Expanding the Phenotype of TUBB2A-Related Tubulinopathy: Three Cases of a Novel, Heterozygous TUBB2A Pathogenic Variant p.Gly98Arg

Tubulinopathies are a group of conditions caused by variants in 6 tubulin genes that present with a spectrum of brain malformations. One of these conditions is TUBB2A-related tubulinopathy. Currently, there are 9 reported individuals with pathogenic variants within the TUBB2A gene, with common manifestations including, but not limited to, global developmental delay, seizures, cortical dysplasia, and dysmorphic corpus callosum. We report 3 patients identified by exome and genome sequencing to have a novel, pathogenic, missense variant in TUBB2A (p.Gly98Arg). They presented similarly with intellectual disability, hypotonia, and global developmental delay and varied with respect to the type of cortical brain malformation, seizure history, diagnosis of autism spectrum disorder, and other features. This case series expands the natural history of TUBB2A-related tubulinopathy while describing the presentation of a novel, pathogenic, missense variant in 3 patients.

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X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽

10.1371/journal.pgen.1009608 ◽

2021 ◽

Vol 17 (6) ◽

pp. e1009608

Author(s):

Jia-Hui Sun ◽

Jiang Chen ◽

Fernando Eduardo Ayala Valenzuela ◽

Carolyn Brown ◽

Diane Masser-Frye ◽

...

Keyword(s):

Developmental Delay ◽

Prolonged Exposure ◽

De Novo ◽

Missense Variant ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

Decay Kinetics ◽

Gain Of Function ◽

Ca1 Neurons ◽

Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

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Shukla-Vernon Syndrome: A Second Family with a Novel Variant in the BCORL1 Gene

Genes ◽

10.3390/genes12030452 ◽

2021 ◽

Vol 12 (3) ◽

pp. 452

Author(s):

Babylakshmi Muthusamy ◽

Anikha Bellad ◽

Satish Chandra Girimaji ◽

Akhilesh Pandey

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Protein Complexes ◽

Neurodevelopmental Disorder ◽

Missense Variant ◽

Global Developmental Delay ◽

Dysmorphic Features ◽

Pathogenic Variants ◽

Behavioral Abnormalities ◽

Novel Variant

Shukla-Vernon syndrome (SHUVER) is an extremely rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral anomalies, and dysmorphic features. Pathogenic variants in the BCORL1 gene have been identified as the molecular cause for this disorder. The BCORL1 gene encodes for BCL-6 corepressor-like protein 1, a transcriptional corepressor that is an integral component of protein complexes involved in transcription repression. In this study, we report an Indian family with two male siblings with features of Shukla-Vernon syndrome. The patients exhibited global developmental delay, intellectual disability, kyphosis, seizures, and dysmorphic features including bushy prominent eyebrows with synophrys, sharp beaked prominent nose, protuberant lower jaw, squint, and hypoplastic ears with fused ear lobes. No behavioral abnormalities were observed. Whole exome sequencing revealed a novel potentially pathogenic arginine to cysteine substitution (p.Arg1265Cys) in the BCORL1 protein. This is the second report of Shukla-Vernon syndrome with a novel missense variant in the BCORL1 gene. Our study confirms and expands the phenotypes and genotypes described previously for this syndrome and should aid in diagnosis and genetic counselling of patients and their families.

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Failure of Israeli pediatric residency curricula to cover child development and special education issues: results of a national survey on levels of knowledge

Israel Journal of Health Policy Research ◽

10.1186/s13584-021-00480-y ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Itay Tokatly Latzer ◽

Zachi Grossman ◽

Nimrod Sachs ◽

Orr Yahal ◽

Daniel Even-Zohar ◽

...

Keyword(s):

Special Education ◽

Child Development ◽

Developmental Delay ◽

Knowledge Score ◽

National Sample ◽

Autism Spectrum ◽

Resident Training ◽

Global Developmental Delay ◽

Education Systems ◽

History Of

Abstract Background There is an increasing prevalence of developmental difficulties among Israeli children. We aimed to assess whether pediatricians are equipped to diagnose and manage them. Methods We assessed the knowledge of basic child development issues and availability of services and content of special education systems among a randomly selected national sample of residents and senior Israeli pediatricians. This was done via an 70-itemed survey developed especially for this study which consisted of seven main subjects: developmental milestones, global developmental delay, autism spectrum disorder, attention deficit hyperactivity disorder, protocol for referring to a child development institute, availability and facilities of special education systems, and medical conditions associated with developmental delay. Results A total of 310 pediatricians (an 86 % usable response rate) participated. The total median knowledge score was 32.1 % (IQR 17.8–53.5 %). Knowledge was significantly better among senior pediatricians (p < .001), those working in an office-based setting (p < .001), and those who were parents (p < .001) or had a family history of a developmental condition (p = .003). Most responders (94 %) felt that their resident training in child development was inadequate, and that they do not have sufficient access to resources and guidelines about child development and special education systems (80 %). Conclusions The gap in knowledge on topics of child development and special education systems among Israeli pediatricians stems from inadequacies in the current curricula of pediatric residencies. The alarmingly low scores of our survey on these issues call for prompt revamping of the syllabus to include them.

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A de novo missense variant in MED13 in a patient with global developmental delay, marked facial dysmorphism, macroglossia, short stature, and macrocephaly

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.62238 ◽

2021 ◽

Author(s):

Alice P. Rogers ◽

Kathryn Friend ◽

Lesley Rawlings ◽

Christopher P. Barnett

Keyword(s):

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Missense Variant ◽

Global Developmental Delay ◽

Facial Dysmorphism

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Pitt Hopkins-Like Syndrome 1 with Novel CNTNAP2 Mutation in Siblings

Child Neurology Open ◽

10.1177/2329048x211055330 ◽

2021 ◽

Vol 8 ◽

pp. 2329048X2110553

Author(s):

Rea Mittal ◽

Ashutosh Kumar ◽

Roger Ladda ◽

Gayatra Mainali ◽

Ermal Aliu

Keyword(s):

Developmental Delay ◽

Focal Epilepsy ◽

Autism Spectrum ◽

Compound Heterozygous ◽

Sequencing Analysis ◽

Gait Abnormality ◽

Pathogenic Variants ◽

Obstructive Sleep ◽

Management Guidance ◽

Intragenic Deletions

Pitt Hopkins-like syndrome 1 (PTHLS1, OMIM # 610042) is an ultra-rare autosomal recessive condition with a prevalence of <1/1,000,000. Intragenic deletions of CNTNAP2 has been implicated in PTHLS1, however to our knowledge a compound heterozygous deletion of exon 4 and a c.1977_1989del13; p.V660Ffsx9 frameshift variant have not been published previously. In this case report, the proband is a seven year old female with PTHLS1, developmental delay, autism spectrum disorder, focal epilepsy, hypotonia, refractory errors, strabismus, and obstructive sleep apnea. Whole exome sequencing analysis revealed biallelic pathogenic variants of the CNTNAP2 gene. Proband has a three year old sister who has who has a similar phenotype including, developmental delay, epilepsy, gait abnormality, refractory errors, strabismus. Family variants were tested and she shared the same CNTNAP2 variants as her sister. The sisters described highlight two novel variants leading to PTHLS1. Genetic workup is essential in identification and management guidance in these populations.

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Study of perinatal factors in children with developmental delay

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20164602 ◽

2016 ◽

Vol 4 (1) ◽

pp. 182 ◽

Cited By ~ 1

Author(s):

Goli Sri Charan ◽

Jayant Vagha

Keyword(s):

Birth Weight ◽

Developmental Delay ◽

Gestational Age ◽

Birth Asphyxia ◽

Global Developmental Delay ◽

Developmental Quotient ◽

Birth History ◽

History Of ◽

Observational Descriptive Study ◽

Birth Body Weight

Background: Birth history gives important information in children with developmental delay. Developmental challenge in children is an emerging problem across the globe, which is largely associated with improved neonatal survival. The present study highlights the importance of birth history in children with developmental delay in our hospital. The objective of this study was to study the perinatal events in children with developmental delay.Methods: Observational descriptive study was conducted on children between 6 months to 5 years who were admitted in Pediatric wards with suspected history of developmental delay. DDST II scale was performed on these children and children who failed on Denver II scale were recruited into the study. Birth history was noted in detail, if available, documentation of birth events was asked for and noted. Developmental history with developmental quotient (DQ), were noted in detail.Results: 135 children had developmental delay, 113 (83.70%) were born by vaginal delivery and 22 (16.30%) were born by caesarian section, 46 (34.18%) had no cry at birth and remaining 89 (65.92%) had normal cry at birth. 104 (77.04%) were born by term gestation and 31 (22.96%) were born preterm. Birth weight was normal in 78 (57.7%) children, LBW was seen 47 (34.81%) and 5 children each with VLBW and ELBW and 35 (25.93%) were IUGR. On comparing the children born gestational age and birth body weight with all four domains, there was no significant difference.Conclusions: Global developmental delay was more common in children born at preterm, low birth weight, IUGR and children who had birth asphyxia. Birth weight and gestational age did not significantly affect any particular domain of development.

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Clinical characterization of children and adolescents with NF1 microdeletions

Child s Nervous System ◽

10.1007/s00381-020-04717-0 ◽

2020 ◽

Vol 36 (10) ◽

pp. 2297-2310 ◽

Cited By ~ 1

Author(s):

Hildegard Kehrer-Sawatzki ◽

Lan Kluwe ◽

Johannes Salamon ◽

Lennart Well ◽

Said Farschtschi ◽

...

Keyword(s):

Children And Adolescents ◽

Developmental Delay ◽

Clinical Care ◽

Severe Disease ◽

Autism Spectrum ◽

Whole Body ◽

Global Developmental Delay ◽

Disease Manifestation ◽

Tumour Load ◽

The Mean

Abstract Purpose An estimated 5–11% of patients with neurofibromatosis type 1 (NF1) harbour NF1 microdeletions encompassing the NF1 gene and its flanking regions. The purpose of this study was to evaluate the clinical phenotype in children and adolescents with NF1 microdeletions. Methods We retrospectively analysed 30 children and adolescents with NF1 microdeletions pertaining to externally visible neurofibromas. The internal tumour load was determined by volumetry of whole-body magnetic resonance imaging (MRI) in 20 children and adolescents with NF1 microdeletions. Furthermore, the prevalence of global developmental delay, autism spectrum disorder and attention deficit hyperactivity disorder (ADHD) were evaluated. Results Children and adolescents with NF1 microdeletions had significantly more often cutaneous, subcutaneous and externally visible plexiform neurofibromas than age-matched patients with intragenic NF1 mutations. Internal neurofibromas were detected in all 20 children and adolescents with NF1 microdeletions analysed by whole-body MRI. By contrast, only 17 (61%) of 28 age-matched NF1 patients without microdeletions had internal tumours. The total internal tumour load was significantly higher in NF1 microdeletion patients than in NF1 patients without microdeletions. Global developmental delay was observed in 28 (93%) of 30 children with NF1 microdeletions investigated. The mean full-scale intelligence quotient in our patient group was 77.7 which is significantly lower than that of patients with intragenic NF1 mutations. ADHD was diagnosed in 15 (88%) of 17 children and adolescents with NF1 microdeletion. Furthermore, 17 (71%) of the 24 patients investigated had T-scores ≥ 60 up to 75, indicative of mild to moderate autistic symptoms, which are consequently significantly more frequent in patients with NF1 microdeletions than in the general NF1 population. Also, the mean total T-score was significantly higher in patients with NF1 microdeletions than in the general NF1 population. Conclusion Our findings indicate that already at a very young age, NF1 microdeletions patients frequently exhibit a severe disease manifestation which requires specialized long-term clinical care.

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PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

Neuropediatrics ◽

10.1055/s-0038-1661396 ◽

2018 ◽

Vol 49 (05) ◽

pp. 330-338 ◽

Cited By ~ 4

Author(s):

Anna Schossig ◽

Tobias Haack ◽

Reka Kovács-Nagy ◽

Matthias Braunisch ◽

Christine Makowski ◽

...

Keyword(s):

Developmental Delay ◽

Early Onset ◽

Brain Mri ◽

Missense Variant ◽

Global Developmental Delay ◽

Multiplex Family ◽

Consistent Finding ◽

Whole Exome ◽

Severe Developmental Disabilities ◽

Stem Lesions

Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

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Verbal and nonverbal outcomes of toddlers with and without autism spectrum disorder, language delay, and global developmental delay

Autism & Developmental Language Impairments ◽

10.1177/2396941518764764 ◽

2018 ◽

Vol 3 ◽

pp. 239694151876476 ◽

Cited By ~ 6

Author(s):

Abigail D Delehanty ◽

Sheri Stronach ◽

Whitney Guthrie ◽

Elizabeth Slate ◽

Amy M Wetherby

Keyword(s):

Young Children ◽

Developmental Delay ◽

Social Communication ◽

Expressive Language ◽

Developmental Outcomes ◽

Autism Spectrum ◽

Global Developmental Delay ◽

Developmental Level ◽

Communication Delays ◽

Children With Asd

Background and Aims Children with autism spectrum disorder (ASD) exhibit a heterogeneous clinical phenotype with wide variability in their language and intellectual profiles that complicates efforts at early detection. There is limited research examining observational measures to characterize differences between young children with and without ASD and co-occurring language delay (LD) and global developmental delay (GDD). The first aim of this study was to compare early social communication measured in the second year of life in children diagnosed at age 3 with ASD, developmental delays (DD), and typical development (TD). The second aim was to compare early social communication in six subgroups of children: ASD, ASD+LD, ASD+GDD, LD, GDD, and TD. Our third aim was to determine the collective and unique contributions of early social communication to predict verbal and nonverbal developmental outcomes at three years of age for children with and without ASD. Methods Analyses of covariance controlling for maternal education were employed to examine group differences in social communication in 431 toddlers recruited through screening in primary care. Multiple linear regression analyses were conducted to evaluate associations between the Communication and Symbolic Behavior Scales (CSBS) Behavior Sample composite standard scores and Mullen Scales of Early Learning T scores for children with and without ASD. Results Distinct patterns of early social communication were evident by 20 months. Children with TD differed significantly from children with ASD and DD on all three CSBS Behavior Sample composites. Children with ASD had significantly lower scores than those with DD and TD on the social and symbolic composites. Among the six subgroups, all three composites of the CSBS Behavior Sample differentiated children with TD from all other subgroups. Children with ASD+GDD scored significantly lower than all other subgroups on social and symbolic composites. Patterns of social communication emerged for children with and without ASD, which held among subgroups divided by developmental level. The CSBS Behavior Sample social and symbolic composites contributed unique variance in predicting developmental outcomes in both groups. The speech composite contributed unique variance to expressive language, receptive language, and visual reception in children without ASD, and contributed uniquely to expressive language only for children with ASD. Conclusions The CSBS Behavior Sample, an observational measure for children aged 12–24 months, detected social communication delays and explained a significant amount of variance in verbal and nonverbal outcomes a year later in this large sample of young children grouped by ASD diagnosis and developmental level. Implications In light of the continued search for early predictors of ASD and developmental delay, our findings underscore the importance of monitoring early social communication skills, including the expression of emotions, eye gaze, gestures, rate of communication, joint attention, understanding words, and object use in play. There is a need for clinical utility of screening and evaluation tools that can detect social communication delays in very young children. This would enable intervention for infants and toddlers who show social communication delays which may be early signs for ASD or other DD, rather than waiting to confirm a formal diagnosis.

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