first report of successful treatment of a hyperkinetic movement disorder in the setting of EEF1A2 mutation. A trial with tetrabenazine should be considered in cases with significant choreoathetosis.

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

10.1101/2021.02.11.430742 ◽

2021 ◽

Author(s):

Marjolein J.A. Weerts ◽

Kristina Lanko ◽

Francisco J. Guzmán-Vega ◽

Adam Jackson ◽

Reshmi Ramakrishnan ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Neurodevelopmental Disorder ◽

Epileptic Activity ◽

Language Delay ◽

Global Developmental Delay ◽

Sequence Variants ◽

Loss Of Function ◽

Phenotypic Spectrum

ABSTRACTPathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability

eLife ◽

10.7554/elife.32451 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 13

Author(s):

Poh Hui Chia ◽

Franklin Lei Zhong ◽

Shinsuke Niwa ◽

Carine Bonnard ◽

Kagistia Hana Utami ◽

...

Keyword(s):

Intellectual Disability ◽

Germline Mutation ◽

Growth Delay ◽

Global Developmental Delay ◽

Loss Of Function ◽

C Elegans ◽

Calcium Calmodulin Dependent ◽

Severe Intellectual Disability

Calcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p.His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.In vivo, CAMK2AH477Y failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders.

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