scholarly journals Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

2020 ◽  
Author(s):  
Theresa Brunet ◽  
Kirsty McWalter ◽  
Katharina Mayerhanser ◽  
Grace M. Anbouba ◽  
Amy Armstrong-Javors ◽  
...  
Keyword(s):  
De Novo ◽  
Splice Variants ◽  
Muscle Tone ◽  
Three Dimensional ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Related Disorder ◽  
Aggregated Data ◽  
Phenotypic Spectrum ◽  
Gastrointestinal Problems

Abstract Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. Conclusion Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

scholarly journals SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

2020 ◽  
Author(s):  
Ilaria Dutto ◽  
Julian Gerhards ◽  
Antonio Herrera ◽  
Alexandra Junza ◽  
Oscar Yanes ◽  
...  
Keyword(s):  
De Novo ◽  
Autism Spectrum ◽  
Zebrafish Embryos ◽  
Biosynthesis Pathway ◽  
Purine Nucleotide ◽  
Adenylosuccinate Lyase ◽  
Dna Damage Signaling ◽  
Phenotypic Spectrum ◽  
Neurotoxic Effects ◽  
Independent Effects

AbstractAdenylosuccinate Lyase (ADSL) functions in the de novo purine biosynthesis pathway. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal purine nucleotide levels but exhibit accumulation of the dephosphorylated ADSL substrates SAICAr and S-Ado. SAICAr was implicated in the neurotoxic effects of ADSLD, although its role remains unknown. We examined the effects of ADSL depletion in human cells and found increased DNA damage signaling, that was rescued by nucleosides, and impaired primary ciliogenesis, that was rescued by reducing SAICAr. By analyzing ADSL deficient chicken and zebrafish embryos we observed impaired neurogenesis and microcephaly, and neuroprogenitor attrition in zebrafish was rescued by reducing SAICAr. Zebrafish embryos also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and SAICAr accumulation contribute to neurodevelopmental pathology in ADSLD and defective ciliogenesis may influence the ADSLD phenotypic spectrum.

scholarly journals Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families

2021 ◽  
Vol 22 (4) ◽  
pp. 1660
Author(s):  
Isaac Baldwin ◽  
Robin L. Shafer ◽  
Waheeda A. Hossain ◽  
Sumedha Gunewardena ◽  
Olivia J. Veatch ◽  
...  
Keyword(s):  
Behavioral Problems ◽  
De Novo ◽  
Clinical Laboratory ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Genomic Variation ◽  
Future Research ◽  
Symptom Presentation ◽  
Clinical Genetic ◽  
Genetic Evaluations

The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.

scholarly journals Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

2021 ◽  
Author(s):  
Ricardo Harripaul ◽  
Ansa Rabia ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Ashlyn Rodrigues ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
De Novo ◽  
Splice Variants ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Loss Of Function ◽  
Candidate Sequence

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that affects about 1 in 55 children worldwide and imposes enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identified de novo copy number variants (CNVs) and point mutations that contribute significantly to the genetic architecture of ASD, but the majority of these studies were conducted in outbred populations, which are not ideal for detecting autosomal recessive (AR) inheritance. However, several studies have investigated ASD genetics in consanguineous populations and point towards AR as an under-appreciated source of ASD variants. Here, we used trio whole exome sequencing (WES) to look for rare variants for ASD in 115 proband-mother-father trios from populations with high rates of consanguinity, namely Pakistan, Iran, and Saudi Arabia. In total, we report 87 candidate sequence variants, with 57% biallelic, 21% autosomal dominant/de novo, and the rest X-linked. 52% of the variants were loss of function (LoF) or putative LoF (splice site, stop loss) and 47% non-synonymous. Our analysis indicates an enrichment of previously identified and candidate AR genes. These include variants in genes previously reported for AR ASD and/or intellectual disability (ID), such as AGA, ASL, ASPA, BTN3A2, CC2D1A, DEAF1, HTRA2, KIF16B, LINS1, MADD, MED25, MTHFR, RSRC1, TECPR2, VPS13B, ZNF335, and 32 previously unreported candidates, including 15 LoF or splice variants, in genes such as DAGLA, EFCAB8, ENPP6, FAXDC2, ILDR2, PKD1L1, SCN10A, and SLC36A1. We also identified candidate biallelic exonic loss CNVs a number of trios, implicating genes including DNAH7, and DHRS4/DHRS4L2.

scholarly journals Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples

2016 ◽  
Author(s):  
Jack A. Kosmicki ◽  
Kaitlin E. Samocha ◽  
Daniel P. Howrigan ◽  
Stephan J. Sanders ◽  
Kamil Slowikowski ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Population Based ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Aggregated Data ◽  
Pathogenic Variants ◽  
Standing Variation ◽  
Reference Samples

AbstractRecent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9246 families with autism spectrum disorder, intellectual disability, or developmental delay, we show ~1/3 of de novo variants are independently observed as standing variation in the Exome Aggregation Consortium’s cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further use a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes that contain the observed signal of associated de novo protein truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs; though the strongest de novo impacted genes contribute little to this, suggesting the excess of inherited risk resides lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.

scholarly journals Differential Functional Changes of Nav1.2 Channel Causing SCN2A-Related Epilepsy and Status Epilepticus During Slow Sleep

2021 ◽  
Vol 12 ◽  
Author(s):  
Pu Miao ◽  
Siyang Tang ◽  
Jia Ye ◽  
Jihong Tang ◽  
Jianda Wang ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
De Novo ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Related Disorder ◽  
Functional Changes ◽  
Whole Cell Patch Clamp ◽  
Slow Sleep ◽  
Infantile Seizures ◽  
Functional Features

Background: Nav1.2 encoded by the SCN2A gene is a brain-expressed voltage-gated sodium channel known to be associated with neurodevelopment disorders ranging from benign familial neonatal infantile seizures (BFIS) to developmental and epileptic encephalopathy (DEE) and autism spectrum disorder. Interestingly, status epilepticus during slow sleep (ESES), which aggravates cognitive impairment, has been found in SCN2A-related epilepsy. However, the functional features and the relationship between SCN2A and ESES have not been researched.Method: We herein investigated the functional consequences of an unpublished de novo V911A and the other two published variants in patients with SCN2A-related disorder and ESES by whole-cell patch-clamp studies in transfected HEK293T cells.Results: The unpublished V911A and published K1933M variants detected in patients with DEE exhibited a profound gain-of-functional (GOF) change. Another published BFIS variant S863F significantly reduced current density as a loss-of-functional (LOF) change. The refractory epilepsy in the patient with V911A was controlled by using the precise treatment of oxcarbazepine (OXC) since the age of 3 months. ESES was found at 18 months during the seizure-free period. We finally chose an aggressive treatment for eliminating ESES by using methylprednisolone combined with levetiracetam and nitrazepam instead of the precise treatment of OXC.Conclusion: Both GOF and LOF variants in the SCN2A gene can lead to ESES among the phenotypes of DEE and BFIS. We should monitor the electroencephalogram regularly in the patients with SCN2A-related epilepsy even during their seizure-free period.

scholarly journals A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

2021 ◽  
Author(s):  
Danny Antaki ◽  
Adam Maihofer ◽  
Marieke Klein ◽  
James Guevara ◽  
Jakob Grove ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Rare Variants ◽  
De Novo ◽  
Autism Spectrum ◽  
Parental Age ◽  
De Novo Mutations ◽  
Polygenic Risk ◽  
Behavioral Traits ◽  
Sex Effects ◽  
Phenotypic Spectrum

The genetic etiology of autism spectrum disorder (ASD) is multifactorial with contributions from rare variants, polygenic risk, and sex. How combinations of factors determine risk for ASD is unclear. In 11,313 ASD families (N = 37,375 subjects), we investigated the effects rare and polygenic risk individually and in combination. We show that genetic liability for ASD differs by sex, with females having a greater polygenic load, and males having a lower liability threshold as evident by a negative correlation of rare and polygenic risk. Multiple genetic factors were associated with differing sets of behavioral traits with effects that differed by sex. Furthermore, the correlation of parental age with genetic risk for ASD was attributable to de novo mutations and sex-biased effects of inherited risk in parents. Our results demonstrate that a phenotypic spectrum of ASD is attributable to the relative loadings and gene-by-sex effects of rare and common variation.

scholarly journals Further delineation of the phenotypic spectrum of pathogenic variants in MED13

2021 ◽  
Author(s):  
Inna S. Povolotskaya ◽  
Natalya V. Vetrova ◽  
Svetlana O. Zhikrivetskaya ◽  
Elizaveta V. Musatova ◽  
Valeriia S. Klestova ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Genetic Variants ◽  
De Novo ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Incomplete Penetrance ◽  
Cgg Repeat ◽  
Neurodevelopmental Disease ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum

Abstract Introduction:Diagnostic yield of the genetic testing in search for the molecular basis of neurodevelopmental diseases remains low due to incomplete knowledge of the phenotypic spectrum of pathogenic variants in a specific gene. Recently the MED13 gene was linked to neurodevelopmental disease. Methods:Four families with children affected by autism spectrum disorder (ASD) were recruited to the study. Extensive genetic testing was performed for each proband: CGG repeat expansion analysis in FMR1 gene; whole exome sequencing (WES); array comparative genomic hybridization (aCGH); maternity and paternity confirmation. Genetic variants which were revealed by WES were verified with Sanger sequencing or aCGH in probands and their relatives. Results:Four rare heterozygous genetic variants in MED13 gene were identified in four unrelated patients with clinical features matching MED13-associated phenotype: intellectual disability (ID) of various degrees, speech delay, ASD and mild facial dysmorphisms. Three of the variants occurred de novo, while one was inherited maternally, in accordance with previous findings, suggesting incomplete penetrance. A patient with a de novo missense mutation in the intrinsic disordered region of MED13 developed seizures similarly to the only other reported patient with a pathogenic missense variant in this region. Limitations:Additional functional studies are needed to elucidate molecular mechanisms of the disease and distinguish between pathogenic and non-pathogenic variation.Conclusion:Our data strongly support the role of MED13 in neurodevelopmental disease by eliminating other common genetic defects. We expand the phenotypic spectrum of the disease causing variants: pathogenic missense variants in the intrinsic disordered region of MED13 may lead to a phenotype with seizures and incomplete penetrance of the maternally inherited variants may occur.

Hearing and Neurodevelopmental Outcomes of Young Infants with Parechovirus-A and Enterovirus Meningitis: Cohort Study in Singapore Children and Literature Review

2020 ◽  
Author(s):  
Elis Yuexian Lee ◽  
Jessica Hui Yin Tan ◽  
Chew Thye Choong ◽  
Nancy Wen Sim Tee ◽  
Chia Yin Chong ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Oropharyngeal Dysphagia ◽  
Significant Risk ◽  
Developmental Outcomes ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Cortical Blindness ◽  
Speech Delay ◽  
Neurodevelopmental Outcomes ◽  
Young Infants

Abstract Parechovirus-A (PeV-A) and Enterovirus (EV) commonly cause childhood aseptic meningitis. Bacterial meningitis in children has been associated with devastating long-term sequelae. However, developmental outcomes are unclear in Parechovirus meningitis. This study aims to review the clinical findings and developmental outcomes of infants with PeV-A and EV meningitis. We performed a retrospective study of infants aged 90 days or younger being admitted to our hospital with PeV-A meningitis between November 2015 and July 2017, with positive cerebrospinal fluid (CSF) PeV-A PCR and negative blood and CSF bacterial cultures. Hearing and neurodevelopmental outcomes were compared with a previous cohort of infants aged 90 days or younger with EV meningitis admitted from January 2015 to December 2015. A total of 161 infants were included in our study, of which 68 infants (42.2%) had PeV-A meningitis and 93 infants (57.8%) had EV meningitis. We assessed their developmental outcome at 6 months, 1 year, and 2 years post-meningitis. At 2 years post-meningitis, three infants with PeV-A meningitis had developmental delay (5.5%), whereas none with EV meningitis had developmental delay. One patient had speech delay and autism spectrum disorder, while two had mild speech delay. When compared with our cohort of EV meningitis ≤90 days old, children with PeV-A meningitis ≤90 days old were more likely to have developmental delay 2 years post-meningitis (odds ratio 2.4, 95% confidence interval 2.0–3.0, p = 0.043). None of the patients with PeV-A or EV meningitis had sensorineural hearing loss or neurological sequelae, such as cortical blindness, oropharyngeal dysphagia, hydrocephalus, epilepsy, or cerebral palsy. Infants with PeV-A meningitis had a significant risk of developmental delay 2 years post-meningitis compared with those with EV meningitis. It is important to follow-up the developmental milestones of infants diagnosed with PeV-A meningitis for at least 2 years; and when they develop developmental delay, to ensure that they receive appropriate intervention.

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