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

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

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-abn.102 ◽

2018 ◽

Vol 89 (10) ◽

pp. A29.4-A30 ◽

Cited By ~ 1

Author(s):

Ela M Akay ◽

Ian S Schofield ◽

Ming H Lai ◽

Rhys H Thomas

Keyword(s):

Intellectual Disability ◽

Language Impairment ◽

Cervical Vertebrae ◽

Snp Array ◽

Global Developmental Delay ◽

Prior History ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Gene Encoding ◽

Original Cohort

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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Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2020.103850 ◽

2020 ◽

Vol 63 (4) ◽

pp. 103850

Author(s):

Anne Slavotinek ◽

Johanna M. van Hagen ◽

Louisa Kalsner ◽

Shashidhar Pai ◽

Laura Davis-Keppen ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Intellectual Disability ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Sequence Variants

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Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94

Genes ◽

10.3390/genes11090967 ◽

2020 ◽

Vol 11 (9) ◽

pp. 967

Author(s):

Mohamed H. Al-Hamed ◽

Nada Alsahan ◽

Maha Tulbah ◽

Wesam Kurdi ◽

Wafa’a I. Ali ◽

...

Keyword(s):

Developmental Disorder ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Facial Features ◽

Chromosomal Microarray Analysis ◽

Speech Delay ◽

Loss Of Function ◽

Pathogenic Variants ◽

Antenatal Sonography ◽

First Time

Background: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of TMEM94 are associated with IDDCDF. Methods and Results: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the TMEM94 gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families. Conclusions: This study provides confirmation that TMEM94 variants may cause IDDCDF. For the first time we describe the pathogenicity of TMEM94 defects detected during the prenatal period.

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Association of maternal diabetes with neurodevelopmental disorders: autism spectrum disorders, attention-deficit/hyperactivity disorder and intellectual disability

International Journal of Epidemiology ◽

10.1093/ije/dyaa212 ◽

2020 ◽

Author(s):

Shuyun Chen ◽

Sixian Zhao ◽

Christina Dalman ◽

Håkan Karlsson ◽

Renee Gardner

Keyword(s):

Diabetes Mellitus ◽

Attention Deficit Hyperactivity Disorder ◽

Autism Spectrum Disorders ◽

Intellectual Disability ◽

Attention Deficit ◽

Neurodevelopmental Disorders ◽

Maternal Diabetes ◽

Autism Spectrum ◽

Hyperactivity Disorder ◽

Spectrum Disorders

Abstract Background Maternal diabetes has been associated with a risk of neurodevelopmental disorders (NDDs) in offspring, though the common co-occurrence of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID) is rarely considered, nor is the potential for confounding by shared familial factors (e.g. genetics). Methods This population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish national registers, to follow 2 369 680 individuals born from 1987 to 2010. We used population-averaged logit models to examine the association between exposure to maternal type 1 diabetes mellitus (T1DM), pre-gestational type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), and odds of NDDs in offspring. Subgroup analysis was then performed to investigate the timings of GDM diagnosis during pregnancy and its effect on the odds of NDDs in offspring. We compared these results to models considering paternal lifetime T1DM and T2DM as exposures. Results Overall, 45 678 individuals (1.93%) were diagnosed with ASD, 20 823 (0.88%) with ID and 102 018 (4.31%) with ADHD. All types of maternal diabetes were associated with odds of NDDs, with T2DM most strongly associated with any diagnosis of ASD (odds ratioadjusted 1.37, 95% confidence interval 1.03–1.84), ID (2.09, 1.53–2.87) and ADHD (1.43, 1.16–1.77). Considering common co-morbid groups, the associations were strongest between maternal diabetes and diagnostic combinations that included ID. Paternal T1DM and T2DM diagnoses were also associated with offspring NDDs, but these associations were weaker than those with maternal diabetes. Diagnosis of GDM between 27 and 30 weeks of gestation was generally associated with the greatest risk of NDDs in offspring, with the strongest associations for outcomes that included ID. Conclusion The association of maternal diabetes with NDDs in offspring varies depending on the co-morbid presentation of the NDDs, with the greatest odds associated with outcomes that included ID. Results of paternal-comparison studies suggest that the above associations are likely to be partly confounded by shared familial factors, such as genetic liability.

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